ISSN 1883-9606

2022

Vol.145

ANNUAL REPORT OF
THE GRADUATE SCHOOL OF MEDICINEAND
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2021 ---- March 2022

ANNUAL REPORT OF THE GRADUATE SCHOOL OF
MEDICINE
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2021-March 2022

Introduction
This is volume 145(the edition of year 2022) of the annual report by the University of Tokyo’s
Graduate School of Medicine and Faculty of Medicine.
In it are recorded the past year’s research, educational, clinical, and other activities of the
Graduate School of Medicine and Faculty of Medicine and the Tokyo Society of Medical Sciences.
It reports our accomplishments, and each year we make such a document freely available bypublishing it on compact disk and on the Internet, expecting it to be used for internal and external
evaluations.
The University of Tokyo’s Faculty of Medicine was founded 160 years ago. Since then we haveconsistently driven Japan’s progress in medical research, medical education, and clinical care, andin some fields we have become world leaders.
We have more than 1000 students in the Graduate School of Medicine, and with as many as 150
foreign researchers and students we are an international center for medical research and education.
Pursuing excellence in our research, educational, and clinical activities, we will continue meetingthe needs for tomorrow’s pioneers in medical sciences and clinical care.

Shigeo Okabe, Dean
Graduate School of Medicine and Faculty of Medicine
The University of Tokyo
October, 2022

i

CONTENTS
Introduction
History
Organization Teaching, Research, Secretarial and
Administrative Staffs
The University of Tokyo, Graduate School of Medicine
Molecular Cell Biology
1. Cell Biology and Anatomy ·····················································································

1

Department of Cell Biology ····················································································

2

Department of Structural Biology ·············································································

4

Department of Cytoarchitectonics ·············································································

6

Department of Cellular Neurobiology ········································································

8

2. Biochemistry and Molecular Biology ·········································································

10

Department of Molecular Biology ·············································································

11

Department of Cellular Signaling ··············································································

16

Department of Physiological Chemistry and Metabolism ··················································

20

Department of Advanced Structural Studies ·································································

23

Functional Biology
1. Physiology ········································································································

26

Department of Integrative Physiology ········································································

27

Department of Cellular and Molecular Physiology ·························································

29

Department of Neurophysiology ···············································································

33

2. Pharmacology ····································································································

35

Department of Cellular and Molecular Pharmacology ·····················································

36

Department of Systems Pharmacology ·······································································

38

Pathology, Immunology and Microbiology
1. Pathology ·········································································································

42

Department of Pathology and Diagnostic Pathology ·······················································

43

Department of Molecular Pathology ··········································································

47

ii

2. Microbiology ·····································································································

51

Department of Microbiology ···················································································

52

Department of Infection Control and Prevention ····························································

55

3. Immunology ······································································································

60

Department of Immunology ····················································································

61

Radiology and Biomedical Engineering
1. Radiology ·········································································································

66

Department of Radiology ·······················································································

67

2. Biomedical Engineering ························································································

70

Department of System Physiology ············································································

71

Department of Chemical Biology and Molecular Imaging ·················································

75

Department of Biosystem Construction & Control ·························································

78

Division of Integrative Genomics ·············································································

81

Neuroscience
1. Basic Neuroscience ······························································································

84

Department of Neuropathology ················································································

85

Department of Neurochemistry ················································································

89

2. Integrative Medical Neuroscience ·············································································

95

Department of Child Neuropsychiatry··········································································

96

3. Clinical Neuroscience ···························································································

98

Department of Neuropsychiatry ···············································································

99

Department of Neurology ·······················································································

103

Department of Neurosurgery ···················································································

110

Social Medicine
1. Occupational, Environmental and Preventive Medicine ···················································

118

Department of Molecular Preventive Medicine ·····························································

119

Department of Public Health / Department of Health Policy················································

122

2. Forensic Medicine, and Medical Informatics and Economics ·············································

128

Department of Forensic Medicine ·············································································

129

Department of Biomedical Informatics ·······································································

133

iii

Internal Medicine
1. Medicine Ⅰ ······································································································

137

Department of Cardiovascular Medicine ·····································································

138

Department of Respiratory Medicine ·········································································

143

Department of Gastroenterology ···············································································

147

2. Medicine Ⅱ ······································································································

151

Department of Nephrology and Endocrinology ·····························································

152

Department of Diabetes and Metabolic Diseases ····························································

157

Department of Hematology and Oncology ···································································

164

Department of Allergy and Rheumatology ···································································

168

Department of Infectious Diseases (Internal Medicine) ····················································

171

Department of Stress Science and Psychosomatic Medicine ··············································

175

3. Clinical Laboratory Medicine and Pathology ································································

178

Department of Clinical Laboratory Medicine (See Department of Clinical Laboratory [P.468] )Department of Transfusion Medicine ·········································································

179

Reproductive, Developmental and Aging Sciences
1. Obstetrics and Gynecology ·····················································································

182

Department of Reproductive Endocrinology ·································································

183

Department of Gynecologic Oncology ········································································

186

Department of Perinatal Medicine ·············································································

189

Department of Molecular and Cellular Reproductive Medicine ···········································

192

2. Pediatric Sciences ································································································

195

Department of Pediatrics, Department of Developmental Pediatrics ·····································

196

Department of Pediatric Surgery ···············································································

201

3. Aging Sciences ···································································································

205

Department of Geriatric Medicine, Department of Aging Research ······································

206

Surgical Sciences
1. Surgery ············································································································

212

Department of Thoracic Surgery ···············································································

213

Department of Cardiac Surgery ················································································

217

Department of Gastrointestinal Surgery ······································································

222

Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation Division ·····

225

Department of Urology ··························································································

228

iv

Department of Surgical Oncology ·············································································

235

Department of Vascular Surgery ···············································································

240

Department of Brest and Endocrine Surgery ·································································

243

2. Sensory and Motor System Medicine ·········································································

245

Department of Dermatology ····················································································

246

Department of Plastic and Reconstructive Surgery ··························································

249

Department of Oral-Maxillofacial Surgery ···································································

252

Department of Orthopaedic Surgery ···········································································

256

Department of Ophthalmology ·················································································

265

Department of Otolaryngology and Head and Neck Surgery ··············································

268

Department of Rehabilitation Medicine ·······································································

275

3. Vital Care Medicine ·····························································································

278

Department of Anesthesiology ·················································································

279

Department of Acute Medicine ··················································································

283

Health Sciences and Nursing
1. Health Sciences ··································································································

286

Department of Health Sociology(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.364] )Department of Mental Health ··················································································

287

Department of Biostatistics / Epidemiology and Preventive Health Sciences ···························

292

Department of Social Gerontology(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.364] )Department of Biomedical Ethics & Department of Health Promotion Sciences ·······················

295

2. Preventive and Administrative Nursing ·······································································

298

Department of Nursing Administration / Advanced Clinical Nursing ····································

299

Department of Family Nursing ·················································································

303

Department of Community Health Nursing / Public Health Nursing ·····································

305

3. Clinical Nursing ··································································································

308

Department of Gerontological Home Care and Long-term Care Nursing/Palliative Care Nursing ···309

Department of Midwifery and Women’s Health ·····························································

313

Department of Psychiatric Nursing ············································································

316

Department of Gerontological Nursing / Wound Care Management ·····································

320

v

International Health
1. International Social Medicine ··················································································

329

Department of Global Health Policy ············································································

330

Department of Community and Global Health ·······························································

333

2. International Biomedical Sciences ············································································

337

Department of Human Genetics ················································································

338

Department of Developmental Medical Sciences ···························································

339

Department of Human Ecology ················································································

341

Department of Biomedical Chemistry ·········································································

345

School of Public Health
1. Epidemiology and Health Sciences ·············································································

348

Department of Biostatistics(See Department of Biostatistics / Epidemiology and Preventive Health Sciences [P.292] )Department of Social and Preventive Epidemiology ························································

349

Department of Clinical Epidemiology and Health Economics ··············································

351

Department of Health Communication ········································································

360

2. Behavioral Health Sciences ······················································································

363

Department of Mental Health (See Department of Mental Health [P.287] )Department of Health Sociology and Health Education(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.364] )Departments of Health and Social Behavior & Health Education and Health Sociology ···············

364

Department of Biomedical Ethics & Department of Health Promotion Sciences(See Department of Biomedical Ethics & Department of Health Promotion Sciences [P.295] )3. Health Services Sciences ·························································································

368

Department of Health Policy(See Department of Public Health / Department of Health Policy [P.122] )Department of Healthcare Informatics (See Department of Biomedical Informatics [P.133] )Department of Clinical Information Engineering ····························································

369

Department of Forensic Medicine and Medical Law(See Department of Forensic Medicine [P.129] )Department of Global Environmental Health ································································

371

Endowed Department ···································································································

373

Department of Artificial Intelligence in Healthcare ·························································

374

Health Economy and Society Policy ············································································

376

vi

Department of medical research and the management of musculoskeletal pain ························

379

Science for joint reconstruction (See Department of Orthopaedic Surgery [P.256] )Department of Bone & Cartilage Regenerative Medicine(See Central Clinical Facilities Division of Tissue Engineering [P.542] )Department of Osteoimmunology ··············································································

383

Department of Computational Diagnostic Radiology and Preventive Medicine ························

387

Research on Cell Therapy of Regenerative Medicine ························································

391

Department of Home Care Medicine ··········································································

394

Department of Therapeutic Strategy for Heart Failure ······················································

396

Department of Biostatistics and Bioinformatics ·······························································

399

Department of Advanced Cardiology ·········································································

403

Laboratory for Advanced Research on Pathophysiology of Metabolic Diseases ·························

407

Department of Advanced Clinical Science and Therapeutics ··············································

409

Department of Comprehensive Radiation Oncology ·························································

411

Department of Molecular Structure and Dynamics ··························································

414

Department of Immunotherapeutics ···········································································

416

Social Cooperation Program ···························································································

419

Department of Advanced Nursing Technology ······························································

420

Department of Eat-loss Medicine(See Central Clinical Facilities Division of Tissue Engineering [P.542] )Department of Medical Information Engineering ·····························································

422

Department of Healthcare Quality Assessment ······························································

424

Department of Next-Generation Locomotive Imaging System ·············································

428

Next-Generation Precision Medicine Development Laboratory ············································

431

Department of Tissue Stem Cells and Life Dentistry ·······················································

434

Department of Prevention of Diabetes and Lifestyle-Related Diseases ··································

436

Department of Pain & Palliative Medical Sciences ···························································

438

Department of Innovative Dementia Prevention ······························································

441

Department of Health Services Research ·····································································

445

Division of Chronic Kidney Disease (CKD) Pathophysiology ············································

453

Department of Retinal Biology and Pathology ································································

457

Department of Lipidomics ······················································································

460

Department of Preventive Medicine for Locomotive Organ Disorders ··································

464

vii

University Hospital
Clinical Divisions ····································································································
Internal Medicine
Cardiovascular Medicine (See Department of Cardiovascular Medicine [P.138] )Respiratory Medicine (See Department of Respiratory Medicine [P.143] )Gastroenterology (See Department of Gastroenterology [P.147] )Nephrology and Endocrinology (See Department of Nephrology and Endocrinology [P.152] )Diabetes and Metabolic Diseases (See Department of Diabetes and Metabolic Diseases [P.157] )Hematology and Oncology (See Department of Hematology and Oncology [P.164] )Allergy and Rheumatology (See Department of Allergy and Rheumatology [P.168] )Infectious Diseases (See Department of Infectious Diseases (Internal Medicine) [P.171] )Neurology (See Department of Neurology [P.103] )Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research [P.206] )Psychosomatic Medicine(See Department of Stress Science and Psychosomatic Medicine [P.175] )Surgery
Stomach and Esophageal Surgery (See Department of Gastrointestinal Surgery [P.222] )Colon and Rectal Surgery (See Department of Surgical Oncology [P.235] )Hepatobiliary Pancreatic Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation
Division [P.225] )Vascular Surgery (See Department of Vascular Surgery [P.240] )Breast and Endocrine Surgery(See Department of Metabolic Care and Endocrine Surgery [P.243] )Artificial Organ and Transplantation Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation
Division [P.225] )Cardiovascular Surgery (See Department of Cardiac Surgery [P.217] )Thoracic Surgery (See Department of Thoracic Surgery [P.213] )Neurosurgery (See Department of Neurosurgery [P.110] )Anesthesiology and Pain Relief Center (See Department of Anesthesiology [P.279] )Urology and Andrology (See Department of Urology [P.228] )Gynecologic Surgery (See Obstetrics and Gynecology [P.182] )Sensory and Motor System Medicine
Dermatology (See Department of Dermatology [P.246] )Ophthalmology (See Department of Ophthalmology [P.265] )Orthopaedic Surgery and Spinal Surgery (See Department of Orthopaedic Surgery [P.256] )

466

viii

Otorhinolaryngology and Head and Neck Surgery(See Department of Otorhinolaryngology and Head & Neck Surgery [P.268] )Rehabilitation Medicine (See Department of Rehabilitation Medicine [P.275] )Plastic, Reconstructive and Aesthetic Surgery(See Department of Plastic and Reconstructive Surgery [P.249] )Oral-Maxillofacial Surgery and Orhtodontics(See Department of Oral-Maxillofacial Surgery [P.252] )Pediatrics,Perinatal and Women’s Medicine
Pediatrics(See Department of Pediatrics, Department of Developmental Pediatrics [P.196] )Pediatrics Surgery (See Department of Pediatric Surgery [P.201] )Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of Gynecologic Oncology /Department of Perinatal Medicine [P.183/P.186/P.189] )Neuropsychiatry
Neuropsychiatry (See Department of Neuropsychiatry [P.99] )Radiology
Radiology (See Department of Radiology [P.67] )Acute Medicine
Acute Medicine (See Department of Acute Medicine [P.283] )Central Clinical Facilities ···························································································

467

Department of Clinical Laboratory ············································································

468

Surgical Center ···································································································

473

Radiology Center ·································································································

476

Department of Pharmacy ························································································

479

Department of Transfusion Medicine and Immunohematology(See Department of Transfusion Medicine [P.179] )Rehabilitation Center ····························································································

483

Central Supply Service ··························································································

486

Department of Intensive Care Unit (See Department of Acute Medicine [P.283] )Department of Pathology ·······················································································

487

Department of Corneal Transplantation ·······································································

491

Department of Cell Therapy and Transplantation Medicine ···············································

494

Department of Endoscopy and Endoscopic Surgery ························································

497

Department of Hemodialysis and Apheresis ···································································

500

Department of Infection Control and Prevention(See Department of Infection Control and Prevention [P.55] )ix

Department of Planning, Information, and Management(See Department of Biomedical Informatics [P.133] )University Hospital Medical Information Network (UMIN) Center ······································

504

Department of Clinical Research Governance ·······························································

507

Department of Child Psychiatry ················································································

509

Tissu Bank ··········································································································

512

Center for Epidemiology and Preventive Medicine ·························································

514

Department of Pain and Palliative Medicine ··································································

518

Department of Disaster Medical Management ·······························································

522

International Medical Center ···················································································

524

Clinical Nutrition Center ························································································

525

Department of Clinical Genomics ·············································································

531

BioResource Center ·······························································································

533

Clinical Resarch Division
Clinical Research Promotion Center ··········································································

535

Division of Tissue Engineering ················································································

542

Cooperative Unit of Medicine and Engineering Research ·················································

546

Genomic Research Support Center ············································································

551

Organization of Clinical Management
Advanced Medical Center for Heart Failure ···································································

554

Swallowing Center ································································································

557

Immune-Mediated Diseases Therapy Center ··································································

560

Medical Community Network and Discharge Planning Center ·············································

562

Department of Cancer Resource Center ········································································

564

Center for Disease Biology and Integrative Medicine ··························································

566

Laboratory of Molecular Biomedicine for Pathogenesis ·····················································

567

Laboratory of Structural Physiology ············································································

569

Laboratory of Biomedical Equipment and Biomaterials ····················································

573

Laboratory of Clinical Biotechnology ··········································································

575

Laboratory of Microenvironmental and Metabolic Health Sciences ·······································

580

Laboratory of Animal Resources ···············································································

585

Laboratory of Molecular Radiology ···········································································

588

Laboratory of Biomedical Informatics··········································································

591

x

The International Research Center for Medical Education (IRCME) ··········································

594

Department of Medical Education Studies ·····································································

595

Department of International Cooperation for Medical Education ··········································

597

Global Nursing Research Center·····················································································

599

Center for Diversity in Medical Education and Research ························································

606

Office of International Academic Affairs ·········································································

608

MD Scientist Training Program ····················································································

610

Museum of Health and Medicine ··················································································

613

Office for Human Research Studies (OHRS) ·····································································

615

The Office for Clinical Practice and Medical Education ························································

617

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

xi

History
1858

May

Practitioners, trained in Dutch (European) medicine in Edo (Tokyo), laid out money to establish
the Shutojo (vaccination center) in Kanda Mitamagaike.

Nov.

Shutojo was destroyed in a fire that had spread from Kanda Aioicho. Shutojo continued its
operations at other sites such as the residence of Ito Genboku.

1859

Sep.

Shutojo was reconstructed at Shitaya Izumibashi Dohri.

1860

Oct.

Shutojo became an official medical institution of the Shogunate Government.

1861

Oct.

Shutojo was renamed as Seiyo Igaku-Sho (Institute of Western Medicine) and offered courses ofWestern Medicine in the fields of Education, Autopsy, and Vaccination.

1863

Feb.

Seiyo Igaku-Sho was renamed as Igaku-Sho (Institute of Medicine).

1868

Jul.

Igaku-Sho, affiliated with the Military Hospital which had been moved from Yokohama to Todo
residence in Shitaya, was renamed as Daibyoin (the Great Hospital).

1869
1871

Feb.

The Daibyoin was renamed as Igakko-Ken-Byoin (Medical School and Hospital).

Dec.

Igakko-Ken-Byoin was renamed as Daigaku Toko (University East Building).

Jul.

The Ministry of Education was established and Daigaku-Toko was renamed as Toko (East
Building).

1872

Aug.

A School System was established. Toko was renamed as Daiichi-Daigaku-Ku- Igakko (The First
University District Medical School).

1874

May

Daiichi-Daigaku-Ku-Igakko was renamed as Tokyo-Igakko (Tokyo Medical School).

1876

Nov.

Tokyo-Igakko was moved to Hongo.

1877

Apr.

Tokyo Igakko, affiliated with Tokyo-Kaisei School, was renamed as The University of Tokyo.
Tokyo Medical School was renamed as The University of Tokyo Faculty of Medicine.

1886

Mar.

The University of Tokyo was renamed as Imperial University, and The University of Tokyo
Faculty of Medicine was renamed as the Imperial University Medical College. A Graduate
School was established.

1897

Jun.

The Imperial University was renamed as Tokyo Imperial University.

1917

Aug.

Eiraku Hospital, affiliated with the Ministry of Education Medical Practice License Examination,
moved to Tokyo Imperial University and was renamed as Koishikawa Hospital affiliated with
Tokyo Imperial University Medical College.

1919

Apr.

A faculty system was established renaming Tokyo Imperial University Medical College as theFaculty of Medicine.

1931

Feb.

The first building of the Faculty of Medicine was constructed.

1936

Jan.

The Brain Research Laboratory was built with funds donated by Mr. Hisasaburo Horikoshi.

Nov.

The second building of the Faculty of Medicine (main building) was constructed.

1947

Oct.

Tokyo Imperial University was renamed as The University of Tokyo.

1950

Apr.

The Institute of Nursing was renamed as The University Nursing School.

1953

Apr.

The School of Health Care and Nursing was founded.

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

xii

Jul.

The Graduate School was founded, and the Division of Medical Doctor Biological Science wasestablished. The Brain Research Laboratory became the Brain Research Institute of the Facultyof Medicine.

1956

Apr.

The Midwives School was established.

1958

Apr.

The Division of Pharmaceutical Sciences became an independent faculty.

May

The University of Tokyo Faculty of Medicine celebrated its centennial anniversary.

Mar.

The Medical Library was built in commemoration of the centenary.

Apr.

The Institute of Medical Electronics was established.

Apr.

The Research Institute of Logopedics and Pediatrics was established. The School of Health Care

1961
1965

and Nursing was reorganized as the School of Health Sciences. The Graduate School of The
University of Tokyo was reorganized and the Division of Medical Doctor Biological Science
became the Faculty of Medicine. The Health science Course was established in the Medical
Science Division.
1966

Sep.

The third building of the Faculty of Medicine was constructed.

1971

Apr.

The Laboratory of Animal Experiments was established.

1973

Mar.

The Animal Center for Biomedical Research was constructed.

1983

Jan.

An annex of the third building of the Faculty of Medicine was constructed.

1985

Sep.

The office of International Academic Affairs was established.

1987

Apr.

Specialized courses were introduced to the Graduate School of Medicine.

1992

Apr.

The School of Health Sciences became the School of Health Science and Nursing. The School ofInternational Health was established in the Medical Science Division.

1995

Jul.

The Radiation Research Institute was established.

Apr.

As a result of the shift to the chair system of the Graduate School of Medicine, four divisions,Third Basic Medicine, Social Medicine, Third and Fourth Clinical Medicine, were replaced with
Pathology, Immunology and Microbiology, Social Medicine, Reproduction and Development,
and Aging Science and Surgery.

1996

Apr.

As a result of the shift to the chair system of the Graduate School of Medicine, three divisions,First Clinical Medicine, Health Science, and International Health, were replaced with Internal
Medicine, Health Science and Nursing, and International Health.

1997

Apr.

As a result of the shift to the chair system of the Graduate School of Medicine, three divisions,First and Second Basic Medicine, and Second Clinical Medicine, were replaced with Molecular
Cell Biology, Functional Biology, Radiology and Biomedical Engineering, and Neuroscience.
As a result of the above-mentioned reorganization, three institutes, the Institute of Brain
Research, the Institute of Medical Electronics, and the Institute of Logopedics and Phoniatrics
were made redundant.

1999

Apr.

The Master course of Medical Science was established in the Graduate School of Medicine. This
course accepts graduates of all faculties except those from Schools of Medicine, Dentistry, andVeterinary Medicine.

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

2000

Apr.

xiii

The International Research Center for Medical Education was established (A shared facility foreducation and research).

2001

Apr.

The University Branch Hospital was united with the University Hospital.

2002

Mar.

Nursing School and Midwives School was Closed.

2002

Mar.

Experimental Building (First Stage) was constructed.

2003

Apr.

The Center for Disease Biology and Integrative Medicine was established.
The Radiation Research Institute and the Laboratory of Animal Experiments were integrated into
the Center for Disease Biology and Integrative Medicine.

2004

Apr.

All the National Universities owned by the Japanese Government became National University
Corporations and the University of Corporation.

2005

Mar.

Experimental Building (Second Stage) was constructed.

2007

Apr.

The School of Public Health was established. This school offers programs for Master of Public
Health.

2008

May

The University of Tokyo Faculty of Medicine and the University of Tokyo Hospital celebrated
their 150th anniversary.

2010

Apr.

The School of Health Science and Nursing became the School of Integrated Health Sciences.

2011

Jan.

The Museum of Health and Medicine was established.

2012

Apr.

The Office for research Ethics Support was established.

2013

Apr.

The International Research Center for Medical Education became a facility of the Graduate
School of medicine.

2013

Oct.

The Life Sciences Core facility was established.

2015

Apr.

The Office for Clinical Practice and Medical Education was established.

2016

Apr.

The Advisory office for Conflicts of interest was established.

2017

Apr.

The Global Nursing Research Center was established.

2017

Apr.

The Institute for Life Science Research and Education was established.

2017

Apr.

The Research Institute for Biomedical Science and Engineering was established.

2019

May

The Bioethics Collaborative Research Organization was established.

2020

Apr.

The Collaborative Research Organization for Structural Life Sciences was established.

2021

Apr.

UTokyo Center for Diversity in Medical Education and Research was established.

xiv

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

Organization Chart
Cell Biology
Cell Biology and Anatomy
Molecular Cell Biology

Structural Biology
Structural Cell Biology
Cellular Neurobiology
Molecular Biology

Biochemistry and Molecular Biology

Cellular Signaling
Physiological Chemistry and Metabolism
Clinical Genome Informatics

Collaborative Department

Lipid Science
Cancer Cellular Signaling
Advance Structural Studies
Integrative Physiology

Physiology
Functional Biology

Cellular and Molecular Physiology
Neurophysiology

Pharmacology

Cellular and Molecular Pharmacology
Systems Pharmacology

Collaborative Department

Brain Functional Dynamics

Pathology

Molecular Pathology

Pathology and Diagnostic Pathology

Surgical Pathology
Microbiology
Pathology, Immunology
and Microbiology
Immunology

Microbiology
Infection Control and Prevention
Immunology
Clinical Immunology
Infection Pathology

Collaborative Department

Tumor Pathology
Molecular Oncology
Diagnoatic Radiology

Radiology

Radiotherapy
Nuclear Medicine

Radiology and Biomedical
Engineering

System Physiology
Biomedical Engineering

Chemical Biology and Molecular Imaging
Biosystem Construction and Control
Neuropathology

Basic Neuroscience

Neurochemistry
Neurobiology
Developmental Neuroscience

Neuroscience

Integrativ Medical Neurosciences

Cognitive Neuroscience
Systems Medical Neuroscience
Child Neuropsychiatry
Neuropsychiatry

Clinical Neuroscience

Neurology
Neurosurgery

Collaborative Department

Biomedical Neural Dynamics

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

xv

Preventive Medicine
Occupational, Environmental andPreventive Medicine

Public HealthRadiological HealthSocial Medicine

Forensic Medicine

Forensic Medicine, and Medical
Informatics and Economics

Medical Informatics

Collaborative Department

Cancer Epidemiology

Cancer Control Policy and Research

Cancer Communication
Cardiovascular Medicine
Vascular Biology
Medicine I

Respiratory Medicine
Gastroenterology
Nephrology
Endocrinology
Nutrition and Metabolism

Internal Medicine
Medicine II

Hematology and Oncology
Allergy and Rheumatology
Infectious Diseases
Stress Sciences and Psychosomatic
Medicine
Clinical Laboratory Medicine

Clinical Laboratory Medicine
and Pathology

Transfusion Medicine

Collaborative Department

Molecular Diabetology
Reproductive Endocrinology

Obstetrics and Gynecology

Gynecological Oncology
Perinatal Medicine
Molecular Reproductive Endocrinology
Pediatrics

Reproductive,
Developmental andAging Sciences

Pediatric Sciences

Developmental Pediatrics
Pediatric Surgery
Pediatric Oncology

Aging Sciences

Collaborative Department

Geriatrics
Aging Research
Health Policy for Children and Families
Medical Science for Life and Aging
Thoracic Surgery
Cardiovascular Surgery
Gastrointestinal Surgery
Hepatobiliary Pancreatic Surgery

Surgery

Urology
Artificial Organ and Transplantation
Division
Surgical Oncology
Vascular Surgery
Breast and Endocrine Surgery

Surgical Sciences

Dermatology
Plastic and Reconstructive Surgery
Oral and Maxillofacial Surgery
Sensory and Motor System Medicine

Orthopaedic Surgery
Ophthalmology

xvi

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022
Otolaryngology and Head and Neck
Surgery
Rehabilitation Medicine
Vital Care Medicine

Anesthesiology
Emergency and Critical Care Medicine
Health Sociology
Mental Health

Health Sciences

Epidemiology and Preventive Health
Sciences
Social Gerontology
Health Promotion Sciences
Biostatistics

Graduate School of
Medicine

Biomedical Ethics
Advanced Clinical Nursing
Nursing Administration
Health Sciences andNursingPreventive and Administrative Nursing

Family Nursing
Community Health Nursing
Public Health Nursing
Gerontological Home Care andLong-term Care Nursing
Palliative Care Nursing

Clinical Nursing

Midwifery and Woman’s Health
Psychiatric Nursing
Gerontological Nursing
Wound Care Management

Collaborative Department
International Social Medicine
International HealthPublic Mental Health Policy
Global Health Policy
Community and Global Health
Human Genetics

International Biomedical Sciences

Developmental Medical Sciences
Human Ecology
Biomedical Chemistry

Medical Science (Master’s
Program)

Biostatistics
Epidemiology and Health Sciences

Social and Preventive Epidemiology
Health Economics and Epidemiology Research
Health Communication
Mental Health
Health Sociology and Health Education

School of Public HealthBehavioral Health Sciences

Health and Social Behavior
Health Promotion Science
Biomedical Ethics
Health Policy
Healthcare Informatics

Health Services Sciences

Clinical Information Engineering
Forensic Medicine and Medical Law
Global Environmental Health

Collaborative Department
Laboratory of Molecular Biomedicine for
Pathogenesis
Laboratory of Structural Physiology
Center for Disease Biology
and Integrative medicine

Laboratory of Biomedical Equipment andBiomaterial
Laboratory of Clinical Biotechnology
Laboratory of Environmental Health Sciences

Public Health Science

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

Laboratory of Animal Resources

International ResearchCenter for Medical
Education
Global Nursing ResearchCenterLaboratory of Molecular Radiology

Section of Animal Research

Division of Research Resources and Support

Section of Radiation Biology

Department of Medical Education Studies

Section of Bioinformatics

Department of International Cooperation for
Medical Education
Division of Care Innovation
Division of Nursing System
Office of International Academic Affairs
Medical Library
Medical Scientist Training Program
Museum of Health and Medicine

Institution

Office for Human Research Studies
Office for Life Science Research Equipment Supprt
Life Sciences Core Facility
Office for Clinical Practice and Medical Education
Advisory Office for Conflicts of interest
Department of Bone & Cartilage Regenerative
Medicine
Immunotherapeutics

Endowed Department

Department of Advanced Clinical Science andTherapeutics
Computational Diagnostic Radiology andPreventive Medicine
Department of Molecular Neurology
Clinical Trial Data Management
Ubiquitous Preventive Medicine
Science for Joint Reconstruction
Department of Therapeutic Strategy for Heart
FailureDepartment of Molecular Structure and Dynamics
Department of Home Care Medicine
Department of Advanced Translational Researchand Medicine in Management of Pulmonary
Hypertension
Department of Advanced Cardiology
Department of medical research and management
for musculoskeletal pain
Department of Osteoimmunology
Department of medical and pharmaceuticalcommunity healthcare
Health Economy and Society Policy
Departmento of Biostatics and Bioinformatics
Laboratory for Advanced Research on
Pathophysiology of Metabolic Diseases
Artificial Intelligence in Healthcare
Department of Lipidomics

Social Cooperation
ProgramAdvanced Nursing Technology
Tissue stem cell / life dentistry
Department of Next Generation Locomotive
Imaging System
Department of Preventive Medicine for Locomotive
Organ Disorders
Department of Eat-loss Medicine
Department of Health Services Research

General Affairs Office

Skincare Science

Personnel Office

Imaging Nursing Science

Finance Office

Department of Healthcare Quality Assessment

Contract Office

Department of Innovative Dementia Prevention

External Fund Management Office

Department of Functional Genomics and
Immunological Diseases

Accounting Officexvii

xviiiThe Tokyo Journal of Medical Sciences. Vol. 145, October 2022

Department of Prevention of Diabetes and Life-style
Related Disease

Faculty of Medicine
Graduate School of
Medicine

Facilities Office
Research Support Office

Department of Next-Generation
Pathology Information Networking

Educational Affairs

Chronic kidney disease pathophysiology

Graduate Student Affairs

Administrative office
Administrative Division

Acquisition Office Medical Library
Cataloging Office Medical Library
Information Service Medical LibraryCenter for Disease Biology
and Integrative medicine

Administrative Office

Cell Biology and Anatomy
Biochemistry and Molecular Biology
Physiology
Pharmacology
Pathology
School of Medicine
Faculty of
Medicine

Microbiology
Immunology
Radiology
Biomedical Engineering
Basic Neuroscience
Speech and Cognitive Sciences
Clinical Neuroscience
Occupational, Environmental and Preventive
Medicine
Medical Principles and Medical Ethics
Forensic Medicine, and Medical Informatics andEconomics
Medicine I
Medicine II
Clinical Laboratory Medicine and Pathology
Obstetrics and Gynecology
Pediatric Science
Aging Science
Surgery
Sensory and Motor System Medicine
Vital Care Medicine
Family Nursing
Comunity Health Nursing
Fundamental Nursing
Gerontological Nursing
Midwifery and Women’s Health

School of Integrated
Health Sciences

Adult Health and Nursing
Mental Health and Nursing
Health Sociology
Health Administration
Epidemiology and Biostatistics
Human Ecology
Biochemistry and Nutrition
Maternal and Child HealthInternal Medicine

General Internal Medicine
Cardiovascular Medicine
Respiratory Medicine
Gastroenterology
Nephrology and Endocrinology
Diabetes and Metabolic Diseases
Hematology and Oncology
Allergy and Rheumatology

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

xix

Infectious Diseases
Neurology
Geriatric Medicine
Clinical Divisions

Psychosomatic Medicine
General Surgery
Stomach and Esophageal Surgery
Colon and Rectal Surgery
Hepatobiliary and Pancreatic Surgery

University
Hospital

Vascular Surgery
Breast and Endocrine Surgery
Surgery

Artificial Organ and Transplantation Surgery
Cardiothoracic Surgery
Thoracic Surgery
Neurosurgery
Anesthesiology and Pain Relief Center
Urology and Andrology
Gynecologic Surgery
Dermatology
Ophthalmology
Orthopaedic Surgery and Spinal Surgery

Sensory and Motor System Medicine

Otolaryngology and Head and Neck Surgery
Rehabilitation Medicine
Plastic, Reconstructive and Aesthetic Surgery
Oral-Maxillofacial Surgery and Orthodontics
Pediatrics

Pediatrics, Perinatal and
Women's Medicine

Pediatric Surgery
Obstetrics and Gynecology

Central ClinicalFacilities

Neuropsychiatry

NeuropsychiatryRadiology

Radiology

Acute Medicine

Acute Medicine

Pharmaceutical Department

General Affairs Group

Nursing Department

Labor and Personnel Group

Administration Department

Procurement and Facility Management Group

Legal and Compliance Office

Management Strategy Group

Department of Clinical Laboratory

Research Support Group

Surgical Center

Medical Management GroupRadiology Center

Medical Accounting Group

Department of Blood Transfusion
Perinatal Center
Rehabilitation Center
Department of Medial Engineering
Central Supply Service
Intensive Care Unit
Pathology
Department of Corneal Transplantation
Department of Cell Therapy and Transplantation
Medicine
Department of Endoscopy and Endoscopic Surgery
Department of Hemodialysis and Apheresis
Infection Control and Prevention Service

xx

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

Department of Healthcare Information Management
University Hospital Medical Information Network
CenterOrgan Transplantation Center
Labor Safety and Health Management Office
Staff Wellness Consulting RoomChild Psychiatry
Tissue Bank
Center for Epidemiology and Preventive Medicine
Center for International Preventive Medicine
Center for Liaison and Public Relations
Database Center of the National University
Hospitals
Department of Chemotherapy
Department of Medical Record Management
Critical Care and Emergency Medical
Center/Emergency Room
Department of Pain and Palliative Medicine
Children's Medical Center
Department of Disaster Medical Management
International Medical Center
Clinical Nutrition Center
Department of Pediatric and Neonatal Intensive
Care
Department of Clinical Genomics
BioResource Center
Clinical Research Promotion Center
22nd Century Medical and Research Center
Department of Tissue Engineering
Clinical Research
Division

Cooperative Unit of Medicine and Engineering
Research
Translation Research Center
Genomic Research Support Center
Unite for Early and Exploratory ClinicalDevelopment
Department of Personnel Administration and
Human Resource Management

Medical Specialists Training Center
Medical Support Center
Office of Performance Monitoring

Department of Performance Monitoring and Risk
Management
Organization of ClinicalManagement Support

Medical Safety Management Center
Infection Control Center
Department of Highly Advanced Novel Medical
Technologies Evaluation
Department of Unapproved New Drugs andMedical Devices Evaluation

Department of Education and Staff Development

General Education Center
Clinical Simulation Center
Hospitality Center

Department of Hospital Planning and Management
Department of Research Support

Department of Clinical Research GovernanceCenter for Brain imaging in Health and Diseases

Inpatient Services Administration
Organization of ClinicalManagement

Outpatient Services Administration
Central Clinical Services Administration

Admission and Discharge Center
Cancer Board
Advanced Medical Center for Heart Failure
Marfan Syndrome Center
Vascular Board
Perioperative Assessment Center

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

xxi

Swallowing Center
Epilepsy Center
Immune-Mediated Diseases Therapy Center
SSc Center
Osteoporosis Center
Center for Female Pelvic Medicine
and Reconstructive Surgery
Spine Center
Children,AYA and Family CenteredMental Care Center
Hip Fracture Board
Palliative Care Consulation Team
Nutrition Support Team
Division of patient support services

Medical Community Network and Discharge
Supporting Center
Cancer Resource Center
Patient Relations and Clinical Ethics Center

xxii

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

Teaching, Research, Secretarial
andAdministrative Staffs
Chief Members of Administration
Dean, Graduate School of Medicine

Shigeo Okabe(Dean, Faculty of Medicine)
Chairman, School of Health Sciences and Nursing

Masahiro Umezaki

Director, Medical Library

Hideo Yasunaga

Director General, University Hospital

Yasuyuki Seto

Director, Center for Disease Biology and Integrative Medicine

Masanobu Kano

Director, International Research Center for Medical Education

Tatsuya Yamasoba

Director, Global Nursing Research Center

Hiromi Sanada

Graduate School of Medicine
Molecular Cell Biology
Department of Cell Biology and Anatomy

Department of Biochemistry and Molecular Biology

Professor

Yasushi Okada

Professor

Masahide Kikkawa

Professor

Shigeo Okabe

Professor

Noboru Mizushima

Professor

Makoto Murakami

Professor

Hiroki Kurihara

Professor

Radostin Stoyanov
Danev

Functional Biology
Department of Physiology

Department of Pharmacology

Professor

Kenichi Ohki

Professor

Masanori Matsuzaki

Professor

Masanobu Kano

Professor

Kenzo Hirose

Professor

Hiroki Ueda

Professor

Tetsuo Ushiku

Professor

Kohei Miyazono

Professor

Masanori Hatakeyama

Professor

Kyoji Moriya

Professor

Hiroshi Takayanagi

Professor

Osamu Abe

Pathology, Immunology and Microbiology
Department of Pathology
Department of Microbiology
Department of Immunology
Radiology and Biomedical Engineering
Department of Radiology

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

Department of Biomedical Engineering

xxiii

Professor

Kiyoshi Miyagawa

Professor

Yasuteru Urano

Professor

Katsutoshi Oda

Professor

Takeshi Iwatsubo

Professor

Haruhiko Bito

Professor

Kiyoto Kasai

Professor

Tatsushi Toda

Professor

Nobuhito Saito

Department of Occupational, Environmental and Preventive

Professor

Shumpei Ishikawa

Medicine

Professor

Yasuki Kobayashi

Department of Forensic Medicine, and Medical Informatics

Professor

Hirotaro Iwase

and Economics

Professor

Kazuhiko Ohe

Professor

Issei Komuro

Professor

Takahide Nagase

Professor

Mitsuhiro Fujishiro

Professor

Masaomi Nangaku

Professor

Toshimasa Yamauchi

Professor

Mineo Kurokawa

Professor

Keishi Fujio

Professor

Kyoji Moriya

Professor

Yutaka Yatomi

Professor

Hitoshi Okazaki

Department of Obstetrics and Gynecology

Professor

Yutaka Osuga

Department of Pediatric Science

Professor

Motohiro Kato

Professor

Jun Fujishiro

Professor

Masahiro Akishita

Professor

Jun Nakajima

Professor

Minoru Ono

Professor

Yasuyuki Seto

Professor

Kiyoshi Hasegawa

Professor

Haruki Kume

Professor

Soichiro Ishihara

Neuroscience
Department of Basic Neuroscience
Department of Integrative Medical Neuroscience
Department of Clinical Neuroscience

Social Medicine

Internal Medicine
Department of Medicine I

Department of Medicine II

Department of Clinical Laboratory Medicine and Pathology
Reproductive, Developmental and Aging Science

Department of Aging Science
Surgical Sciences
Department of Surgery

xxiv

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

Department of Sensory and Motor System Medicine

Department of Vital Care Medicine

Professor

Shinichi Sato

Professor

Mutsumi Okazaki

Professor

Kazuto Hoshi

Professor

Sakae Tanaka

Professor

Makoto Aihara

Professor

Tatsuya Yamasoba

Professor

Toru Ogata

Professor

Kanji Uchida

Professor

Kento Doi

Professor

Norito Kawakami

Professor

Yutaka Matsuyama

Professor

Hideki Hashimoto

Professor

Akira Akabayashi

Professor

Mari Ikeda

Professor

Noriko Yamamoto

Professor

Noriko Yamamoto

Professor

Megumi Haruna

Professor

Norito Kawakami

Professor

Hiromi Sanada

Professor

Masahiro Hashizume

Professor

Masamine Jinba

Professor

Akihiro Fujimoto

Professor

Moi Meng Ling

Professor

Masahiro Umezaki

Professor

Tomoyoshi Nozaki

Professor

Yutaka Matsuyama

Professor

Satoshi Sasaki

Professor

Hideo Yasunaga

Professor

Takahiro Kiuchi

Professor

Norito Kawakami

Professor

Hideki Hashimoto

Professor

Akira Akabayashi

Professor

Yasuki Kobayashi

Professor

Kazuhiko Ohe

Professor

Hiroshi Oyama

Professor

Hirotaro Iwase

Health Sciences and Nursing
Department of Health Sciences

Department of Preventive and Administrative Nursing
Department of Clinical Nursing

International Health
Department of International Social Medicine
Department of International Biomedical Sciences

School of Public Health
Department of Epidemiology and Health Sciences

Department of Behavioral Health Sciences

Department of Health Services Sciences

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

xxv

Center for Disease Biology and Integrative Medicine
Laboratory of Molecular Biomedicine for Pathogenesis

Professor

Toru Miyazaki

Laboratory of Structural Physiology

Professor

Haruo Kasai

Division of Biomedical Equipment and Biomaterials

Professor

Taichi Ito

Laboratory of Clinical Biotechnology

Professor

Ungil Chung

Laboratory of Microenvironmental and Metabolic Health Sciences Professor

Makoto MurakamiLaboratory of Animal Resources

Professor

Atsu Aiba

Laboratory of Molecular Radiology

Professor

Kiyoshi Miyagawa

Professor

Masato Eto

Center for Diversity in Medical Education and Research

Associate Professor

Yoshihiro Satomura

Medical LibraryProfessor

Hideo Yasunaga

International Academic Affairs

Professor

Shinichi Sato

Medical Scientist Training Program

Professor

Kenzo Hirose

Museum of Health and Medicine

Professor

Kazuhiko Ohe

Office for Human Research Studies

Professor

Masaomi Nangaku

Life Sciences Core Facility

Associate Professor

Yoshihiro Kita

Office for Clinical Practice and Medical Education

Professor

Masato Eto

Division of Research Resources and Support
International Research Center for Medical Education
Global Nursing Research Center

Promotion of CPC Education and General Integrative Medicine Lecturer

Masako Ikemura

Endowed Departments
Artificial Intelligence in Healthcare

Project Associate professor

Yoshimasa Kawazoe

Department of Bone & Cartilage Regenerative Medicine

Project Associate professor

Atsuhiko Hikita

Department of Immunotherapeutics

Project Professor

Kazuhiro Kakimi

Department of Advanced Clinical Science andProject Associate professor

Mutsuo Harada

Project Professor

Naoto Hayashi

Science for Joint Reconstruction

Project professor

Toru Moro

Therapeutic Strategy for Heart Failure

Project Associate professor

Eisuke Amiya

Department of Advanced Translational Research andProject Associate professor

Yuichi Ikeda

Medical research and Management for Musculoskeletal

Project Professor

Koh Matsudaira

Department of Osteoimmunology

Project Associate professor

Kazuo Okamoto

Department of medical and pharmaceutical community

Project Professor

Hirohisa Imai

Department of Healthcare economics and Health policy

Project Professor

Tomoyuki Takura

Department of Biostatistics and Bioinformatics

Project Professor

Daisuke Koide

Therapeutics
Computational Diagnostic Radiology and Preventive
Medicine

Department of Molecular Structure and Dynamics

pain

healthcare

xxvi

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

Department of Molecular Neurology

Project Professor

Syoji Tsuji

Laboratory for Advanced Research on Pathophysiology

Project Associate Professor

Miki Iwabu

Department of Home Care Medicine

Project Associate Professor

Takashi Yamanaka

Department of Advanced Cardiology

Project Associate Professor

Katsuhito Fujiu

Research on Cell Therapy of Regenerative Medicine

Project Associate Professor

Dehua Chang

Comprehensive radiation oncology

Project Professor

Keiichi Nakagawa

Department of Lipidomics

Project Professor

Yoshiya Oda

Advanced Nursing Technology

Project Associate professor

Ryoko Murayama

Department of Health Services Research

Project Associate professor

Taisuke Jo

Skincare Science

Project Associate professor

Takeo Minematsu

Imaging Nursing Science

Project Associate professor

Nao Tamai

Healthcare Quality Assessment

Project Professor

Hiroaki Miyata

Department of Innovative Dementia Prevention

Project Associate professor

Tomoko Wakabayashi

Department of Next-Generation Pathology Information

Project Professor

Takeshi Sasaki

Project Associate professor

Satoko Yamaguchi

Chronic Kidney Disease Pathophysiology

Project Professor

Reiko Inagi

Department of Functional Genomics andProject Associate professor

Tomohisa Okamura

Tissue stem cell / life dentistry

Project Professor

Makoto Komura

Department of Next Generation Locomotive Imaging

Project Associate professor

Yuki Taniguchi

Department of Eat-loss Medicine

Project Associate professor

Kazumichi Yonenaga

Department of Preventive Medicine for Locomotive

Project Professor

Noriko Yoshimura

Project Associate professor

Hidenori Kage

Department of Pain & Palliative Medical Sciences

Project Associate professor

Maiko Hasegawa

Department of Retinal Biology and Pathology

Project Professor

Sumiko Watanabe

Medical information engineering

Project Associate professor

Taichi Kinof Metabolic Diseases

Clinical Trial Data Management

Social Cooperation Program

Networking
Department of Prevention of Diabetes andLifestyle-Related Diseases

Immunological Diseases

SystemOrgan Disorders
Next-Generation Precision Medicine Development
Laboratory

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

xxvii

University Hospital
Clinical Divisions
General Internal Medicine

Head

Masahiro Akishita

Cardiovascular Medicine

Head

Issei Komuro

Respiratory Medicine

Head

Takahide Nagase

Gastroenterology

Head

Mitsuhiro Hujishiro

Nephrology and Endocrinology

Head

Masaomi Nangaku

Diabetes and Metabolic Medicine

Head

Toshimasa Yamauchi

Hematology and Oncology

Head

Mineo Kurokawa

Allergy and Rheumatology

Head

Keishi Fujio

Infectious Diseases

Head

Kyoji Moriya

Neurology

Head

Tatsushi Toda

Geriatric Medicine

Head

Masahiro Akishita

Psychosomatic Medicine

Head

Kazuhiro Yoshiuchi

General Surgery

HeadSoichiro Ishihara

Stomach and Esophagus Surgery

Head

Yasuyuki Seto

Colon and Rectal Surgery

HeadSoichiro Ishihara

Hepatobiliary Pancreatic Surgery

HeadKiyoshi Hasegawa

Vascular Surgery

HeadSoichiro Ishihara

Breast and Endocrine Surgery

Head

Masahiko Tanabe

Artificial Organ and Transplantation Surgery

HeadKiyoshi Hasegawa

Cardiovascular Surgery

HeadMinoru Ono

Thoracic Surgery

Head

Jun Nakajima

Neurosurgery

Head

Nobuhito Saito

Anesthesiology and Pain Relief Center

Head

Kanji Uchida

Urology and Andrology

Head

Haruki Kume

Gynecologic Surgery

Head

Yutaka Ohsuga

Dermatology

HeadShinichi Sato

Ophthalmology

Head

Makoto Aihara

Orthopaedic Surgery and Spinal Surgery

Head

Sakae Tanaka

Otorhinolaryngology and Head and Neck Surgery

Head

Tatsuya Yamasoba

Rehabilitation Medicine

Head

Toru Ogata

Plastic, Reconstructive and Aesthetic Surgery

Head

Mutsumi Okazaki

Oral-Maxillofacial Surgery and Orthodontics

Head

Kazuto Hoshi

Pediatrics

Head

Motohiro Kato

Pediatric Surgery

Head

Jun Fujishiro

Obstetrics and Gynecology

Head

Yutaka Ohsuga

Neuropsychiatry

Head

Kiyoto Kasai

Radiology

Head

Osamu Abexxviii

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

Acute Medicine

Head

Kento Doi

Pharmaceutical Department

Head

Hiroshi Suzuki

Department of Clinical Laboratory

Head

Yutaka Yatomi

Surgical Center

Head

Kazuhiko Fukatsu

Radiology Center

Head

Osamu Abe

Department of Blood Transfusion

Head

Hitoshi Okazaki

Perinatal Center

Head

Yutaka Ohsuga

Rehabilitation Center

Head

Toru Ogata

Department of Medical Engineering

Head

Kento Doi

Central Supply Service

Head

Kazuhiko Fukatsu

Intensive Care Unit

Head

Kento Doi

Pathology

Head

Tetsuo Ushiku

Department of Corneal Transplantation

Head

Makoto Aihara

Department of Cell Therapy and Transplantation Medicine

Head

Mineo Kurokawa

Department of Endoscopy and Endoscopic Surgery

Head

Yousuke Nakai

Department of Hemodialysis and Apheresis

Head

Masaomi Nangaku

Infection Control and Prevention Service

Head

Kyoji Moriya

Department of Healthcare Information Management

Head

Kazuhiko Ohe

University Hospital Medical Information Network Center

Head

Takahiro Kiuchi

Organ Transplantation Service

Head

Jun Nakajima

Labor Safety and Health Management Office

HeadTomotaka Yamamoto

Child Psychiatry

Head

Yukiko Kano

Tissue Bank

Head

Sumihito Tamura

Epidemiology and Preventive Medicine

Head

Nobutake Yamamichi

Center for Liaison and Public Relations

Head

Yutaka Osuga

Department of Chemotherapy

HeadKiyoshi Miyagawa

Department of Medical Record Management

Head

Kazuhiko Ohe

Critical Care and Emergency Medical Center/ER

Head

Kento Doi

Department of Pain and Palliative Medicine

Head

Masahiko SumitaniChildren’s Medical Center

Head

Naoto Takahashi

Department of Disaster Medical Management

Head

Kento DoiInternational Medical Center

Head

Sumihito Tamura

Department of Clinical Nutrition Therapy

Head

Naoto Kubota

Department of Pediatric and Neonatal Intensive Care

Head

Naoto Takahashi

Department of Clinical Genomics

Head

Katsutoshi Oda

Clinical Research Promotion Center

Head

Takashi Moritoyo

22nd Century Medical and Research Center

Head

Yutaka Osuga

Department of Tissue Engineering

Head

Kazuto Hoshi

Central Clinical Facilites

The Tokyo Journal of Medical Sciences. Vol. 145, October 2022

xxix

Cooperative Unit of Medicine and Engineering Research

Head

Minoru Ono

Translational Research Center

Head

Issei Komuro

Genomic Research Support Center

Head

Yutaka Osuga

Unit for Early and Exploratory Clinical Development

Head

Takeshi Iwatsubo

The University of Tokyo,
Graduate School of Medicine

Molecular Cell Biology
1. Cell Biology and Anatomy

2

Department of Cell Biology
Professor
Yasushi Okada, M.D.,Ph.D.

Lecturer
Kazuho Ikeda, Ph.D.

Research Associate
Daisuke Takao, Ph. D.

Homepagehttps://www.okada-lab.phys.s.u-tokyo.ac.jp/en/

Introduction and Organization
Our laboratory is one of the laboratories in
Department of Cell Biology and Anatomy, since thereorganization of School of Medicine in 1997. The
current lab was established in 2020 when Yasushi
Okada was appointed as a professor.
Currently the lab members include: Yasushi Okada(professor), Kazuho Ikeda (Lecturer), Daisuke Takao(research associates).

Teaching activities
Our laboratory, together with other laboratories in thisdepartment, is in charge of teaching following
courses:1) Gross Anatomy for medical students.
2) Cell Biology and Histology for medical students.
3) Special training (Free Quarter) for medical
students.
4) Advance cell biology course for graduate students.

Research activities
Our primary goal is to answer the very basic question“What is life”. To answer this question, we are trying
to fill the gap between the world of molecules and theworld of living cells. Direct measurement ofmolecules in living cells would serve as a basic
technology to fill this gap. Thus, we have beenworking on the development of the technologies forthe visualization and non-invasive measurement of themolecular processes in living cells. High-speed,super-resolution live-cell imaging and single-molecule
measurement in living cells are the two maintechnologies we develop.
By using these technologies, we are trying tounderstand the regulatory mechanisms of motor
proteins during axonal transport. Despite the manystudies in the past decades by our group and others, it
is still unclear how the biophysical properties of motor
proteins are related to their biological functions. For
example, a point mutation in kinesin-1 can cause
hereditary spastic paraplegia, but it is unclear why thismutation selectively affects neurons in the longest
tract in the aged patients.
Through these studies and development, we haverealized the importance of the cellular states, and our
microscope technologies can also be applied to themeasurement of the cellular states. Thus, we haveproposed a project for the visualization, prediction,and control of cellular states.

References
1.

Aoyama-Ishiwatari S, Okazaki T, Iemura S,
Natsume T, Okada Y, Gotoh T. NUDT21 links
mitochondrial IPS-1 to RLR-containing stressgranules and activates host antiviral defense. The

3

2.

3.

4.

5.

6.

Journal of Immunology 206 (1), 154-163, 2021
Nakamura TS, Suda Y, Muneshige K, Fujieda Y,
Okumura Y, Inoue I, Tanaka T, Takahashi T,
Nakanishi H, Gao XD, Okada Y, Neiman AM,
Tachikawa H. Suppression of Vps13 adaptor
protein mutants reveals a central role for PI4P in
regulating prospore membrane extension. PLoS
Genet 17(8): e1009727. 2021
Kowada R, Kodani A, Ida H, Yamaguchi M, Lee
IS, Okada Y, Yoshida H. The function of Scox inglial cells is essential for locomotive ability in
Drosophila. Sci Rep. 11:21207. 2021
Ishijima A, Okada Y. Information biophysics ofgradient sensing in organisms. Biophys
Physicobiol. 18:263-264. 2021
Yaginuma H, Okada Y. Live cell imaging of
metabolicheterogeneitybyquantitative
fluorescent ATP indicator protein, QUEEN-37C.
bioRxiv: 2021.10.08.463131. 2021
Yoshida S, Okada Y, Muneyuki E, Ito S.
Thermodynamic role of main reaction pathway
and multi-body information flow in membranetransport. arXiv:2112.04024, 2021 (published in
Phys Rev Res 4, 023229, 2022).

4

Department of Cell Biology &Anatomy (Structural Biology)
Professor
Masahide Kikkawa, M.D., Ph.D.

LecturerHaruaki Yanagisawa, Ph.D.

Project Lecturer
Yoshiyuki Fukuda, Ph.D.

Research Associate
Tsukasa Makino, Ph. D, Hiroshi Yamaguchi, Ph. D

Homepage

http://structure.m.u-tokyo.ac.jp

Introduction and Organization
Our laboratory is one of the laboratories in
Department of Cell Biology and Anatomy. Since thereorganization of School of Medicine in 1997, the lab
was named as “Structural Biology”. The current lab
was established in 2009 when Masahide Kikkawa was
appointed as a professor.
Currently the lab members include: Masahide
Kikkawa (professor), Haruaki Yanagisawa (Lecturer),
Tsukasa Makino, Hiroshi Yamaguchi (research
associates), Akihisa Tsutsumi (project research
associate), (project researcher), Ryohei Sasaki,
Jiancheng An, Yuma Tani, and Yuqing Liu (graduate
students), Ueno Risa and Takemasa Saguchi (MSTP
students), Akiko Oosakaya, Sakamaki Yoichi, andToshie Furuya (technical assistant), Kazuhiro
Nakamura (Advanced Academic Specialist), andMikako Yanagiuchi and Setsuko Yuge (assistantclerk).

Teaching activities
Our lab, together with Kanai and Okabe’s lab, is incharge of teaching following courses:

1) Gross Anatomy for medical students.
2) Cell Biology and Histology for medical students.
3) Special training (Free Quarter) for medical
students.
4) Advance cell biology course for graduate students.

Research activities

Our lab focuses on the structure and function of
eukaryotic flagella/cilia. Flagella/cilia is both“propeller” and “antenna” of cells, whose diameter isabout 250 nm. From the recent studies, it is becoming
clear that flagella/cilia are involved in various
important cell functions.
To study the functions of flagella/cilia, we employ
various imaging techniques, including cryo-electron
microscopy and 3D-tracking microscope incombination with genetic manipulations.
Cryo-electron microscopy and cryo-electron
tomography
One of our strength is in the high-resolution cryoelectron microscopy (cryo-EM). This techniqueenables preserving biological samples by quickly
freezing them and observing the frozen samples
without staining. Using electron microscopy, we are

5

able
to
obtainnano-meter
resolutionofmacromolecular complexes such as axonemes. We
have been developing new techniques, such asasymmetric helical reconstruction and Ruby-Helix
software.
A new project for cryo-electron microscopy started in
October 2017 with a grant from AMED (Japan
Agency for Medical Research and Development). This
project is intended to make cryo-EM techniques
available to many biological/medical researchers. New
state-of-the-art cryo-electron microscopes are used bymany researchers in Japan, including external users.
Model Organism
Our lab currently uses Chlamydomonas, zebrafish, andmice as a model organism for studying cilia/flagella.
To identify molecules that are involved in regulating
dynein, we use various genetic tools, includingclassical mutagenesis, siRNA.
In addition, we are also developing 3D-tracking
microscopy in collaboration with Dr. Oku in
Department of Engineering. We are trying to track
Chlamydomonas cells and simultaneously record
flagella movement to elucidate the mechanism offlagella regulation.

References
1.

2.

3.

4.

5.

6.

7.

T. Kobayashi, A. Tsutsumi, N. Kurebayashi,
K. Saito, M. Kodama, T. Sakurai, M. Kikkawa,T. Murayama, and H. Ogawa. Molecular basis forgating of cardiac ryanodine receptor explains themechanisms for gain- and loss-of function
mutations. Nat Commun, 13(1):2821, 2022.
M. Kikkawa and H. Yanagisawa. Identifying
proteins in the cell by tagging techniques forcryo-electron microscopy. Microscopy (Oxf),
71(Supplement 1):i60–i65, 2022.
H. Nakamura, M. Kikkawa, and T. Murata.
Technical development and sharing of
high-resolution
cryo-electron
microscopes.
Biophys Physicobiol, 18:265–266, 2021.
T. Sakuragi, R. Kanai, A. Tsutsumi, H. Narita,
E. Onishi, K. Nishino, T. Miyazaki, T. Baba,
H. Kosako,
A. Nakagawa,
M. Kikkawa,C. Toyoshima, and S. Nagata. The tertiary
structure of the human Xkr8-Basigin complex
that scrambles phospholipids at plasma
membranes. Nat Struct Mol Biol, 28(10):825–834,
2021.
J. Obata, N. Kawakami, A. Tsutsumi, E. Nasu,
K. Miyamoto, M. Kikkawa, and R. Arai.
Icosahedral 60-meric porous structure ofdesigned supramolecular protein nanoparticle
TIP60. Chem Commun (Camb), 57(79):10226–
10229, 2021.
Y. Zhang,
S. Watanabe,
A. Tsutsumi,
H. Kadokura, M. Kikkawa, and K. Inaba.
Cryo-EM analysis provides new mechanistic
insight into ATP binding to Ca(2+) -ATPase
SERCA2b. EMBO J, page e108482, 2021.
R. Danev, H. Yanagisawa, and M. Kikkawa.
Cryo-EM Performance Testing of Hardware andData Acquisition Strategies. Microscopy (Oxf),
2021.

6

Department of Cytoarchitectonics
Lecturer
Yosuke Tanaka, M. D.

Homepage

http://cb.m.u-tokyo.ac.jp/

Teaching activities
Our teaching responsibility is following.
I.
1) Lecture on Cell Biology, Developmental Biology,
Histology and Neurocytology.
2) Lecture on Gross Anatomy and Neuroanatomy. to
medical students and students of other facultiesII.
1) Laboratory course of Gross Anatomy and
Neuroanatomy.
2) Laboratory course of Histology and Histology of
the Central Nervous System.
to medical students and students of other faculties.
In addition, we offer a special training course (freequarter) of various kinds of molecular cell biology
techniques such as immunocytochemistry, electron
microscopy, biochemistry, molecular biology, biophysics, and cellular and molecular neurobiology
technique to medical students.

Research activities
Our research field covers the molecular cell biologyof the cytoskeleton. We focus on the molecularmechanisms of cell morphogenesis and intracellulartransports.
Our laboratory studies molecular architecture,dynamics and function of the neuronal cytoskeleton
using various new molecular cell biologicalapproaches including new electron microscopy suchas the quick freeze deep etch electron microscopy,
cryo-electron microscopy at atomic resolution, andcryo-ultramicrotomy, biochemistry, immunocytochemistry, molecular biology, molecular genetics suchas gene targeting and transgenic mouse approaches,molecular biophysics and structure biology including

X ray crystallography and cryoelectron microscopy.
In this way we can study structure, dynamics andfunctions of cytoskeleton from gene to cell, tissue andwhole body.
Nerve cells as units of complicated neuronal
networks in the brain develop very polarizedmorphology composed of dendrites, cell body and along axon along the direction of impulse propagation.
The neuronal cytoskeleton plays three major importantroles.
1) It provides dynamic frameworks for neurite
extension and maintenance.
2) It provides structural bases for organelle transports
in the cells. Namely it works as rails and motor
molecules to transport materials from cell center toperiphery and from periphery to cell center.
3) It very importantly regulates release processes oftransmitters and also contributes to anchor receptors at
the postsynaptic sites.
Our laboratory studies molecular architecture,dynamics and function of the cytoskeleton focusing onthese three major roles.
To study these molecular mechanisms, we use newmolecular cell biological approaches including
electron microscopy of molecular resolution,
biochemistry, biophysics, molecular biology andmolecular genetics and X-ray crystallography.

References
1.

Yoshihara S., Jiang X., Morikawa Mo., Ogawa T.,
Ichinose S., Yabe H., Kakita A., Toyoshima M.,
Kunii Ya, Yoshikawa T., Tanaka Y., and N.
Hirokawa. Betaine ameliorates schizophrenic
traits by functionally compensating KIF3-based72.

CRMP2 transport. Cell Rep 35: 108971, April 13,
2021.
Morikawa Ma, Jerath N. U., Ogawa T.,
Morikawa Mo, Tanaka Y., Shy M.E., Zuchner,
S., and N. Hirokawa. KIF1A mutation of humanneuropathies hyperstabilizes the motor-neckinteraction in ATPase cycle. EMBO J. 41(5):e108899, Mar 1, 2022.

8

Department of Cellular
Neurobiology
Professor
Shigeo Okabe, M.D., Ph.D.

Research Associate
Yutaro Kashiwagi, Ph.D., Hisato Maruoka, Ph.D., Keiichiro Minatohara, Ph.D.

Homepage

http://synapse.m.u-tokyo.ac.jp/

Introduction and Organization
The Department of Cellular Neurobiology was
initially established as the Neuroanatomy departmentof former Brain Institute of Medical School ofImperial University of Tokyo in 1936. Since thestructural reconstruction of the School of Medicine in1997, this department became one of the departmentsof Cell Biology and Anatomy of the Graduate Schoolof Medicine. Professor Shigeo Okabe had currently
organized this department since September 2007. The
department is constituted of 23 members.

Education
For medical students, our department takes thefollowing lectures and courses.
1. Cell Biology, Histology, and Neurocytology
2. Gross Anatomy and Neuroanatomy.
3. Free Quarter.
For graduate students, we offer the following
lectures and seminars.
1. Cellular Neurobiology.
2. Cell Biology and Histology.
3. Discussion seminars and progress reports of theexperiment.
4. Joint seminar with other departments

Research
Brain functions, which are dependent on mutualcommunication of a tremendous number of neuronalcells, regulate the behavior of animals and humans.
The main structure specifically differentiated for
information exchange between neurons, is called"synapse." Long-term maintenance of synaptic
properties underlies the stability and reproducibility of
behavior in responses to external stimuli. In turn,
alterations of synaptic properties are thought to be thebasis of behavioral change in the course of animal
development and also after learning. Therefore,
synapses should be stabilized for the long term torealize fidelity of various animal behaviors, but also
should be altered rapidly when animals adapt to a newenvironment. The molecular basis of this dichotomy,
which is unique to synapses, is the main interest of ourlaboratory.
Synapse is the site of signal transmission between
neurons. Most of the synapses are formed during theearly development, and after that, they become stable
after the intensive pruning. We are interested in how
synapse is developed and maintained. The
postsynaptic densities (PSDs) are protein-dense
structures which are located closely to postsynaptic
membranes. PSDs include a variety of receptors,
scaffolding proteins, and signaling molecules. We
focus on PSD proteins and examine their roles insynapse development.
Two-photon excitation microscopy allows imagingof the living brain. We examine synapse remodeling invivo by observing the postsynaptic structures and PSD
proteins tagged by fluorescent probes. We are also
investigating synapse pathology in developmental

9disorders by using mouse models. For both in vitro
and in vivo analyses of synapses, the development of
new imaging technologies is essential. Our laboratory
has made a significant contribution to the quantitativeand high-resolution imaging of synapse dynamics.

Publications
1.

2.

3.

4.

5.

Kashiwagi, Y., Okabe, S. Imaging of spine
synapses using super-resolution microscopy.
Anatomical Science International 2021 96(3):343-358 doi: 10.1007/s12565-021-00603-0.
Obashi, K, Taraska, J. W., Okabe, S. The role ofmolecular diffusion within dendritic spines insynaptic function. Journal of General Physiology
2021 153(4) e202012814. doi: 10.1085/jgp.
202012814.
Yoshida T, Yamagata A, Imai A, Kim J, Izumi H,
Nakashima S, Shiroshima T, Maeda A, IwasawaOkamoto S, Azechi K, Osaka F, Saitoh T,
Maenaka K, Shimada T, Fukata Y, Fukata M,
Matsumoto J, Nishijo H, Takao K, Tanaka S,
Okabe S, Tabuchi K, Uemura T, Mishina M,
Mori H, Fukai S. Canonical versus non-canonicaltranssynaptic signaling of neuroligin 3 tunes
development of sociality. Nature Communications 2021 12(1):1848. doi: 10.1038/s41467-02122059-6.
Tamada K, Fukumoto K, Toya T, Nakai N,
Awasthi JR, Tanaka S, Okabe S, Spitz F, Saitow
F, Suzuki H, Takumi T. Genetic dissection
identifies Necdin as a driver gene in a mousemodel of paternal 15q duplications. Nature
Communications 2021 12(1):4056. doi: 10.1038/
s41467-021-24359-3.
Morris K, Nami M, Bolanos JF, Lobo MA,
Sadri-Naini M, Fiallos J, Sanchez GE, Bustos T,
Chintam N, Amaya M, Strand SE, Mayuku-DoreA, Sakibova I, Biso GMN, DeFilippis A, Bravo D,
Tarhan N, Claussen C, Mercado A, Braun S, Yuge
L, Okabe S, Taghizadeh-Hesary F, Kotliar K,
Sadowsky C, Chandra PS, Tripathi M, Katsaros V,
Mehling B, Noroozian M, Abbasioun K,
Amirjamshidi A, Hossein-Zadeh GA, Naraghi F,
Barzegar M, Asadi-Pooya AA, Sahab-Negah S,
Sadeghian S, Fahnestock M, Dilbaz N, Hussain N,
Mari Z, Thatcher RW, Sipple D, Sidhu K, Chopra

6.

7.

8.

9.

D, Costa F, Spena G, Berger T, Zelinsky D,
Wheeler CJ, Ashford JW, Schulte R, Nezami MA,
Kloor H, Filler A, Eliashiv DS, Sinha D,
DeSalles AAF, Sadanand V, Suchkov S, Green K,
Metin B, Hariri R, Cormier J, Yamamoto V,
Kateb B. Neuroscience20 (BRAIN20, SPINE20,
and MENTAL20) Health Initiative: A Global
Consortium Addressing the Human andEconomic Burden of Brain, Spine, and Mental
Disorders Through Neurotech Innovations andPolicies J Alzheimers Dis. 2021 83(4):1563-1601.
doi: 10.3233/JAD-215190.
Quaglio G, Toia P, Moser EI, Karapiperis T,
Amunts K, Okabe S, Poo MM, Rah JC, Koninck
Y, Ngai J, Richards L, Bjaalie JG. The
International Brain Initiative: enabling collaborative science. Lancet Neurol. 2021 20(12):985-986.
doi: 10.1016/S1474-4422(21)00389-6.
Endo M, Maruoka H, Okabe S. Advanced
Technologies for Local Neural Circuits in the
Cerebral Cortex. Front Neuroanat. 2021
15:757499. doi: 10.3389/fnana.2021.757499.
eCollection 2021.
Terashima H, Minatohara K, Maruoka H, Okabe
S. Imaging neural circuit pathology of autism
spectrum disorders: autism-associated genes,
animal models and the application of in vivo
two-photon imaging. Microscopy (Oxf). 2022
71(Supplement_1):i81-i99. doi: 10.1093/jmicro/
dfab039.
Kamei R, Urata S, Maruoka H, Okabe S. In vivo
Chronic Two-Photon Imaging of Microglia in the
Mouse Hippocampus. J Vis Exp. 2022 6;(185).
doi: 10.3791/64104.

Molecular Cell Biology
2. Biochemistry and Molecular Biology

11

Department of Molecular Biology
Professor
Noboru Mizushima, M.D., Ph.D.

Lecturer
Hayashi Yamamoto, Ph.D.

Research Associate
Yuji Sakai, Ph.D., Saori Yoshii, M.D., Ph.D.

Project Associate Professor
Chieko Saito, Ph.D.

Project Lecturer
Ikuko Koyama-Honda, Ph.D.

Project Research Associate
Junichi Sakamaki, Ph.D., Tomoya Eguchi, M.D., Ph.D.

Homepagehttps://molbiolut.jp/en/

Introduction and Organization
Established in 1893 as a part of Department of
Physiology, this Department became independent in
1897. It was renamed Department of Biochemistry in
1927, First Department of Biochemistry in 1974, andDepartment of Molecular Biology in 1997, according
to the creation of new related departments and thereorganization of Faculty of Medicine. This
Department has been headed by seven professors,each of whom made significant contributions to thedevelopment of biochemistry, nutrition, and molecularbiology in Japan.
Professor
Muneo
Kumagawa,
whoestablished this Biochemistry or Medical Chemistry
Department for the first time in Japan, graduated fromThe University of Tokyo Faculty of Medicine in 1882.
In 1884 he went to Germany to study in Departmentof Pathology, The University of Berlin headed by Dr.
Rudolf Virchow under the supervision of Dr. Ernst
Salkowski. After returning to Japan, he became
Lecturer and was promoted to Professor of thisDepartment. In 1908, he discovered a lack ofglycogenecity in lipids, which has been firmly
established besides some exceptions, and succeeded inpurification of vitamin B1, which had been discoveredby Dr. C. Eijkman in 1906. His lab produced many
famous researchers including Dr. Masahiro Sakaguchi,
who developed a world-famous colorimetric method
for arginine and Dr. Takaoki Sasaki, who firstsucceeded in generating liver cancer with chemicals.
Professor Samuro Kakiuchi graduated fromthe Imperial University of Tokyo, Faculty of Medicine
in 1906 and studied under Professor Kumagawa. After
studying in the US, he came back to succeed the late
Kumagawa. He launched the Journal of Biochemistry
and founded the Japanese Society of Biochemistry.
His students included Professors Kodama andShimazono.
Professor Keizo Kodama graduated from theImperial University of Tokyo in 1918. After studying
at Cambridge University, he became Professor of
Biochemistry at Kyushu Imperial University. In 1943,
he took up a professorship at this Department. His
research was on oxidation and reduction, and12nutrition.
Professor Norio Shimazono, a graduate of
the Imperial University of Tokyo Faculty of Medicine
in 1928, became a professor at Niigata Medical
School. In 1952 he succeeded Professor Kodama. He
studied vitamin B1/ cocarboxylase, ketoacid
metabolism and hexose metabolism.
Professor Tamio Yamakawa graduated fromthe Imperial University of Tokyo Faculty of Medicine,and began studies at the Institute for Infectious
Diseases, the University of Tokyo. He took up a
professorship to succeed Professor Shimazono. He
was a pioneer in glycolipid research and discovered
the involvement of sialic acid in the ABO blood typeantigens.
Professor Masami Muramatsu graduatedfrom the University of Tokyo Faculty of Medicine in
1955. He began studies at the Department of Internal
Medicine, and then went to Baylor College ofMedicine to study under Dr. H. Busch. After comingback to Japan, he took a position at the Cancer
Institute and the took up a professorship at Tokushima
University School of Medicine. In 1982, he succeeded
Professor Yamakawa. He studied ribosomal RNA andcloned interferon and p450 genes.
Professor Hiroto Okayama graduated from
Kumamoto University School of Medicine in 1973.
After taking a Ph.D. degree at Kyoto University
School of Medicine, he went to Stanford University to
study under Dr. P. Berg. After working at the NIH,
USA, he became Professor of Molecular Genetics, atOsaka University Institute for Infectious Diseases. In
1993 he succeeded Professor Muramatsu. At Stanford
and the NIH, he studied gene cloning and developed afull-length cDNA cloning method and a cDNA
expression cloning vector system, and, after returning
to Japan, he studied cell cycle control and cancer.
Professor Noboru Mizushima graduatedfrom Tokyo Medical and Dental University, Faculty of
Medicine in 1991. After receiving Ph.D., he studied at
National Institute for Basic Biology in Okazaki andstarted works on autophagy in yeast and mammals at
Dr. Yoshinori Ohsumi’s laboratory. Taking a position
as a PI at the Tokyo Metropolitan Institute of Medical
Science in 2004, he started studies on physiologicalroles of autophagy. He was promoted to Professor of
Physiology and Cell Biology, in Graduate School andFaculty of Medicine at Tokyo Medical and Dental
University in 2006, and succeeded Professor Okayama
in 2012.

Research Activities
Our current study focuses on the understanding of themolecular mechanism and physiological roles of
autophagy and other intracellular degradation systems.
In 2021, we reported the following novel findings.
1. Molecular mechanism of autophagy
Autophagy is one of the major degradation
pathways in the cell. In autophagy, intracellularcomponents are sequestered by autophagosomes
and then degraded upon fusion with lysosomes.
Yeast genetic studies have identified more than 40
autophagy-related (ATG) genes. Many of thesegenes are conserved in higher eukaryotes, whichallows us to perform genetic analysis of
autophagy in mammals. We are currently
addressing some of the central questions
remaining in the autophagy field and trying toelucidate the mechanisms of (1) regulation of
autophagy, (2) initiation of autophagosome
formation, (3) elongation of the autophagic
membrane, (4) closure, fusion, and degradation of
the autophagosome (5) recognition of selective
substrates. In addition, we are also working on
intracellular degradation systems other than
autophagy.
TMEM41B and VMP1 are endoplasmic
reticulum(ER)-localizing
multi-spanningmembrane proteins required for ER-related
cellular processes such as autophagosome
formation, lipid droplet homeostasis, andlipoprotein secretion in eukaryotes. Both proteins
have a VTT domain, which is similar to the DedA
domain found in bacterial DedA family proteins.
However, the molecular function and structure of
the DedA and VTT domains (collectively referred
to as DedA domains) and the evolutionary
relationships among the DedA domain-containing
proteins are largely unknown. Phylogenetic
analysis revealed that the TMEM41, VMP1,
DedA, and PF06695 families form a superfamilywith a common origin, which we termed the DedA

13

superfamily.
Coevolution-based
structural
prediction suggests that the DedA domain
contains two reentrant loops facing each other inthe membrane. This topology is biochemicallyverified by the substituted cysteine accessibility
method. The predicted structure is topologicallysimilar to that of the substrate-binding region ofseveral ion transporters. Thus, we hypothesizethat VMP1 and TMEM41B have an ion or lipid
transporting activity and that function is importantfor multiple functions of these proteins in the ER(Okawa et al. J Cell Sci 2021).
Autophagy undergoes dynamic positive andnegative regulation in response to multiple formsof cellular stress, but the precise mechanisms are
not fully understood. To investigate the negative
regulatory system of autophagy, we performed agenome-wide CRISPR screen for negative
regulators of autophagy, using the GFP-LC3-RFP
reporter, which can quantify autophagic activities.
We identified phosphoribosylformylglycinamidine
synthase (PFAS), a component of the de novo
purine synthesis pathway, as a negative regulatorofautophagy.
Purinestarvation-induced
autophagy through the TSC-RHEB-mTORC1
signaling axis. Moreover, depletion of pyrimidine
synthesis enzymes activated autophagy as well.
However, mTORC1 activity was not altered bypyrimidine shortage, suggesting a different
mechanism of autophagy induction between
purine and pyrimidine starvation. These findings
provide novel insights into the regulation of
autophagy by metabolites (Mimura et al. J Biol
Chem 2021).
Phase-separated droplets with liquid-like
properties can be degraded by autophagy, but theunderlying mechanism is poorly understood. We
derived a physical model to investigate theinteraction between autophagic membranes andsuch droplets, uncovering that intrinsic wettinginteractions underlie droplet-membrane contacts.
We found that the competition between droplet
surface tension and the increasing tendency ofgrowing membrane sheets to bend determines
whether a droplet is completely engulfed or
isolated in a piecemeal fashion, a process we term
fluidophagy. Our study provides a physicalaccount of how droplet-membrane wetting
underpins the structure and fate of forming
autophagosomes (Agudo-Canalejo et al. Nature2021).
2. Physiological and pathological roles of
autophagy
Using autophagosome-indicator GFP-LC3 miceand various autophagy-deficient mouse models,
we have shown that autophagy is important for the
maintenance of the amino acid pool during
starvation and neonatal periods, preimplantation
development as an amino acid supplying system,
and for intracellular protein quality control toprevent neurodegeneration and tumorigenesis.
In 2021, we revealed a new physiologicalrole for autophagy. It has been known that
autophagy regulates primary cilia formation, but
the underlying mechanism is not fully understood.
We identified NIMA-related kinase 9 (NEK9) as a
GABARAPs-interacting protein and found that
NEK9 and its LC3-interacting region (LIR) are
required for primary cilia formation. Mutation in
the LIR of NEK9 in mice also impaired in vivo
cilia formation in the kidneys. Mechanistically,
NEK9 interacted with MYH9 (also known as
myosin IIA), which has been implicated ininhibiting ciliogenesis through stabilization of theactin network. MYH9 accumulated in NEK9 LIR
mutant cells and mice, and depletion of MYH9
restores ciliogenesis in NEK9 LIR mutant cells.
These results suggest that NEK9 regulates
ciliogenesis by acting as an autophagy adaptor for
MYH9. Given that the LIR in NEK9 is conserved
only in land vertebrates, the acquisition of the
autophagic regulation of the NEK9-MYH9 axis inciliogenesis may have possible adaptive
implications for terrestrial life (Yamamoto et al.
Nat Commun 2021).
3. Methods for monitoring autophagic activity
Measuring autophagic activity is critical todissecting molecular mechanisms and functions ofautophagy but remains challenging due to the lackof a definitive method. We have recently
developed a new fluorescent reporter, GFP-LC3RFP-LC3ΔG, to assess autophagic flux. We have

14

generated a new mouse model ubiquitously
expressing this autophagy flux reporter.
4. Autophagy-independent organelle degradation
The eye lens of vertebrates is composed offiber cells in which all membrane-boundorganelles undergo degradation during terminal
differentiation to form an organelle-free zone. The
mechanism that underlies this large-scaleorganelle degradation remains largely unknown,
although it has previously been shown to be
independent of macroautophagy. We found that
phospholipases in the PLAAT (phospholipase
A/acyltransferase) family are essential for the
degradation of lens organelles such as
mitochondria, the endoplasmic reticulum, andlysosomes. PLAAT translocates from the cytosol
to various organelles immediately before
organelle degradation, in a process that requires
their C-terminal transmembrane domain. The
translocation of PLAAT to organelles depends onthe differentiation of fiber cells and damage toorganelle membranes, both of which are mediatedby Hsf4. After the translocation of PLAAT tomembranes, the phospholipase induces extensive
organelle rupture that is followed by complete
degradation.
Organelle
degradation
by
PLAAT-family phospholipases is essential forachieving optimal transparency and refractivefunction of the lens. These findings expand ourunderstandingof
intracellularorganelle
degradation and provide insights into themechanism by which vertebrates acquired
transparent lenses.

Education
To medical students, we give lectures on biochemistry
and molecular biology. General metabolism, protein
synthesis, protein degradation, and metabolism ofcarbohydrates, amino acids, and nucleic acids are thetopics in our lectures. To graduate students, themolecular biology course consisting of lectures andexperiments is provided.

Publication
1.

2.

3.

4.

5.

6.

7.
8.

9.

Kusumaatmaja, H., May, A.I., Feeney, M.,
McKenna, J.F., Mizushima, N., Frigerio, L.,*Knorr, R.L. Wetting of phase-separated dropletson plant vacuole membranes leads to acompetition between tonoplast budding andnanotube formation. Proc. Natl. Acad. Sci. USA.
118: e2024109118 (2021)
Yamamoto, Y., Chino, H., Tsukamoto, S., Ode,
KL, Ueda H.R., *Mizushima, N. NEK9 regulates
primary cilia formation by acting as a selective
autophagy adaptor for MYH9/myosin IIA. Nat.
Commun. 12:3292 (2021)
Mimura, K., Sakamaki, J.I., Morishita, H.,
Kawazu, M., Mano, H., *Mizushima, N.
Genome-wide CRISPR screening reveals
nucleotide synthesis negatively regulates
autophagy J. Biol. Chem. 296:100780 (2021)*Morishita, H., Eguchi, T., Tsukamoto, S.,
Sakamaki, Y., Takahashi, S., Saito, C.,
Koyama-Honda, I., *Mizushima, N. Organelle
degradation
in
the
lens
by
PLAAT
phospholipases. Nature, 592:634-638 (2021)
Okawa, F., Hama, Y., Zhang, S., Morishita, H.,
Yamamoto, H., Levine, T.P., *Mizushima, N.
Evolution and insights into the structure andfunction of the DedA superfamily containing
TMEM41B and VMP1. J. Cell Sci. 134:
jcs255877 (2021)
Agudo-Canalejo, J., Schultz, S.W., Chino, H.,
Migliano, S., Saito, C., Koyama-Honda, I.,
Stenmark, H., Brech, A., May, A.I., Mizushima,N., *Knorr, R. L. Wetting regulates autophagy ofphase-separated compartments and the cytosol.
Nature 591:142-146 (2021)
Klionsky, D.J. et al. Autophagy in major humandiseases. EMBO J. 40: e108863 (2021)*Morishita, H., Eguchi, T., *Mizushima, N. A
new insight into the lens: cytosolic PLAAT
phospholipases degrade organelles to make thelens transparent. Autophagy 17: 2645-2647(2021)*Mizushima, N., *White E, *Rubinsztein DC.
Breakthroughs and bottlenecks in autophagy
research. Trends Mol. Med. 11; S1471-4914(21)00179-9 (2021)

15

10. Yamamoto, Y., *Mizushima, N. Autophagy andciliogenesis. JMA J. 15:207-215 (2021)
11. Zhang, S., Hama, Y., *Mizushima, N. The
evolution of autophagy proteins: diversificationin eukaryotes and potential ancestors inprokaryotes. J. Cell. Sci. 134: jcs233742 (2021).
12. Hama, Y., Zhang, S., *Mizushima, N. ZZ
domains keep cytosol to vacuole delivery
whiZZing along. EMBO J 25: e108777 (2021)
13. Klionsky D.J., et al. Guidelines for the use andinterpretation of assays for monitoring autophagy(4th edition). Autophagy 17:1-382 (2021)
14. Morishita, H., Kanda, Y., *Mizushima, N. No air
without autophagy: autophagy is important forlung and swim bladder inflation. Autophagy,
17(4):1040-1041 (2021)
15. Schultz, S.W., Agudo-Canalejo, J., Chino, H.,
Migliano, S., Saito, C., Koyama-Honda, I.,
Stenmark, H., Brech, A., Mizushima, N., *Knorr,
R. L., *May, A.I. Should I bend or should I grow:themechanismsofdroplet-mediatedautophagosome formation. Autophagy, 17:10461048 (2021)
16. Yim, W.W., *Mizushima, N. Autophagosome
maturation stymied by SARS-CoV-2. Dev. Cell
56:400-402 (2021).

16

Department of Cellular Signaling
Professor
Makoto Murakami, Ph.D.

Assistant Professor
Yoshitaka Taketomi, Ph.D.

Home Page

http://lmmhs.m.u-tokyo.ac.jp

Introduction
The Department of Cellular Signaling, belonging to
the Molecular Cell Biology, is organized by Murakami,
who is also a professor of the Laboratory ofMicroenvironmental and Metabolic Health Sciences,from August 2018 to March 2022. The laboratory iscomposed of one professor and one assistant professor
as well as members of the Laboratory ofMicroenvironmental and Metabolic Health Sciences.

Research activities
The main theme of this research project is to clarify
the role of lipids in health and diseases. Lipids
represent the largest source of energy in livingorganisms, are main components constituting cell
membranes, and also act as signal molecules. Lipids
are environmental nutritional factors ingested fromfoods, as well as tissue microenvironmental regulatorsthat spatiotemporally coordinate biological responses
after being metabolized to specific bioactive lipids. By
performing comprehensive lipid analysis (lipidomics)
on gene-manipulated mice for lipid-metabolizing
enzymes, particularly those in the phospholipase A2(PLA2) family, we aim to elucidate the molecularpathophysiology of diseases (e.g. metabolic andimmune diseases) that are problematic in modern
society. Based on this, we will promote the research of
Quality of Lipids (QOL) for Quality of Life (QOL)
and aim at building a theoretical foundation for
diagnosis, prevention and treatment of diseases
involving alteration of lipid metabolism.

1) Metabolic diseases
We previously reported that PLA2G5 (sPLA2-V),
secreted from hypertrophic white adipocytes duringobesity, hydrolyzes phosphatidylcholine (PC) in LDL
to release oleic and linoleic acids, which attenuate M1
polarization of macrophages and thereby protect fromdiet-induced obesity, adipose tissue inflammation, andinsulin resistance (Sato et al, Cell Metab, 2014), andthat PLA2G2D (sPLA2-IID), secreted from M2-likemacrophages in white adipose tissue, releases ω3polyunsaturated fatty acids (PUFAs) to promote
cold-induced adipocyte browning and thereby
thermogenesis (Sato et al, Cell Rep, 2020). In addition,
we have recently found that PLA2G2E (sPLA2-IIE) ishighly induced in brown and beige adipocytes in
response to cold and that its genetic deletion leads topartial impairment of adipocyte browning andthermogenesis.
Choline supplies methyl groups for regeneration ofmethionine and the universal methyl donor
S-adenosylmethionine (SAM) in the liver. Although
PC is the main cellular reservoir for choline, thepathway for hepatic PC catabolism that generates freeendogenous choline remains unexplored. We foundthat PNPLA7, a lysophospholipase that catalyzes thehydrolysis of lysophosphatidylcholine (LPC) toglycerophosphocholine (GPC), is crucial for thispathway. Pnpla7-deficient mice show marked
decreases in hepatic GPC, choline, betaine and SAM,
accompanied by various signs of methionine
insufficiency including impaired triglyceride storage
and secretion, hypoglycemia, increased energy
expenditure, reduced fat mass with adipocyte

17browning, and decreased epigenetic histone and DNA
methylation. Accordingly, Pnpla7-/- mice are lean,display growth retardation, and die prematurely. We
further found that mice lacking PNPLA8 (iPLA2γ),
which acts as PLA1/A2, recapitulate most of these
phenotypes, suggesting that PNPLA8 lies upstream of
PNPLA7. Thus, the methyl group flux from choline
endogenously generated through PC breakdown by the
PNPLA8-PNPLA7 axis is essential for liver functions
and systemic energy homeostasis (submitted).
2) Skin diseases
Lipids play crucial roles in skin homeostasis anddiseases. We previously reported that PLA2G2F(sPLA2-IIF), which is specifically expressed inepidermal keratinocytes, mobilizes lysoplasmalogen,a unique lysophospholipid that promotes epidermal
hyperplasic diseases such as psoriasis and skincancer (Yamamoto et al, J Exp Med, 2015), and thatPNPLA1, a member of the intracellular iPLA2 family
whose mutations cause autosomal recessive
congenital ichthyosis, acts as a transacylase to
produce ω-O-acylceramide, an essential lipid for skinbarrier function (Hirabayashi et al, Nat Commun,2017). PLA2G4E (cPLA2ε), which is expressed inepidermal keratinocytes, exhibits a uniqueN-acyltransferase activity that transfers a fatty acidfrom the sn-1 position of PC to the amino group ofphosphatidylethanolamine (PE) to give rise to N-acyl
PE (NAPE), a precursor of the non-canonicalbioactivelipid
N-acylethanolamine(NAE).
Pla2g4e-deficient mice display exacerbation ofpsoriasis with marked reduction of various NAE
species, suggesting that PLA2G4E plays a role inputting a brake on psoriasis by generating theanti-inflammatory lipid mediator NAE (Liang et al,
FASEB J 2022).
PLA2G3 (sPLA2-III) is expressed in epidermal
keratinocytes and its global or skin-specific deletion
leads to perturbation of skin barrier function due tofragile cornified envelope and loosened epidermal
tight junction. Accordingly, following topical antigen
challenge, global or skin-specific Pla2g3-deficient
mice display more severe atopic dermatitis-like
symptoms with increased expression of type 2
cytokines, serum IgE levels, eosinophil infiltration,scratching behavior, and disturbed skin microbiota.
Global or skin-specific deletion of EP4 (PGE2

receptor) or FP (PGF2α receptor) largely if not solely
recapitulate these phenotypes, and treatment with FP
or EP4 agonists rescue skin abnormalities in
Pla2g3-deficient mice. Moreover, global or
skin-specific Pla2g3-deficient mice exhibited more
severe asthma following topical antigen challenge.
These results suggest that the PLA2G3-driven
PGE2-EP4/PGF2α-FP signaling in keratinocytes plays
an important role in skin barrier formation andthereby skin homeostasis, perturbation of whichleads to exacerbation of atopic march.
3) Allergic and other immunological diseases
We previously reported that PLA2G3, an sPLA2
isoform secreted from mast cells (MCs), promotes MCmaturation by driving the paracrine PGD2 circuit incooperation with microenvironmental fibroblasts(Taketomi et al, Nat Immunol 2013; Taketomi et al,
Cells 2021) and that PAF-AH2, a unique PLA2 thathydrolyzes oxidized phospholipids, ensures optimal
MC activation and thereby allergic responses throughproducing unique EPA/DHA metabolites (ω3epoxides) (Shimanaka et al, Nat Med 2017).
Furthermore, we have recently found that PLA2G3 isalso coupled with an additional lipid mediator,
lysophosphatidic acid (LPA), which acts in concert
with PGD2 to facilitate MC maturation.
PLA2 subtypes that regulate T cell immunity are
unknown. By transcriptional and functional screeningof PLA2 enzymes expressed in T cells, we have foundthat PLA2G12A (sPLA2-XIIA) is induced in Th17
cells and participates in Th17 differentiation. Global
or CD4+ T cell-specific Pla2g12a-deficient mice havelower psoriatic inflammation with decreased Th17 andγδT cells in the skin and lymph nodes. We are now
analyzing a particular lipid mediator that acts
downstream of PLA2G12A in inducing Th17
immunity.
4) Gut microbiota
Despite the restricted intestinal expression of
PLA2G2A (sPLA2-IIA) in BALB/c mice, its genetic
deletion leads to amelioration of skin carcinogenesis.
Metagenome, transcriptome and metabolome analyses
have revealed that Pla2g2a deficiency alters the gut
microbiota, accompanied by notable changes in theintestinal expression of genes related to immunity andmetabolism as well as the levels of various blood
metabolites and fecal bacterial lipids, suggesting that

18

PLA2G2A contributes to shaping of the gut
microbiota (Miki et al, JCI Insight, 2022). Pla2g2a-/mice also display an alteration in passive cutaneous
anaphylaxis (Taketomi et al, Metabolites 2022). These
results highlight a new aspect of PLA2G2A as amodulator of gut microbiota, perturbation of which
affects distal skin responses.
5) Cancer
Extracellular vesicles (EVs) including exosomes
act as intercellular communicators by transferring
protein and microRNA cargoes, yet the role of EV
lipids remains unclear. We have recently found thatthe pro-tumorigenic action of lymphoma-derived EVs
is augmented via sPLA2-driven lipid metabolism.
Hydrolysis of EV phospholipids by PLA2G10(sPLA2-X), which is induced in a specific populationof macrophages in Epstein-Barr virus (EBV)-induced
lymphoma, increases the production of fatty acids,
lysophospholipids and their metabolites. Additionally,sPLA2-treated EVs are smaller, self-aggregate, show
better uptake, and increase cytokine expression andlipid mediator signaling in recipient tumor-associatedmacrophages. Lymphoma growth in EBV-infected
mice is suppressed by a sPLA2 inhibitor, while treating
the mice with sPLA2-modified EVs can reverse thisphenotype. Thus, the sPLA2-driven EV modification
promotes tumor development (Kudo et al, Cell Metab
2022). It is anticipated that modification of EVs by
sPLA2s may occur universally in various cancers aswell as in allergic and metabolic diseases, a possibility
that is currently under investigation.
6) Infectious diseases
PLA2G2D expressed in dendritic cells and M2
macrophages attenuates anti-viral Th1 immunity bysupplying ω3 PUFAs and PGD2 (Miki et al, J Exp Med2013). In collaboration with a foreign group, we havereported that Pla2g2d deficiency protects mice frompneumonia caused by coronavirus infection (RoyWong et al, Nature 2022). Therefore, PLA2G2D may
be an attractive drug target for treatment of
COVID-19.
7) Neuronal and retinal diseases
Mutations in the PNPLA6 gene cause neuronal andretinal degeneration such as hereditary spastic
paraplegia (SPG39), Boucher-Neuhauser syndrome,
Oliver-McFariane syndrome, and Laurence-Moon
syndrome. PNPLA6 acts a phospholipase B (PLA1/A2+ lysophospholipase), hydrolyzing PC to give rise totwo fatty acids and GPC, in cells. Intriguingly,
neuron-specific deletion of PNPLA6 and its closest
homolog PNPLA7 leads to neurodegenerative
disorders similar to hereditary spastic paraplegia andthat tamoxifen-inducible eye-specific deletion of
PNPLA6 results in retinal degeneration. Retinaldegeneration in these mice can be prevented by eye
drops of choline, a PC degradation product. Clarifying
the regulatory roles of lipid metabolism driven by
PNPLA6/PNPLA7 will shed light on the molecularmechanism underlying the PNPLA6-related neuronaland retinal disorders.
Furthermore, in collaboration with an externalgroup, we found that a particular sPLA2 isoform thatis induced after cerebral infarction is involved inneuroprotection by mobilizing a unique lipid mediator(submitted).

Teaching activities
The Department of Cellular Signaling has importantmissions to train postdoctoral fellows to become
promising scientist leaders in the field of medical
sciences and to provide biochemistry and molecularbiology for graduate and undergraduate students. The
following lectures have been provided to students.
Graduate education
Lectures, Seminars, and laboratory practices, aswell as guidance for the dissertation for the Master’sand Doctor’s degrees, have been provided.
Undergraduate education
Lectures on biochemistry and molecular biology
have been provided to medical students (M0). Fourundergraduate students (three M2 students and one
M4 student) participate in the Murakami’s teamthroughout the year.

Publications
1. Miki Y, Taketomi Y, Kidoguchi Y, Yamamoto K,
Muramatsu K, Nishito Y, Park J, Hosomi K,
Mizuguchi K, Kunisawa J, Soga T, Boilard E,
Gowda SGB, Ikeda K, Arita M, Murakami M.
Group IIA secreted phospholipase A2 controls

19

2.

3.

4.

5.

6.

7.

skin carcinogenesis and psoriasis by shaping the
gut microbiota. JCI Insight. 7, e152611, 2022.
Doré E, Joly-Beauparlant C, Morozumi S,
Mathieu A, Lévesque T, Allaeys I, Duchez AC,
Cloutier N, Leclercq M, Bodein A, Payré C,
Martin C, Petit-Paitel A, Gelb MH, Rangachari M,
Murakami M, Davidovic L, Flamand N, Arita M,
Lambeau G, Droit A, Boilard E. The interaction of
secreted phospholipase A2-IIA with themicrobiota alters its lipidome and promotes
inflammation. JCI Insight. 7, e152638, 2022.
Kudo K, Miki Y, Carreras J, Nakayama S,
Nakamoto Y, Ito M, Nagashima E, Yamamoto K,
Higuchi H, Morita S, Inoue A, Aoki J, Ando K,
Nakamura N, Murakami M, Kotani A. Secreted
phospholipase A2 modifies extracellular vesicles
and accelerates B-cell lymphoma. Cell Metab. 34,
1-19, 2022.
Roy Wong LY, Zheng J, Wilhelmsen K, Li K,
Ortiz ME, Schnicker NJ, Pezzulo AA,
Szachowicz PJ, Klumpp K, Aswad F, Rebo J,
Narumiya S, Murakami M, Meyerholz DK,
Fortney K, McCray PB, Perlman S. Eicosanoid
signaling as a therapeutic target in middle-aged
mice with severe COVID-19. Nature. 605, 146-151,
2022.
Shibata T, Kawana H, Nishino Y, Ito Y, Sato H,
Onishi H, Kano K, Inoue A, Taketomi
Y, Murakami M, Kofuji S, Nishina H, Miyazawa
A, Kono N, Aoki J. Abnormal male reproductionand embryonic development induced bydownregulation of a phospholipid fatty
acid-introducing enzyme Lpgat1 in zebrafish. Sci
Rep. 12, 7312, 2022.
Liang L, Takamiya R, Miki Y, Heike K, Taketomi
Y, Sugimoto N, Yamaguchi M, Shitara H. Nishito
Y, Kobayashi T, Hirabayashi T, Murakami M.
Group IVE cytosolic phospholipase A2 limits
psoriatic inflammation by mobilizing theanti-inflammatory lipid N-acylethanolamine.
FASEB J. 36, e22301, 2022.
Taketomi Y, Miki Y, Murakami M. Old but new:Group IIA phospholipase A2 as a modulator of gut
microbiota. Metabolites. 12, 352, 2022. (Review)

20

Department of Physiological
Chemistry and Metabolism
Professor
Hiroki Kurihara, M.D.

Lecturer
Yukiko Kurihara, M.D.

Research Associate
Kazuo Tonami, M.D.

Associate
Yasunobu Uchijima, Ph.D.

URL http://bio.m.u-tokyo.ac.jp/home-j.html
Introduction and Organization
The Department of Physiological Chemistry andNutrition, the predecessor of the present department,
was founded in 1952. Upon the restructuring of theuniversity system in 1997, the department was
renamed ‘Department of Physiological Chemistry andMetabolism’ as one unit of the Specialty of Molecular
Cell Biology. The present members include the above
stuffs, 2 postdoctoral fellows, 4 graduate students(doctor course) and 1 secretary. Professor Tomoichiro
Asano (Hiroshima University) is invited as a part-time
lecturer to instruct graduate students and give lecturesto undergraduate students.

Teaching Activities
We give a series of lectures and laboratory courses
on biochemistry and molecular biology forundergraduate students from Faculty of Medicine andFaculty of Science. We also accept undergraduate
students taking the MD-researcher developing
program, “Free Quarter” and “Early-Exposureto-Medicine” courses every year. Several students arestaying in our lab beyond the term to join our
research.

For graduate students, we hold progress-reportmeeting and journal club every week, and sometimes
invite established scientists for seminar to encourage
scientific discussion.

Research Activities
Our research is aimed at understanding molecularmechanisms underlying morphogenesis of the craniofacial and cardiovascular structures.
(1) Craniofacial development
The branchial (pharyngeal) arches are a segmental
series of bulging structures common and characteristic
for all vertebrate embryos. They are mainly formed bymigratory cranial neural crests, which give rise tovarious skeletal components including the jaw andmiddle ear structures. We have revealed that
endothelin-1 (ET-1), first identified as anendothelium-derived vasoconstrictor peptide, and its
receptor ETAR signaling acts as a molecular switchthat determines the lower jaw identity by using mouse
genetics. In another work, we clarified that the
tympanic membranes of mammals and reptiles/birds
are independently acquired as a product of convergent
evolution by showing that lower-to-upper jaw

21transformation induced by inactivation of ET-1/ETAR
signaling results in loss of the tympanic membrane inmouse, but causes duplication of the tympanic
membrane in chicken. Recently, human ETAR genemutations causing craniofacial abnormalities andalopecia were identified, and the causal relationshipwas confirmed by our experiments recapitulating thesame mutations in mice. We are now collaborating
researchers in the field of molecular dynamics toclarify the mechanisms underlying the pathogenic
mutations.
Furthermore, we demonstrated that the therianmammal’s premaxilla (rostralmost upper jaw bone) is
derived from the maxillary prominence of themandibular arch through comparative morphologicaland developmental analyses. The developmental
primordium that produces the premaxilla innon-mammalian tetrapods rarely contributes to theupper jaw in therian mammals, but rather forms amotile nose. We propose that these previously
unrecognized rearrangements allowed key innovations,such as the highly sensible tactile perception andolfactory function, in mammalian evolution.
(2) Cardiac development
Recently, we found that the cranial neural crest
from the preotic region, rather than post-otic ‘cardiac’
neural crest cells, migrate into the heart anddifferentiate into coronary artery smooth muscle cells
in the proximal region. Ablation of the preotic neuralcrest in chick embryos causes abnormalities incoronary septal branch and orifice formation.
Appropriate migration and deployment of neural crest
cells and subsequent smooth muscle differentiation
require multicellular interactions involving ET-1/
ETAR signaling possibly through G12/13-mediated,
Dlx5/Dlx6-independet mechanisms, whereas ET-1/
ETAR signaling is involved in ventral identification of
the pharyngeal arches through Gq/11-mediated, Dlx5/
Dlx6-dependet mechanisms. These findings indicatethat the ET-1/ETAR signaling pathway is involved incraniofacial and cardiac development throughdifferent trimeric G-proteins.
(3) Angiogenesis
Angiogenesis is a morphogenetic process that
produces branching vascular structures during

embryogenesis and various (patho-)physiologicalconditions. We have identified characteristic cellularbehaviors in angiogenic processes, including dynamicchanges in forward-backward movement, tip cell
overtaking and resultant cell mixing. Although thecellular behaviors appear complex and arbitrary,different types of mathematical modeling (stochastic
vs. deterministic) and experimental verification
indicated that some deterministic cell-cell interactions
are critical for vascular elongation and possibly
branching. Recently, we found differences inbranch-forming capacity among cell types and someregularities in directional cell movement using in vitro
angiogenesis experiments using mouse vascularexplants and an endothelial cell line by refinedcell-tracking system. Together with single-cell
analyses of cell movement and gene expression, novel
mathematical modeling and experimental verification
using constitutional approaches are under way incollaboration with Professor Tetsuji Tokihiro(Graduate School of Mathematical Sciences, The
University of Tokyo) and his colleagues, to elucidate
the possible cellular mechanisms underlying branchformation in angiogenesis.

References
1.

2.

3.

Vu TH, Takechi M, Shimizu M, Kitazawa T,
Higashiyama H, Iwase A, Kurihara H, Iseki S.
Dlx5-augmentation in neural crest cells reveals
early development and differentiation potential ofmouse apical head mesenchyme. Sci. Rep.
11(1):2092, 2021.
Arima Y, Nakagawa Y, Takeo T, Ishida T, Yamada
T, Hino S, Nakao M, Hanada S, Umemoto T,
Suda T, Sakuma T, Yamamoto T, Watanabe T,
Nagaoka K, Tanaka Y, Kawamura YK, Tonami K,
Kurihara H, Sato Y, Yamagata K, Nakamura T,
Araki S, Yamamoto E, Izumiya Y, Sakamoto K,
Kaikita K, Matsushita K, Nishiyama K, Nakagata
N, Tsujita K. Murine neonatal ketogenesis
preserves mitochondrial energetics by preventing
proteinhyper-acetylation.
Nat
Metab.
3(2):196-210, 2021.
Maruyama K, Naemura K, Arima Y, Uchijima Y,
Nagao H, Yoshihara K, Singh MK, Uemura A,
Matsuzaki F, Yoshida Y, Kurihara Y, Wada Y,

22

4.

5.

6.

7.

8.

9.

Miyagawa-Tomita S, Kurihara H. Semaphorin3EPlexinD1 signaling is required for coronary
artery and lymphatic vessel development, withclinical implications in myocardial recovery.
iScience 24(4):102305, 2021.
Maruyama K, Naemura K, Yoshihara K,
Imanaka-Yoshida K, Kurihara H, MiyagawaTomita S. Surgical protocol for permanent
ligation of the left anterior descending coronary
artery in mice to generate a model of myocardial
infarction. STAR Protoc. 2(3):100775, 2021.
Higashiyama H, Koyabu D, Hirasawa T,
Werneburg I, Kuratani S, Kurihara H.
Mammalian face as an evolutionary novelty. Proc.
Natl. Acad Sci. U.S.A. 118(44): e2111876118,
2021.
Kurihara H, Mada J, Tokihiro T, Tonami K,
Ushijima T, Yura F. Angiogenesis: dynamics ofendothelial cells in sprouting and bifurcation. In
Mathematical Modeling for Genes to Collective
Cell Dynamics (ed. Tokihiro T. Springer,
Singapore) pp. 25-83, 2021.
Aouci R, Soudany ME, Maakoul Z, Fontaine A,
Kurihara H, Levi G, Narboux-Nême N. Dlx5/6
expression levels in mouse GABAergic neurons
regulate adult parvalbumin neuronal density andanxiety/compulsive behaviours. Cells 11(11):1739, 2022.
Higashiyama H, Koyabu D, Kurihara H.
Evolution of the therian face through complete
loss of the premaxilla. Evol. Dev. (in press)
Haneda Y, Miyagawa-Tomita S, Uchijima Y
Iwase A, Asai R, Kohro T, Wada Y, Kurihara H.
Diverse contribution of amniogenic somatopleural cells to cardiovascular development: withspecial reference to thyroid vasculature. Dev.
Dyn. (in press)

23

Department of Advanced
Structural Studies
Professor
Radostin Danev, Ph.D.

JSPS fellow
Fabian Eisenstein, Ph.D.

Homepage http://danevlab.m.u-tokyo.ac.jp
Introduction and Organization

Research activities

Our laboratory was established in 2018. We aresupported by grants from the Japan Science andTechnology Agency (JST), the Japan Society for the
Promotion of Science (JSPS) and Takeda Science
Foundation. Our research also benefits from indirect
support through an instrumentation facility grant fromthe Japan Agency for Medical Research andDevelopment (AMED). The lab members are Radostin
Danev (professor) and Fabian Eisenstein (JSPS
fellow).

Our research is aimed at elucidating the structurefunction relationships of proteins and cellularcomponents. Through our work, we hope to contributeto the fundamental knowledge about the molecularmechanisms behind chronic diseases, and thereby tohelp develop effective treatments.
For the past four years, we have been investigating animportant class of membrane proteins called G
protein-coupled receptors (GPCRs). GPCRs constitutethe largest family of membrane proteins in the humangenome. They are responsible for the detection andtransduction of many extracellular signals that
regulate various physiological processes across theplasma membrane. Because of their broad regulatory
functions, GPCRs are implicated in numerous chronic
diseases, such as diabetes, obesity, nervous systemdisorders, migraine, asthma, allergies, cardiovasculardisorders, cancer, and others. Consequently, they also
represent the biggest group of drug targets and are thesubject of more than 30% of approved drugs.
To understand the mechanisms of GPCR activationand signal transduction at the atomic level, we use themodern and very prolific method of cryo-EM single
particle analysis. In an ongoing international
collaboration with a group at Monash University inAustralia, which specializes in GPCR pharmacology
and has substantial experience in expression andpurification of target complexes, we are studying
receptor activation by both native and synthetic

Teaching activities
We conduct training and provide support for the usersof the recently opened cryo-electron microscopy(cryo-EM) facility at the Graduate School of Medicine.
This includes specialized lectures at cryo-EM courses
within the University of Tokyo and other research
institutions in Japan and abroad. We also give
introductory lectures about structural biology as partof the following programs:
1) MD scientist training program (MDSTP)
2) Master student class3) Ph.D. student guidance4) School of Medicine Introductory Lecture5) Biophysical Chemistry II course at the School of
Science24

ligands. In the past three years, our results comprise
more than 40 sub-3 Å unmodified full-length GPCR
structures, approximately half of which are at
resolutions better than 2.5 Å. This is an unprecedented
achievement in structural biology, both in terms of thenumber of structures and their resolution. Our successis not coincidental. To reach such a level of
performance, we conducted a careful systematicquantification and optimization of the cryo-EM
experimental parameters for sample preparation anddata collection. We adopted a highly efficientsynergistic experimental approach that combined datacollection from real samples with testing of individual
experimental factors. The method had the advantage
of not requiring extra observation time on the costly
and heavily booked electron cryo-microscopes. The
results from this work led us toward a better
experimental design and allowed us to routinely
produce sub-2.5 Å resolution results in our recent
studies. Most prominently, in the summer of 2020 wewere able to produce the first sub-2 Å resolution
reconstructions of GPCR complexes.
2020 was also the year when true cryo-EM atomic
resolution (~1.2 Å) was demonstrated by two groups
in the UK and Germany with “easy” test samples. In
their experiments, they used newly developed
hardware components to achieve such performance.
We were also able to reach very similar (~1.3 Å)
resolution while testing the newly installed Krios G4
microscope at our facility, which has an“off-the-shelf” configuration and does not containspecial hardware. The exceptional results from ourgroup and many other groups that utilize thestate-of-the-art cryo-EM facility at the University ofTokyo showcase both the accelerating evolution of
cryo-EM as a technique and the great success andproductivity of the facility.
Despite the rapid growth of the cryo-EM field, there
are still many areas where further advances are
possible and/or needed. To address such quiescentareas, in addition to our GPCR structural studies weare working on the development of new experimental
methods for cryo-EM. One of our current projects
aims to develop and implement a high-speed real-timesynchronous modulation of the electron beam that will
expand the capabilities of the microscope. With theso-called FADE method (fast and accurate defocus

modulation), we hope to transform the instrumentfrom a static and rigid system into a dynamic andtunable optical platform. This will give researchers
more freedom to tune their experiments for optimal
performance. We finished the development andconstruction of the first FADE hardware prototype,and it is already installed on one of the microscopes at
the facility (JEOL JEM-F200). After initial testingwith non-biological test samples and resolving several
practical issues, the FADE system is now fully
operational, and we have started collecting FADE
datasets of biological cryo-samples. Hardware-wise,
the system performs as expected and produces data ofhigh quality. The main challenge at present is theanalysis of the data. All existing software packages forcryo-EM data processing are designed forconventional constant defocus data. To process FADE
data, we must modify or write our own dataprocessing routines and we are currently working inthis direction.
Other areas of our research include cryo-electron
tomography (cryo-ET) of cellular samples, in
combination with advanced sample preparation
through cryogenic focused ion beam milling(cryo-FIB). The ability to observe proteins andcomplexes in their native environment within a cell,“in situ”, offers tremendous opportunities for
fundamental biological, pharmacological, and medical
contributions. Nevertheless, the cryo-ET field is stillin its infancy and there are multiple challenges related
to sample preparation and data acquisition. This
makes the research even more interesting andrewarding. In the coming years, we hope to makecontributions to the methodology and achievements ofcryo-ET and help to one day reach the ultimate(utopian) goal of “visual proteomics”; where
researchers will be able to identify each individual
protein and its interactions with neighboring proteins
within an electron cryo-tomogram of a cellularvolume.
In the near future, we plan to expand ourinvestigations towards state-of-the-art deep learning
experiment automation for both cryo-EM single
particle analysis and cryo-electron tomography. Deeplearning (DL) methods have become ubiquitous, and it
is surprising that at present there are no DL-based
automation frameworks for cryo-EM and cryo-ET.

25

Currently, many steps during an experiment are
performed manually. Most of these actions involve
image evaluation and feature recognition and are
therefore perfect candidates for DL algorithms, whichhave already proven to be capable of human-level
performance in such tasks. With more automation, theexperiments will become more efficient, for example,
allowing researchers to easily operate the microscopes
remotely while working on other important tasks. The
quality and amount of data will improve and thereby
the level and number of scientific results will increase.

7.

8.

References
1.

2.

3.

4.

5.

6.

Josephs TM, Belousoff MJ, Liang YL, Piper SJ,
Cao J, Garama DJ, Leach K, Gregory KJ,
Christopoulos A, Hay DL, Danev R, Wootten D,
Sexton PM. Structure and dynamics of the CGRP
receptor in apo and peptide-bound forms. Science.
2021 Apr 9;372(6538):eabf7258.
Danev R. Practical considerations: defocus,
stigmation, coma-free illumination, and phase
plates. In: Glaeser RM, Nogales E, Chiu W,
editors. Single-particle Cryo-EM of Biological
Macromolecules. IOP Publishing. 2021
Mobbs JI, Belousoff MJ, Harikumar KG, Piper
SJ, Xu X, Furness SGB, Venugopal H,
Christopoulos A, Danev R, Wootten D, Thal DM,
Miller LJ, Sexton PM. Structures of the humancholecystokinin 1 (CCK1) receptor bound to Gs
and Gq mimetic proteins provide insight intomechanisms of G protein selectivity. PLoS Biol.
2021 Jun 4;19(6):e3001295.
Zhang X, Belousoff MJ, Liang YL, Danev R,
Sexton PM, Wootten D. Structure and dynamics
of semaglutide- and taspoglutide-bound GLP1R-Gs complexes. Cell Rep. 2021 Jul 13;36(2):109374.
Danev R, Belousoff M, Liang YL, Zhang X,
Eisenstein F, Wootten D, Sexton PM. Routine
sub-2.5 Å cryo-EM structure determination of
GPCRs. Nat Commun. 2021 Jul 15;12(1):4333.
Draper-Joyce CJ, Bhola R, Wang J, Bhattarai A,
Nguyen ATN, Cowie-Kent I, O'Sullivan K, Chia
LY, Venugopal H, Valant C, Thal DM, Wootten D,
Panel N, Carlsson J, Christie MJ, White PJ,
Scammells P, May LT, Sexton PM, Danev R,

9.

Miao Y, Glukhova A, Imlach WL, Christopoulos
A. Positive allosteric mechanisms of adenosine
A1 receptor-mediated analgesia. Nature. 2021
Sep;597(7877):571-576.
Zhang X, Johnson RM, Drulyte I, Yu L, Kotecha
A, Danev R, Wootten D, Sexton PM, Belousoff
MJ. Evolving cryo-EM structural approaches for
GPCR drug discovery. Structure. 2021 Sep 2;29(9):963-974.e6.
Johnson RM, Zhang X, Piper SJ, Nettleton TJ,
Vandekolk TH, Langmead CJ, Danev R, Sexton
PM, Wootten D. Cryo-EM structure of the dual
incretin receptor agonist, peptide-19, in complex
with the glucagon-like peptide-1 receptor.
Biochem Biophys Res Commun. 2021 Nov 12;
578:84-90.
Danev R, Yanagisawa H, Kikkawa M. Cryo-EM
performance testing of hardware and dataacquisition strategies. Microscopy (Oxf). 2021
Nov 24;70(6):487-497.

Functional Biology
1. Physiology

27

Department of Integrative
Physiology
Professor
Kenichi Ohki, M.D., Ph.D.

Homepagehttps://physiol1.m.u-tokyo.ac.jp/ern24596/en/

Introduction
This laboratory was initially established in 1877 as
The First Department of Physiology, and reorganizedin 1997 as Laboratory of Integrative Physiology in the
Department of Physiology. Our laboratory cooperates
with other laboratories in the Department of
Physiology, that is, Laboratory of Molecular/Cellular
Physiology and Laboratory of Neurophysiology, inteaching activities for undergraduate courses and thenursing school. The fields in which our laboratory
specializes span the entire spectrum of animalfunctions of physiology, including general physiology,
sensory physiology, endocrinology, neurophysiology,
higher nervous functions and cognitive neurosciences.

Teaching activities
The staff members as well as experts from otheruniversities take part in giving lectures and laboratory
courses to the undergraduate students of the Medical
School. The lectures are aimed at providing a clear
understanding of the hierarchical functional organizations of living systems. The curriculum is updated
every year. For example, a new electrocardiogram
experiment in humans was introduced to thelaboratory course, in which students learned humanphysiology of electrocardiogram, its practicalprocedure in clinical settings and its cellularphysiological origins. This practice gained popularity
and interest among students. We accept Free-Quarter
students every year. Usually these students' activities
are not limited to one Quarter. Some of these students
completed their own projects, and gave oralpresentations in international meetings and publishedoriginal papers in top-rank international journals. It is
not rare that students who enjoyed his/her
Free-Quarter decided to get into the Ph-D. course
after the completion of the 2-year clinical training andstarted to study neurophysiology in our laboratory.
Furthermore, we accepted a Ph-D.-M.D course student
who enjoyed his Free-Quarter and decided to get into
the Ph-D.-M.D course. Thus the Free-Quarter system
has proved to provide an excellent basis for bringing
up M.D. researchers for future Japanese basic
medicine.
To facilitate communication among research groups
in our laboratory, a weekly conference is held for
discussing current research activities. We also have amonthly joint seminar with Department of Pharmacology. As a part of teaching activity for the graduate
students, we have another weekly seminar, in which
the graduate students learn how to give presentations
and hold discussions and debates.

Research activities
Most of our research is focused on the higher brain
function of the mammalian central nervous system.
(1) Integration of information processed separately in
distributed brain regions is essential for brain function.
This integration is supported by long-range projection
neurons that connect distant brain regions.
Information that long-range projection neurons send
to their projection targets depends on the cooperativeinteractions among these neurons. However, how thisinteraction is realized in cortical circuits is not wellunderstood. We investigated this interaction using

28

callosal projection neurons (CPNs) in layer 2/3 ofmouse visual cortex as a model of long-range
projections.
Retrograde dye was injected into the visual cortex
of one hemisphere, and CPNs in the opposite
hemisphere were retrogradely labeled. Subsequently,
using two-photon calcium imaging, visual response
properties were compared between CPNs and othercells (non-CPNs). In the non-CPNs, many cells
responded to visual stimuli presented on thecontralateral eye or on both eyes, and fewer cells
responded selectively to the stimuli to the ipsilateraleye. In contrast, some CPN responded selectively tovisual inputs from the ipsilateral eye. In addition, CPN
cell pairs showed more synchronized activity
compared to other pairs, CPNs -non-CPNs or pairs of
non-CPNs. To examine synaptic connections between
CPNs, we conducted patch-clamp recording from cell
pairs in the brain slice preparation. We found more
direct synaptic connections in the pairs of CPNs thanother cell pairs.
These results indicate that CPNs form a functional
network through direct synaptic connections between
CPNs. The results also suggest functional networks
dependent on the projection target as a universal
property of the cortical network.
(2) The cerebral cortex is characterized by a cluster ofneurons with similar response properties. Although
there exist functional maps (functional architectures)such as orientation selectivity columns in the primaryvisual cortex (V1), the functional architecture of color
information has not been well understood in primates.
In V1, the CO blob (blob) is known as ahistologically identified structure. Since many cells
within the blob show color selective responses, it isthought that the blob corresponds to a functionalarchitecture dedicated to color representation. Intrinsic
imaging that has a low spatial resolution support thisview, whereas some electrophysiological studies could
not identify clear cluster of color selectivity neurons
corresponding to the blob. Thus, the functionalarchitecture of color representation has not been
confirmed. We therefore performed two-photon
calcium imaging to investigate fine arrangements ofthe functional architecture of color representation inmonkey V1.

We examined color responses using spatially
uniform color stimuli and found that neurons
responding to the color stimuli formed clusters thatcoincided with blobs. Furthermore, these clusters hadcolumnar substructures, each composed of a
population of cells with specific color selectivity.
Cells within the blob are known to respond well to
low spatial frequency stimuli. Color selectivity
neurons also respond to lines or bars with specificorientations. Therefore, the above results could be
attributed to the use of spatially uniform stimuli.
Therefore, we used oriented, drifting color stimuli.
These stimuli revealed the clusters built on the same
substructural framework but with larger subdomains
beyond blobs.
These results suggest that V1 has a functionalarchitecture for color representation that switches
between blobs and blob/interblob system based on
spatial structure of the visual scene.

References(1) Kenta Hagihara, Ayako Wendy Ishikawa,
Yumiko Yoshimura, Yoshiaki Tagawa, Kenichi
Ohki. Long-Range Interhemispheric Projection
Neurons Show Biased Response Properties andFine-Scale Local Subnetworks in Mouse Visual
Cortex Cerebral Cortex, 2021, 31 (2),1307–1315.
(2) Soumya Chatterjee, Kenichi Ohki, R Clay Reid
Chromatic micromaps in primary visual cortex
Nature Communications, 2021, 12(1):2315, 1-9.

29

Department of Cellular andMolecular Physiology
Professor
Masanori Matsuzaki, Ph.D.

Lecturer
Teppei Ebina, Ph.D.

Research Associate
Shin-Ichiro Terada, Ph.D.
Masashi Kondo, Ph.D.

Homepage

http://plaza.umin.ac.jp/~Matsuzaki-Lab/

Introduction and Organization

Research activities

The Department of Cellular and Molecular Physiology
succeeded the former ‘Second Department of Physiology’, and belongs to the Department of Physiology.
We participate in the teaching of physiology atundergraduate school and graduate school.
The present members include the above staff, 1secretary staff, 4 technical staff, 1 project research
associate, 6 graduate students.

Various firing patterns of many cortical neurons
represent information processing in the brain. The
microarchitecture of synaptic connections control
information processing in cortical circuits. The
structure and location of synapses determine andmodify the strength of this information processing.
The aim of our laboratory is to reveal how information
is formed, maintained, selected, and decoded in thebrain at the levels of single cells and of single
synapses. To do so, we mainly use two-photon
microscopy that allows us to see fluorescence signals
from deep within living tissue, developing novel
photostimulation methods and animal behavioral tasks.
The goals of our recent studies are to reveal how
voluntary movement is memorized and represented incortical circuits. In addition, we are working to apply
two-photon microscopy to a non-human primate, thecommon marmoset, in order to understand information processing in the brain, which is relevant tohigh cognitive functions.

Teaching activities
The department provides lectures and practice inphysiology for undergraduate students. We teachimaging, computational neuroscience, and cellular andmolecular physiology methods for free quarter
students. The department provides also lectures andinstructions for laboratory research for graduate andundergraduate students in the fields of neurophysiology and molecular and cellular imaging.
Seminars, progress reports, and journal club forgraduate students are routinely provided. Monthly
joint seminars (Functional Biology Seminars) are also
provided for graduate students.

(1) Neuronal representations of reward-predicting
cues and outcome history with movement in thefrontal cortex

30

The transformation of sensory signals to action is
crucial for survival in all animals. An outcome
following a sensory signal updates the value of thesensory signal. This updated value is then used in thenext response to the same sensory signal to evoke a
specific action to obtain or avoid an outcome. In
decision-making tasks that require goal-directedactions to successfully receive a reward, task-related
and movement-related activities are widely distributed
over the whole dorsal neocortex and whole brain.
To clarify action-type-independent decision-makingrelated information in M2, which plays critical roles invalue estimation, action selection, working memory,and motor planning in the rodent, it is necessary tomeasure the activities of individual neurons within
subdivisions of M2 during simple tasks and to analyze
how individual neurons encode the multiple types of
information. We assumed that the neuronal
representations of the cue value and outcome
information in classical conditioning, a condition that
does not require the learning of an association
between a specific action and its consequence, is thebasis for the processes of the transformation of
sensory cues to appropriate motor actions.
To extract these information types, we trained
head-fixed mice to perform a classical conditioning
task with two sound cues assigned to different
probabilities of water delivery. In addition, in the latestage of learning, we conducted two-photon calcium
imaging of three dorsal frontal areas up to a depth of
800 μm from the cortical surface (dorsomedial frontal
cortex [dmFrC], dorsolateral frontal cortex [dlFrC],
and M1 corresponding to the caudal forelimb motorarea, and the medial prefrontal cortex at depths of
800–1200 μm (mPFC). Although licking movement
dominated the area-averaged activity over the wholedorsal neocortex, dmFrC affected other dorsal frontal
cortical activities, and its inhibition extinguisheddifferences in anticipatory licking between the cues.
Many dorsal frontal and medial prefrontal corticalneurons were task-related. Approximately 40% ofthem were more excited by the low-reward-predicting
cue or unrewarded outcomes than by thehigh-reward-predicting cue or rewarded outcomes,
respectively. Task-related activities of these neurons
and the others were counterbalanced, so that
population activity appeared dominated by licking.

The reward-predicting cue and outcome history weremost strongly represented in dmFrC.
The Granger causality analysis of the cortex-wide
neuronal activity suggests a flow of licking-unaffected
information from dmFrC to dlFrC and M1 during thecue period. The photoinhibition experiment showedthat the inhibition of dmFrC increased the anticipatory
licking in cue B trials more than it did in cue A trials.
The regression model and clustering analysis ofindividual neuronal activity suggest that the
proportion of neurons that were more active during
presentation of cue B than during presentation of cue
A was highest in dmFrC. From these results, we
propose that dmFrC played a critical role in
suppression of the anticipatory licking in cue B trials,
and generally, that dmFrC neurons can initiate otherdorsal frontal cortical activity in the decision-making
process, on the basis of the cue value. Our results alsosuggest that the balance of distinct subsets of neurons
that are active in response to a cue value (or outcome)and a second cue (or outcome), which were observed
even in the condition without appropriate action
selection, are the foundation for decision-making
processes over time.
(2) Calcium imaging of the neural activity
underlying mismatch negativity in common
marmosets
Auditory mismatch negativity (MMN) is an
event-related potential that reflects the preattentive
detection of changes in repetitive and predictive tone
sequence. The amplitude of the MMN is attenuated in
psychotic disorders, including schizophrenia, and thus
is a promising biomarker of these disorders (Näätänen,2003). Indeed, human electroencephalography studies
suggest that the duration of mismatch negativity(dMMN), which is generated by changes in the
duration of the presentation stimulus of an oddballtask, can be used for early diagnosis of schizophrenia(Koshiyama, et al., 2017). However, electroencephalography is not sufficient to reveal how thedMMN is represented at the neural circuit level inauditory cortical areas because of the limited spatial
resolution. To investigate the special processing
mechanisms of dMMN responses in auditory corticalareas, we applied one-photon and two-photon calcium
imaging to record neuronal activity in common

31

marmosets. Marmosets are known as a highly vocal
primate species and have three hierarchicallyconnected auditory areas (core, belt, and parabelt),similar to that in humans. Moreover, these areas are
suitable for calcium imaging because the surface ofthe marmoset auditory cortex is outside the lateralsulcus.
We have shown the functional maps and dMMN
responses of the core auditory areas. First, we
obtained the best frequency maps in awake marmosets.
The tonotopic organization of the maps was consistent
with previous studies utilizing other recording
methods (extracellular recording [Bendor & Wang,2008], voltage-sensitive dye imaging [Nishimura, etal., 2017], and intrinsic signal imaging [Tani, et al.,2018]). The cellular frequency selectivity within thesame local region at different focal depths was alsosimilar to that described previously (Zeng, et al.,2019). Second, the deviance detection responses in thedMMN tasks were clearly detected by one-photon
calcium imaging, and the responses at each imaging
region were induced by its best frequency. The
responses were also recorded from layers I and II/III
of the core region by two-photon imaging. Third, we
found that subanesthetic doses of ketamine inhibitedthe calcium responses for deviance detection. This
study provides new insights into the spatial
representation of neural activities for deviancedetection in primate brain.
(From abstract in the 44th Annual Meeting of theJapan Neuroscience Meeting)(3) Super-wide-field high-speed two-photon
imaging and photo-manipulation microscopy ofbrain activity
Brain activity consists of the coordinated activity of avery large number of neurons. Each region of thebrain processes different information and transfers thecomputed information to another region. Therefore, tounderstand information processing in a local region, it
is necessary to measure many neuronal activities inthat region simultaneously, and to understandinformation processing for the output of individualfunctions such as behavior, it is necessary to measureneuronal activities in multiple regions simultaneously.
We reported an super-wide-field two-photon
microscope in 2018 that makes this possible, and in

this study we have accelerated this imaging andestablished a 10 Hz imaging method with two fields ofview that are separated. The rotation method of thesmall device, which is placed between the objective
lens and the cortical surface to move the field of view,
was changed from the three-stage gear systempresented in 2018 to a belt system. This was achievedby improving elemental components to optimize
operation, such as minimizing vibration during
rotation. A recently developed photodetector that isdurable to visible light incidence stronger than
fluorescence intensity and an LED light source were
newly introduced to the microscope system. Afterevaluating
thedetector's
over-responsetophotostimulation, we developed a method to detect
neuronal response activity at a video rate without
detector over-response by strictly controlling thetiming of photostimulation. By optimizing theexpression of molecular probes for optogenetics andcalcium probes, as well as the stimulation lightintensity and conditions for simultaneous imaging, wewere able to increase the efficiency ofphotostimulation and obtain responses with a highsignal-to-noise ratio.
We demonstrated that these methods can be applied tothe measurement and manipulation of neuronal
activity in mouse M2 and M1. We trained head-fixed
mice to perform a task in which pulling a lever withthe right forelimb was rewarded with a water reward.
We expressed light-responsive proteins in the motor
cortex neurons of these mice using adeno-associatedviruses (AAVs). Simultaneous measurement of M2
and M1 activity during task execution (10 Hz
continuous measurement) and statistical analysis of
the activity allowed us to quantitatively demonstrate
the hierarchy of activity (time course of activity,
pattern of pre-motor activity, amount of cellular
activity information, etc.). Both regions represented
well the forelimb motor information, but themodalities differed not only in single cells but also in
populations. We also demonstrated that transient
manipulation of the neuronal activity input to M2 canalso induce changes in M2 neuronal activity andbehavior according to the timing of the manipulation.
(4) Development of an automated injection robotthat enables wide-field calcium imaging of more32

than 10,000 neurons
Robotics has played a major role in the advancementof biological research over the past few decades. In
the neurosciences, experimental manipulations, suchas craniotomy, whole-cell patch clamping, andelectrode implantation, have been automated, ensuring
not only stable and accurate operations, but also
facilitating the spread of advanced neurotechnology.
The injection of AAVs is one of the most commonlyused experimental manipulations in the neurosciences.
However, despite it being a time-consuming techniquerequiring considerable skill on the part of the operator,
there have been no reports of its automation so far.
We constructed an automated virus injection robotthat enables precise and repetitive injection. There
were two major challenges that had to be overcome todevelop this injection robot, namely individual
differences in brain surface and preservation of thevascular network. We overcame the former bymeasuring the brain surface with an infrared-distancesensor precisely controlled by a multi-axis robot, andthe latter by adopting an image recognition technologythat recognizes blood vessels and an algorithm that
distributes injection sites in a spatially even pattern
without damaging vessels.
To demonstrate the utility of this new methodology,
we conducted wide-field Ca2+ imaging of mice
multi-site injected with a Ca2+ indicator. By injecting asmall amount of undiluted AAV solution into morethan 100 sites in a 6 × 8 mm2 area of the dorsal
cerebral cortex, we were able to deliver AAV widely
and uniformly. Furthermore, owing to the precise andfast manipulation of the robot, each injection cycle
took only about 20 seconds to complete, and all the
injection cycles took about one hour. We also
succeeded in recording cellular-level signals from
more than 10,000 neurons simultaneously in a single
focal plane using an epifluorescence microscope.
The application of this system is not limited towide-field Ca2+ imaging in mice. This approach would
be applicable not only to other animals, such as
marmosets or macaques, but also to the monitoring ofa wide range of sensor proteins.”(From abstract in the 44th Annual Meeting of theJapan Neuroscience Meeting)

References
1.

2.

3.

4.

Matsuzaki M. and Ebina T. Optical deep-cortex
exploration in behaving rhesus macaques. Nature
Communications 12, 4656, 2021. (Comment)
Inoue T., Terada S., Matsuzaki M., and Izawa J.A
small-scale robotic manipulandum for motor
control study with rodents. Advanced Robotics
35, 898-906, 2021.
Kondo M. and Matsuzaki M. Neuronal
representations of reward-predicting cues andoutcome history with movement in the frontal
cortex. Cell Reports 34, 108704, 2021.
Okamoto K., Ebina T., Fuji N., Konishi K., SatoY., Kashima T., Nakano R., Hioki H., Takeuchi
H., Yumoto J., Matsuzaki M., and Ikegaya Y.
Tb3+-doped fluorescent glass pipettes for biology.
Science Advances 7, eabd2529, 2021.

33

Department of Neurophysiology
Professor
Masanobu Kano, M.D., Ph.D.

Research Associate
Takaki Watanabe, Ph.D.

Research Associate
Kazuto Sakoori, Ph.D.

Homepage

http://plaza.umin.ac.jp/~neurophy/

Introduction and Organization
This laboratory was founded in 1953 as Departmentof Neurophysiology, Institute for Brain Research. In
1997, it was integrated into Graduate School of
Medicine. The current members of this laboratory are
4 faculty members (professor, lecturer, 2 research
associate), 1 postdoctoral fellows, 8 graduate students,
7 technicians. We teach neurophysiology for medical
undergraduates and for students in the Master andPh.D. courses. Our research aims at elucidating
cellular and molecular mechanisms underlying
regulation of synaptic transmission and postnatal
development of neuronal circuits.

Teaching activities
We teach neurophysiology for medical undergraduates in lectures and practical courses. Lectures
are designed for students to learn basic mechanisms
underlying the generation of electrical signals,
synaptic transmission and their regulations in the
nervous system and roles of the spinal cord, brain
stem and cerebellum in sensori-motor functions.
Students also learn how functional neural circuits inthe brain are formed and matured during postnatal
development. In the practical courses, students
perform two types of classical experiments ofneurophysiology. First, students make intracellular
recording from frog skeletal muscle fibers andexamine the endplate potential for understanding basic

properties of synaptic transmission. Second, students
record electromyogram (EMG) from humangastrocnemius muscles and learn how the stretch
reflex works.
We accept Free-Quarter students. Students areencouraged to experience patch-clamp recordings
from neurons either in brain slices or in dissociatedcultures, or to experience recordings of neuronal
activities from living animals.
For the training of Master and Ph.D. course students,
we have a weekly conference for discussing current
research activities. A laboratory member summarizes
his/her recent experimental data or presents papers
closely related to his/her research.

Research activities
The brain consists of neuronal circuits in which
neurons are connected through numerous synapses. To
understand the brain function, it is necessary to
elucidate mechanisms of synaptic transmission andthose underlying changes in synapses related todevelopment, learning and memory (synaptic
plasticity). We take various methodological approaches including electrophysiology, pharmacology,
morphology, and genetic engineering of mouse. We
particularly focus on observing neuronal activities inreal time in intact neurons. We use whole-cell patch
clamp recording, calcium imaging, two-photon imaging and their combinations in various preparations(cultured neurons, brain slices and intact animals) and34

investigate molecular mechanisms of synaptic transmission and plasticity.
The main subjects of our research are as follows(1) Refinement of synaptic organization during
cerebellar development:
In early postnatal days, all Purkinje cells in the
cerebellum are innervated by multiple climbing fibers.
These surplus climbing fibers are eliminatedeventually with the progress of postnatal development,
and most Purkinje cells become innervated by single
climbing fibers by the end of the third postnatal weekin mice. We investigate the mechanisms how single
climbing fibers are selected and how the surplus
climbing fibers are eliminated.

(3)(2) Retrograde synaptic modulation mediated byendogenous cannabinoids:
We reported in 2001 that endogenous cannabinoids
are released from postsynaptic neurons in an
activity-dependent manner, act retrogradely onto
presynaptic cannabinoid receptors and suppress
transmitter release. Since then, we have been
investigating the mechanisms of this retrograde
modulation. We are also interested in elucidating thephysiological significance of this phenomenon
including learning and memory, addiction, andanxiety.

(4)(3) Synaptic integration in intact animals:
To understand the physiological function ofsynapses in vivo, we analyze synaptic transmission
and integration in single neurons in the intact brain byusing in vivo two-photon imaging and whole-cellrecording. We also develop new methods toimplement these experiments.

(6)

References(1) Tsujimura A, Kamae Y, Kawasaki H, Nagai H,
Kano M, Tabata T. Carbon powder-filled
microelectrode: An easy-to-fabricate probe forcellular electrochemistry. Anal Biochem. 2021
Sep 15;629:114316. doi: 10.1016/j.ab.2021.
114316. Epub 2021 Jul 24.
(2) Lai ESK, Nakayama H, Miyazaki T, Nakazawa T,
Tabuchi K, Hashimoto K, Watanabe M, Kano M.

(5)

(7)

(8)

An autism-associated neuroligin-3 mutation
affects developmental synapse elimination in the
cerebellum. Front Neural Circuits. 2021 Jun
28;15:676891. doi: 10.3389/fncir.2021.676891.
eCollection 2021.
Toriumi K, Berto S, Koike S, Usui N, Dan T,
Suzuki K, Miyashita M, Horiuchi Y, Yoshikawa
A, Asakura M, Nagahama K, Lin HC, Sugaya Y,
Watanabe T, Kano M, Ogasawara Y, Miyata T,
Itokawa M, Konopka G, Arai M. Combined
glyoxalase 1 dysfunction and vitamin B6
deficiency in a schizophrenia model systemcauses mitochondrial dysfunction in theprefrontal cortex. Redox Biol. 2021 Sep;45:102057. doi: 10.1016/j.redox.2021.102057. Epub
2021 Jun 24.
Yamasaki M, Aiba A, Kano M, Watanabe M.
mGluR1 signaling in cerebellar Purkinje cells:
Subcellular organization and involvement in
cerebellar function and disease. Neuropharmacology. 2021 Aug 15;194:108629. doi:
10.1016/j.neuropharm.2021.108629. Epub 2021
Jun 4.
Song B, Kang CY, Han JH, Kano M, Konnerth A,
Bae S. In vivo genome editing in single
mammalian brain neurons through CRISPR-Cas9
and cytosine base editors. Comput Struct
Biotechnol J. 2021 Apr 25;19:2477-2485. doi:
10.1016/j.csbj.2021.04.051. eCollection 2021.
Nagahama K, Fujino S, Watanabe T, Uesaka N,
Kano M. Combining electrophysiology andoptogenetics for functional screening ofpyramidal neurons in the mouse prefrontal cortex.
STAR Protoc. 2021 Apr 15;2(2):100469. doi:
10.1016/j.xpro.2021.100469. eCollection 2021
Jun 18.
Nagao S, Hirai H, Kano M, Yuzaki M. Masao
Ito-A Visionary neuroscientist with a passion forthe cerebellum. Neuroscience. 2021 May 10;
462:1-3. doi: 10.1016/j.neuroscience.2021.02.
028.
Carrier-Ruiz A, Sugaya Y, Kumar D, Vergara P,
Koyanagi I, Srinivasan S, Naoi T, Kano M,
Sakaguchi M. Calcium imaging of adult-bornneurons in freely moving mice. STAR Protoc.
2020 Dec 31;2(1):100238. doi: 10.1016/j.xpro.
2020.100238. eCollection 2021 Mar 19.

Functional Biology
2. Pharmacology

36

Department of Cellular
and Molecular Pharmacology
Professor
Kenzo Hirose, M.D., Ph.D.

Lecturer
Shigeyuki Namiki, Ph. D., Daisuke Asanuma, Ph. D.

Assistant Professor
Hirokazu Sakamoto, Ph. D.

Homepage

http://www.pharmacol.m.u-tokyo.ac.jp

Introduction and Organization
Our department was founded in 1885 andcollaborates with the Department of Systems
Pharmacology in the education of undergraduate
medical students.

Teaching activities
Pharmacology lectures and laboratory courses forthe medical students are given by the staff members ofboth Departments of Pharmacology. We also invite
seven outside expert lecturers to cover rapidly
developing fields in pharmacology and related
medical sciences. The laboratory courses include bothtraditional and advanced pharmacological experiments.
A new intensive laboratory course for medical
students started in the year 2001, and we participatedin the program. We also give lectures for graduate
students including master course students and Ph.D.
candidates.

Research activities
A goal of our research is to elucidate regulation
mechanisms of cell function through the developmentof novel technologies. The main subjects of ourresearch are as follows.

1) Development of high-performance fluorescenceprobes for visualizing neurotransmitters
Imaging techniques which visualize neurotransmittersin living neurons are powerful methods to understandthe mechanism underlying synaptic transmission inneuronal circuits. To facilitate this process, wedeveloped a high-throughput screening system basedon 96-well plate format protocol. After screening, we
obtained high-performance glutamate probes showing
large fluorescence changes upon glutamate binding.
This result indicates that our screening system should
be applicable to develop fluorescence probes for
signaling molecules other than glutamate in shortperiods.
2) Study of the mechanism underlying the exocytosisof neurotransmitterFor understanding of regulation mechanism
underlying neuronal circuit in mammalian central
nervous system, elucidation of the neurotransmitter
release machinery is indispensable. Aiming at imaging
neurotransmitter glutamate, we developed a novel
optical glutamate probe by our high-throughput
screening system as described above. Using this probe,
we successfully visualized presynaptically released
glutamate with a single synapse resolution in cultured
hippocampal neurons. We quantitatively analyzed
released glutamate at individual synapses and revealed37

that single hippocampal synapses contain several
release units. Furthermore, we have succeeded in
imaging spatiotemporal dynamics of glutamate in theextrasynaptic space in brain slices and in vivo. This
study demonstrated that bursting synaptic activities
cause glutamate spillover from the synaptic cleft toactivate perisynaptic metabotropic glutamate receptors,
and will provide a basis for the research of
extrasynaptic glutamate transmission that is involvedin many important brain functions. These results
indicate that our glutamate probe is useful to directly
assess synaptic functions including presynaptic
modulation and plasticity.
3) Analysis of supra-molecular assemblies ofsynaptic molecules in central synapse
Recently, nanoscale molecular distribution in synapses
is suggested to be a key determinant of synaptic
function. To reveal the relationship between the nanoscale molecular assemblies and synaptic functions, weare trying to perform a super resolution microscopic
analysis in combination with glutamate imaging.
These advanced imaging techniques revealed thatdynamics of neurotransmitter release is precisely
controlled by the highly coordinated nanoscale
molecular assemblies of presynaptic molecules. We
are also trying to identify the functional changes innanoscale molecular assemblies in psychiatric diseasemodel.

References
1.

2.

3.

Aritake T, Hino H, Namiki S, Asanuma D, Hirose
K, and Murata N. Fast and robust multiplane
single molecule localization microscopy using
deep neural network. Neurocomputing, 451,
279-289 (2021)
Kitajima N, Takikawa K, Sekiya H, Asanuma D,
Sakamoto H, Namiki S, Iino M and Hirose K. In
vivo Fluorescence Imaging of Extracellular ATP
in the Mouse Cerebral Cortex with a Hybrid-type
Optical Sensor. Bio-protocol, 11, e4046 (2021)
Takagi, T., Ueno, T., Ikawa, K., Asanuma, D.,
Nomura, Y., Uno, S., Komatsu, T., Kamiya, M.,
Hanaoka, K., Okimura, C., Iwadate, Y., Hirose,K., Nagano, T., Sugimura, K. & Urano, Y.
Visualization and manipulation of actin

4.

cytoskeleton with small-molecular probes. Sci.
Adv. 7(47), eabg8585 (2021).
Endo, Y., Asanuma, D., Namiki, S., Hirose, K.,
Uemura, A., Kubota, Y., & Miura, T. Quantitativemodeling of regular retinal microglia distribution.
Sci. Rep. 11, 22671 (2021).

38

Department of Systems
Pharmacology
Professor
Hiroki R. Ueda, M.D., Ph.D.

Project Associate Professor
Yoichi Minami, Ph.D.

Full-time Lecturer
Koji L. Ode, Ph.D.

Research Associate
Shoi Shi, Ph.D., Daisuke Tone, Ph.D.

Project Research Associate
Ningyuan Wang, Ph.D., Yasuhiro Tomita, M.D., Ph.D.

Homepagehttps://sys-pharm.m.u-tokyo.ac.jp/

Teaching activities
Our department, in collaboration with the department of cellular and molecular pharmacology, takes
responsibility for lectures and laboratory courses on
pharmacology for the undergraduate students of thefaculty. There are 39 lectures per year including thosegiven by seven invited lectures to cover specialized
and currently highlighted fields in pharmacology. We
offer several laboratory courses, and all the membersof the department participate in the courses to provide
close consultation for the students.
For the graduate students, there are series ofseminars on physiology and neuroscience. We also
have research seminars to discuss and stimulate theresearch activities of the graduate students in thedepartment.

Research activities
Department of systems pharmacology is conducting
research to establish organism-level systems biology
and pharmacology using sleep-wake cycle as a model
system, which is common to organisms with a central

nervous system and one of the main factors that
dictate the dynamics of social behavior. With ourmembers from different backgrounds, we would liketo realize systems biology at the organism level
including human, leading to greater understanding andeven control of organismal pathophysiology. To thisend, we specifically focus on the cellular circuits
controlling the sleep/wake cycle and address thehourglass mechanism of sleep, a homeostatic- andcircadian-dependent regulation of sleep amount andtiming. We are also planning on multi-scale research
activities covering a series of length scales;
molecule-to-cell, cell-to-tissue, and tissue-to-organism
to envision such complicated underlying mechanism.
We have been devoting our research to twotechnological challenges; 1) next-generation mammalian reverse genetics, where we can produce
genetically modified mice in a high-throughput
fashion, 2) system-level identification and analysis ofcellular circuits in the whole-organ (especially, thewhole-brain) and whole-body, where we can identify
individual cells or cellular circuits in the whole-organ
and whole-body. Combined with these techniques, we39

investigate how the average (diurnality or
nocturnality), the dispersion (the length of sleepingtime), and the amount (insomniac or hypersomniac
responses) of sleep during circadian time aredetermined by environments and history of activities.
In addition, we are developing human sleep analysis
techniques using wearable devices, and aim to realizea series of human sleep studies that incorporate
large-scale human sleep phenotyping, genomic
analysis, and proof of causality using animal models.
1) Next-generation mammalian reverse genetics
In the conventional method for production ofgenetically-modified mice, a single line ofgene-targeted ES cells is injected into host embryos(typically use blastocysts) to generate chimera micecomprising a mixture of ES- and host-derived cells. In
addition, multiple mating procedures are needed togenerate the desired genetically modified mouse strain,
which typically takes from 9 months to several years.
Such multiple rounds of mating procedures arenecessary to produce gene knockout / knock-in micein the conventional method, which was usually abottleneck to promote organism-level system biology.
Therefore, we propose the concept of "next-generation
mouse genetics" which creates genetically modified
mice without mating and uses it for analysis. We
implemented the concept by developing thetriple-CRISPR method (Sunagawa et al., Cell Rep.
2016) and the ~100% ES cell-derived mice (ES mice)
production method (Ode et al., Mol. Cell 2017; Ukai
et al. Nat Protoc. 2017).
2) System-level identification and analysis of cellular
circuits in the whole-organ and whole-body
The comprehensive identification of molecular
circuits at the organism level also requires accurate(>90%) phenotype analysis. In neuroscience,
sleep/wake behavior is an intriguing phenotype,because sleep disorders (e.g., insomnia or
hypersomnia) are sensitive and informative symptomsof almost all psychological disorders. Sleep/wakestates have been characterized in humans byelectroencephalography (EEG) and electromyography(EMG). Characteristic EEG/EMG patterns during
sleep and waking are preserved in mammals and canbe measured by electrodes surgically implanted in thebrain and muscles. However, such recording requires
special surgical skills, and the surgery is highlyinvasive, requiring a long recovery period (more than
10 days) after implantation before sleep/wakerecording. Furthermore, the EEG/EMG data are often
manually annotated and classified into sleep/wakephenotypes by visual assessment, which can be time
consuming and somewhat subjective. To develop ascalable, non-invasive, fully automated sleep/wakerecording method for comprehensive studies, we havedeveloped 1) an automated EEG/EMG analysis
software (FASTER) (Sunagawa et al., Genes Cell2013), 2) a respiration-based, non-invasive, fully
automated system (SSS) (Sunagawa et al., Cell Rep.
2016).
To highlight the regulatory cellular networks in thesleep/wake rhythm, we facilitate identifying
sleep/wake regulating cells in the whole-brain in acomprehensive and parallelized manner. CUBIC(Clear, Unobstructed Brain/Body Imaging Cocktails
and Computational Analysis) is a great leap forward.
It offers a simple tissue clearing protocol by using
aminoalcohols
andanunprecedented
rapid
whole-brain and whole-body imaging at single-cellresolution (represented by Susaki et al., Cell, 2014;
Tainaka et al., Cell 2014; Tainaka et al., Cell Rep.
2018; Murakami et al., Nat. Neurosci. 2018). The
development of the CUBIC method has evolved into
the development of microscopes for high-speed
imaging (Matsumoto et al., Nat. Protoc. 2019), theextension of technology for immunostaining of
three-dimensional tissues (Susaki et al., Nat. Commun.
2020), and the development of a data analysis
platform for whole-brain single-cell analysis (Mano etal., Cell Rep. Methods 2021). We have also publishedresults of the application of CUBIC to organs otherthan the brain through collaborative research.
3) Mechanism of dynamic homeostasis in sleep/wakecycle: phosphorylation hypothesis of sleep
Sleep amount during a day is under homeostatic
control, in which sleep pressure accumulates during
awake time and gradually decreases during sleep.
Sleep deprivation further promotes the accumulationof sleep pressure, resulting in the longer/deeper sleepin the next cycle. The required sleep duration in a day
is mostly determined genetically as evident from the40fact that each animal spices shows characteristic
different sleep duration. However, detailed molecularmechanisms underlying the control of sleep durationin mammals are still elusive. Using triple-target
CRISPR, SSS, and CUBIC techniques together with acomputational model that simulates the membranepotential of cortex neuron regulated by a group of ionchannels, we have discovered and proposed that
Ca2+-dependent neuronal hyperpolarization pathway
affects sleep duration in mammals (Sunagawa et al.,Cell Reports 2016; Tatsuki et al., Neuron 2016;
Yoshida et al. PNAS 2019; Yamada et al., iScience2022).
We have further been investigating molecules that
regulate the transition and consolidation of sleep andawake phases. In this regard, we have reported aphenotype of Chrm1 and Chrm3 double-knockout
mice produced by triple-CRISPR technology, whichshowed a complete loss of REM sleep (Niwa et al.,Cell Rep. 2018; Yamada and Ueda, Front. Neurosci.
2020). These results were the first report of essential
genes of REM sleep. This study also indicated that
REM sleep, defined through EEG-EMG recordings, is
not critical for the survival of animals.
In the process of investigating the relationshipbetween Ca2+-dependent regulation of neuronal
activity and sleep, we discovered CaMKIIα/β as thefirst sleep-inducing protein kinase in mammals(Tatsuki et al., Neuron 2016). Since then, therelationship between protein phosphorylation andsleep regulation has been suggested by multiple
genetic and biochemical findings—leading to the
proposal of phosphorylation hypothesis of sleep (Odeand Ueda, Front. Psychol. 2021). Phosphorylation/dephosphorylation-mediatedproteinregulation
represents a promising target in sleep–wake regulation
because it can occur on variable dynamics and timescale from minutes to hours, and allows for the
integration of genetic factors (regulation by aminoacid sequence) and environmental factors (posttranslational modification of intracellular signaling
pathways).
4) The development of “Human system biology”
through the analysis of sleep-wake dynamics as amodel platform

Do molecular mechanisms at the single amino acidresidue level, such as specific protein phosphorylation,
control the organism-level phenotype including
human sleep-wake cycle? We will ask this question
leveraging mouse genetics as a springboard to validate
genotype–phenotype relationships.
We have elaborated our technology platforms forhighly precise, large-scale, non-invasive measurements of sleep patterns, derived in mice, to humans.
We developed a novel algorithm, ACCEL, whichclassifies sleep and wake with high sensitivity andspecificity by using jerk of arm movement recordedby wristwatch-type accelerometers (Ode et al.,iScience 2022). Using ACCEL, we estimated thesleep-wake dynamics from the arm acceleration dataof 100,000 people registered in the UK biobank, andsucceeded in classifying human sleep patterns into 16
types (Katori et al., PNAS 2022). Based on the
ACCEL and sleep classification methods, we areworking on social implementation of "sleep checkup"
that will allow many people in our society tounderstand their own sleep status and trigger
necessary changes in their own sleep behavior.
Humans provide a rich source of information on
the roles of genetic and environmental factors insleep–wake control. We hope that our research results
will contribute to the understanding of sleep disorders,circadian rhythm disorders, and associated psychiatricand neurodegenerative diseases, and to the search fortherapeutic strategies.

References
1.

2.

Nojima S, Ishida S, Terayama K, Matsumoto K,
Matsui T, Tahara S, Ohshima K, Kiyokawa H,
Kido K, Ukon K, Yoshida SY, Mitani TT, Doki Y,
Mizushima T, Okuno Y, Susaki EA, Ueda HR,
Morii E. A Novel Three-Dimensional Imaging
System Based on Polysaccharide Staining for
Accurate
Histopathologic
Diagnosis
ofInflammatory Bowel Diseases. Cell. Mol.
Gastroenterol. Hepatol. online ahead of print
Glaser AK, Bishop KW, Barner LA, Susaki EA,
Kubota SI, Gao G, Serafin RB, Balaram P,
Turschak E, Nicovich PR, Lai H, Lucas LAG, Yi
Y, Nichols EK, Huang H, Reder NP, Wilson JJ,
Sivakumar R, Shamskhou E, Stoltzfus CR, Wei X,

41

Hempton AK, Pende M, Murawala P, Dodt HU,
Imaizumi T, Shendure J, Beliveau BJ, Gerner MY,
Xin L, Zhao H, True LD, Reid RC,
Chandrashekar J, Ueda HR, Svoboda K, Liu JTC.
A hybrid open-top light-sheet microscope forversatile multi-scale imaging of cleared tissues.
Nat. Methods. 19, 613-619 (2022)
3. Chino H., Yamasaki A., Ode K.L., Ueda H.R.,
Noda N.N., Mizushima N. Phosphorylation bycasein kinase 2 enhances the interaction between
ER-phagy receptor. TEX264 and ATG8 proteins.
EMBO Rep. 23, e54801 (2022)
4. Katori M., Shi S., Ode K.L., Tomita Y., Ueda H.R.
The 103,200-arm acceleration dataset in the UK
Biobank revealed a landscape of human sleep
phenotypes. Proc. Natl. Acad. Sci. U.S.A. 119,e2116729119 (2022)
5. Yamada T., Shi S., Ueda H.R. A design principleof spindle oscillations in mammalian sleep.
iScience 25, 103873 (2022)
6. Minami Y., Yuan Y., Ueda H.R. High-throughput
Genetically Modified Animal Experiments
Achieved by Next-generation Mammalian
Genetics. J. Biol. Rhythms 37, 135-151 (2022)
7. Ode K.L., Shi S., Katori M., Mitsui K., Takanashi
S., Oguchi R., Aoki D., Ueda H.R. A jerk-basedalgorithm ACCEL for the accurate classificationof sleep–wake states from arm acceleration.
iScience 25, 103727 (2022)
8. Sacconi L., Ueda H.R., Pagès S., Silvestri L.
Fluorescence tissue microscopy. Prog. Biophys.
Mol. Biol. 41, e110157 (2022)
9. Richardson D.S., Guan W., Matsumoto K., Pan
C., Chung K., Ertürk A., Ueda H.R., Lichtman
J.W. TISSUE CLEARING. Nat. Rev. Methods
Primers 1, 84 (2021)
10. Minami Y., Yuan Y., Ueda H.R. Towards
organism-levelsystems
biologybynext-generation genetics and whole-organ cell
profiling. Biophys. Rev. 13, 1113-1126 (2021)
11. Watanabe-Takano H., Ochi H., Chiba A., Matsuo
A., Kanai Y., Fukuhara S., Ito N., Sako K.,
Miyazaki T., Tainaka K., Harada I., Sato S.,
Sawada Y., Minamino N., Takeda S., Ueda H.R.,
Yasoda A., Mochizuki N. Mechanical load
regulates bone growth via periosteal Osteocrin.
Cell Rep. 1, 109380 (2021)

Pathology, Immunology andMicrobiology
1. Pathology

43

Department of Pathology and
Diagnostic Pathology
Professor
Tetsuo Ushiku, M.D., Ph.D.

Project Professor
Takeshi Sasaki, M.D., Ph.D. (Next-Generation Pathology Information Networking)

Associate Professor
Aya Shinozaki-Ushiku, M.D., Ph.D. (Division of Integrative Genomics)

Lecturer
Yoko Tateishi, M.D., Ph.D (~May 31)
Masako Ikemura, M.D., Ph.D. (Office for “Promotion of CPC Education and General
Integrative Medicine”)
Mariko Tanaka (Department of Pathology, Hospital)
Hiroyuki Abe, M.D., Ph.D.

Project Lecturer
Akiko Kunita, Ph.D. (Next-Generation Precision Medicine Development Laboratory)

Research Associate
Naoko Yamauchi, M.D., Ph.D. (~May 31, Hospital Lecturer)
Hirofumi Rokutan, M.D., Ph.D., Ryohei Kuroda, M.D., Ph.D. (Oct 1~), Masaki
Suzuki, Munetoshi Hinata, M.D., Ph.D., Sho Yamazawa, M.D., Ph.D. (Department of
Pathology, Hospital)
Naohiro Makise, M.D., Ph.D., Akiko Iwasaki, M.D., Ph.D., Mayu Hakozaki, M.D.,
Ph.D.
Yoichi Yasunaga, M.D., Ph.D. (~Nov 30, Project Research Associate, "Tsunagu"Fukushima-Kanto Pathology- Forensic Pathology Cooperation Program, Dec 1~,
Department of Pathology and Diagnostic Pathology)

Technical Support Specialist
Kei Sakuma, Kimiko Takeshita, M.T.

Homepage

http://pathol.umin.ac.jp/

44

Introduction and Organization
Department of Pathology and Diagnostic Pathology is
responsible for the practice of diagnostic pathology,
education, and research in cooperation with
Department of Pathology of the University Hospital.
Our aim is to perform pathology as an important partof clinical medicine as well as to establish “nextgeneration pathology” incorporating cutting-edge
science and technology.
Dr. Saito resigned on March 31, 2021. Drs.
Suzuki (Department of Pathology, Hospital) andHakozaki (Department of Pathology and Diagnostic
Pathology) became research associates on Apr 1. Dr
Yasunaga joined as a project research associate of"Tsunagu Program on Apr 1 (until Nov 2021, thenmoved to Department of Pathology and Diagnostic
Pathology on Dec 1).
Ms. Kunita became a project lecturer
Next-Generation Precision Medicine Development
Laboratory on Apr 1, 2021.
Drs. Tateishi and Yamauchi moved to Yokohama
Municipal Citizen’s Hospital and Asahi General
Hospital, respectively, on May 30. Dr. Makise moved
to Chiba Cancer Center on Sep 30. Dr. Kuroda becamea research associate of the Department of Pathology(Hospital) on Oct 1.
Five postgraduate students (Kondo, Fukagawa,
Usui, Urabe and Kuroe) finished the course andreceived Ph.D. In the new fiscal year, 2022, two newstudents will enter the postgraduate course, and there
will be 12 postgraduates.
We are responsible for the pathology practice of
the University of Tokyo Hospital and are carrying
forward the morphology-based research targeting
human diseases. As for the education of the medical
students, we take charge of the following courses;
General Pathology Course for the 1st grade medical
students in collaboration with Department of
Molecular Pathology, Systemic Pathology for the 2nd
grade, Elective Clinical Clerkship for the 4th grade,
and Clinical Clerkship for the 3rd/4th grade students.
Programs for postgraduates and junior residents arealso included in our education activities.
"Tsunagu"Fukushima-Kanto
PathologyForensic Pathology Cooperation Program was plannedin collaboration with Fukushima Medical University

and Juntendo University, headed by Prof. Saito, thedean of Graduate School. The program has been
adopted as one of Activation Program of Basic
Researcher Training of the Ministry of Education,
Culture, Sports, Science and Technology. During four
years between FY2018 and FY2021, 13 postgraduate
students were trained to be specialized in "deathinvestigation, remote pathology diagnosis, andgenomic medicine" with the training system oriented
to region support by rotating among universities. We
hope the students who joined this program will be
future leaders in pathology and forensic medicine.

Teaching activities
We provide General Pathology Course for the 1st
grade of undergraduate students, especially inmorphology.
Each class of Systemic Pathology Course andexercises are held in parallel with that of Systemic
Medicine Course. Due to the COVID-19 pandemic, allof the courses and exercises were given online.
Exercises of Systemic Pathology were conducted byusing a web system which we established in 2020 toaccess whole slide imaging. Students can look at
pathology slides online, and this system works
effectively in student education.
In Clinical Clerkship for all 3rd/4th grade medical
students, following courses are included; autopsy
pathologic practices with a case presentation by paired
students, surgical pathologic practices using various
tumor sections, and a tour of the pathology laboratory.
Both Clinical Clerkship course (4th grade) andFree Quarter program (1st/2nd grade) accepted several
students.
We also set up the lecture series of “Infection/
Immunology/Cancer II” and “Tumor Pathology. We
also provided an intensive exercise course,“Integration of Neuropathology/Radiology/Clinics”.

Research activities
We explore the diagnosis and pathogenesis of disease,especially focusing on gastrointestinal oncogenesis.
Ongoing project includes exploration of highly
aggressive type of gastric cancer with fetal phenotype(e.g. AFP-producing gastric cancer) to clarify its
pathogenesis, genomic abnormalities and to find

45

therapeutic targets (Drs. Rokutan, Kuroda, Yamazawa
and Iwasaki). We are also working on research
projects of digestive system cancers, such as cancer
immune microenvironment, Epstein-Barr viruspositive gastric cancer, hereditary gastric tumors,
duodenal cancer, and pancreatobiliary cancers.
Our department has pathologists with different
expertise, and they are engaged in specific research
projects. The research covers brain tumors andneurodegenerative disease (Drs. Ikemura and
Hakozaki), Epstein-Barr virus-associated neoplasms(Drs. Shinozaki-Ushiku, Abe and Hinata), liver andpancreatobiliary tumors (Drs. Tanaka and Yasunaga),
and lung cancer (Dr. Suzuki). We also collaborate withother laboratories in and outside the University todevelop new technologies such as AI, tissue clearing
technique, and tissue processing robots in pathology
practice (Drs. Abe and Hinata).

References(Case reports are listed in the section of Department of
Pathology)
1.

2.

3.

4.

Abe H, Kunita A, Otake Y, Kanda T, Kaneda A,
Ushiku T, Fukayama M. Virus-host interactions
in carcinogenesis of Epstein-Barr virusassociated gastric carcinoma: Potential roles oflost ARID1A expression in its early stage. PLoS
One. 2021;16(9):e0256440.
Abe H, Ushiku T. Pathological diversity ofgastric cancer from the viewpoint of backgroundcondition. Digestion. 2022;103:45-53.
Abe H, Yasunaga Y, Yamazawa S, Nakai Y,
Gonoi W, Nishioka Y, Murono K, Sasaki K, Arita
J, Kawai K, Nozawa H, Hasegawa K, Ishihara S,
Ushiku T. Histological growth patterns ofcolorectal cancer liver metastases: a strong
prognostic marker associated with invasive
patterns of the primary tumor and p53 alteration.
Hum Pathol. 2022;123:74-83.
Fujii Y, Sato Y, Suzuki H, Kakiuchi N, Yoshizato
T, Lenis AT, Maekawa S, Yokoyama A, Takeuchi
Y, Inoue Y, Ochi Y, Shiozawa Y, Aoki K, Yoshida
K, Kataoka K, Nakagawa MM, Nannya Y,
Makishima H, Miyakawa J, Kawai T, Morikawa
T, Shiraishi Y, Chiba K, Tanaka H, Nagae G,
Sanada M, Sugihara E, Sato TA, Nakagawa T,

Fukayama M, Ushiku T, Aburatani H, Miyano S,
Coleman JA, Homma Y, Solit DB, Kume H,
Ogawa S. Molecular classification anddiagnostics of upper urinary tract urothelial
carcinoma. Cancer Cell. 2021;39(6):793-809.e8.
5. Hinata M, Ushiku T. Detecting immunotherapysensitive subtype in gastric cancer using
histologic image-based deep learning. Scientific
Reports. 2021;11(1):22636.
6. Imai S, Ooki T, Murata-Kamiya N, Komura D,
Tahmina K, Wu W, Takahashi-Kanemitsu A,
Knight CT, Kunita A, Suzuki N, Del Valle AA,
Tsuboi M, Hata M, Hayakawa Y, Ohnishi N,
Ueda K, Fukayama M, Ushiku T, Ishikawa S,
Hatakeyama M. Helicobacter pylori CagA elicits
BRCAness to induce genome instability that may
underlie bacterial gastric carcinogenesis. Cell
Host Microbe. 2021;29(6):941-958.e10.
7. Iwasaki A, Shinozaki-Ushiku A, Kunita A,
Yamazawa S, Sato Y, Yamashita H, Fukayama M,
Seto Y, Ushiku T. Human Leukocyte Antigen
Class I Deficiency in Gastric Carcinoma: An
Adaptive Immune Evasion Strategy Most
Common in Microsatellite Instable Tumors. Am J
Surg Pathol. 2021;45(9):1213-1220.
8. Kashima J, Hishima T, Okuma Y, Horio H,
Ogawa M, Hayashi Y, Horiguchi SI, Motoi T,
Ushiku T, Fukayama M. CD70 in Thymic
Squamous Cell Carcinoma: Potential Diagnostic
Markers and Immunotherapeutic Targets. Front
Oncol. 2022;11:808396.
9. Komura D, Kawabe A, Fukuta K, Sano K,
Umezaki T, Koda H, Suzuki R, Tominaga K,
Ochi M, Konishi H, Masakado F, Saito N, Sato Y,
Onoyama T, Nishida S, Furuya G, Katoh H,
Yamashita H, Kakimi K, Seto Y, Ushiku T,
Fukayama M, Ishikawa S. Universal encoding of
pan-cancer
histology
bydeep
texturerepresentations. Cell Rep. 2022;38(9):110424.
10. Kudo N, Kudoh S, Matsuo A, Motooka Y, Ito T.
ZMYM3 may promote cell proliferation in small
cell lung carcinoma. Acta Histochem Cytochem.
2021;54(5):143–153.
11. Kuroe T, Watanabe R, Kojima M, Morisue R,
Sugano M, Kuwata T, Masuda H, Kusuhara S,
Matsubara N, Oda S, Ushiku T, Ishii G.
Evaluation of the morphological features and

46

12.

13.

14.

15.

16.

unfavorable prognostic impact of dirty necrosis
in renal cell carcinoma. J Cancer Res Clin Oncol.
2021;147(4):1089-1100.
Shi C, Badgwell B, Gibson MK, Grabsch HI,
Hong S, Kumarasinghe P, Lam A, Lauwers G,
O’Donovan M, Tang L, Ushiku T, van der Post C,
Vieth M, Nagtegaal ID (2021). Carcinoma of the
Stomach Histopathology Reporting Guide, 2ndedition. International Collaboration on Cancer
Reporting; Sydney, Australia.
Shi C, Badgwell BD, Grabsch HI, Gibson MK,
Hong SM, Kumarasinghe P, Lam AK, Lauwers G,
O'Donovan M, van der Post RS, Tang L, Ushiku
T, Vieth M, Selinger CI, Webster F, Nagtegaal ID.
Data Set for Reporting Carcinoma of the Stomach
in Gastrectomy. Arch Pathol Lab Med. 2021;
Epub ahead of print.
Shi C, Bourke M, Hong S, Kumarasinghe P, Lam
A, Lauwers G, O’Donovan M, Ushiku T, van derPost C, Vieth M, Nagtegaal ID (2021).
Endoscopic
ResectionoftheStomachHistopathology Reporting Guide, 2nd edition.
International Collaboration on Cancer Reporting;
Sydney, Australia.
Taguchi J, Shibata H, Kabata M, Kato M, Fukuda
K, Tanaka A, Ohta S, Ukai T, Mitsunaga K,
Yamada Y, Nagaoka SI, Yamazawa S, Ohnishi K,
Woltjen K, Ushiku T, Ozawa M, Saitou M,
Shinkai Y, Yamamoto T, Yamada Y. DMRT1mediated reprogramming drives development ofcancer resembling human germ cell tumors withfeatures of totipotency. Nat Commun. 2021;
12(1):5041.
Yachida S, Totoki Y, Noë M, Nakatani Y, Horie
M, Kawasaki K, Nakamura H, Saito-Adachi M,
Suzuki M, Takai E, Hama N, Higuchi R, Hirono
S, Shiba S, Kato M, Furukawa E, Arai Y, Rokutan
H, Hashimoto T, Mitsunaga S, Kanda M, Tanaka
H, Takata S, Shimomura A, Oshima M, Hackeng
WM, Okumura T, Okano K, Yamamoto M,
Yamaue H, Morizane C, Arihiro K, Furukawa T,
Sato T, Kiyono T, Brosens LAA, Wood LD,
Hruban RH, Shibata T. Comprehensive Genomic
Profiling of Neuroendocrine Carcinomas of the
Gastrointestinal System. Cancer Discov. 2022;12(3);692-711.

17. Yamazawa S, Ushiku T. Carcinosarcoma of thestomach: four cases that expand the morphologic
spectrum of gastric cancer with a primitive
phenotype. Virchows Arch. 2022;480(5):10511062.
18. Zhang CD, Takeshima H, Sekine S, Yamashita S,
Liu YY, Hattori N, Abe H, Yamashita H, Fukuda
M, Imamura Y, Ushiku T, Katai H, Makino H,
Watanabe M, Seto Y, Ushijima T. Prediction oftissue origin of adenocarcinomas in theesophagogastric junction by DNA methylation.
Gastric Cancer. 2022;25(2):336-345.

47

Department of MolecularPathology
Professor
Kohei Miyazono, M.D., Ph.D.

Associate Professors
Daizo Koinuma, M.D., Ph.D.
Shogo Ehata, M.D., Ph.D. (Environmental Science Center, until September 2021)

Assistant Professors
Masato Morikawa, M.D., Ph.D.

Homepage

http://beta-lab.umin.ac.jp/

Introduction and organization
Our department has a more than 120-year history
from its establishment as the Department of Pathology.
Kohei Miyazono is Professor of the Department of
Molecular Pathology from August 2000. At the end of
March 2021, he retired from his position. In March
2021, the Department consists of a professor, anassociate professor, an assistant professor, technicalassistants, and some research fellows, including three
graduate students, and a post-doctoral fellow.

Teaching activities
Our department takes responsibility for lectures on“General Pathology” for undergraduate students of theFaculty of Medicine in collaboration with the
Department of Human Pathology. Since we believe itvery important for medical students to study basic
oncology, we teach basic tumor biology in our lecturesof General Pathology. All lecture courses wereconducted online in 2021. In addition, we offer several
laboratory courses for students from molecularpathological points of view.
We also supervise research activities of the graduate
students of the Department. Our laboratory is locatedat the 11th floor at the Research Building of Graduate

School of Medicine. The laboratory is very convenientfor doing research, because most of the experiments
can be done on this floor. We have “Progress Meeting”
once a month and “Monday Seminar” once a month.
We have been collaborating with Prof. Carl-Henrik
Heldin’s group, Uppsala University, Sweden for morethan 25 years.
From 2018, World-leading INnovative Graduate
School Program for Life Science and Technology(WINGS-LST) has started and one of our graduate
students is supported by this program. This program
will stimulate interaction between students andscientists in the program as well as those from otherlaboratories (square.umin.ac.jp/wings-lf/). In addition,
Fostering Advanced Human Resources to Lead Green
Transformation (GX) project started from 2021, andanother student is supported by this program.

Research activities
Our major research interest is to elucidate how
members of the TGF-β (transforming growth factor-β)family transduce signals, and how they regulate
growth, differentiation, and apoptosis of various cells.
From 2017, our research is mainly supported by aGrant-in-Aid for Scientific Research on Innovative
Area on Integrated Analysis and Regulation of

48

Cellular Diversity (17H06326) from MEXT. From
2020, our research is also supported by a Grant-in-Aid
for Scientific Research (A) on “Comprehensive
studies on the mechanisms of cancer metastasis frommolecular signaling to whole-body level” (20H00513)
from the Japanese Society for the Promotion of
Science (JSPS). From 2021, our new project on a new
strategy for treatment of the mesenchymal type ofglioblastoma is accepted (21ck0106705h0001) by the
Practical Research for Innovative Cancer Control
Program of Japan Agency for Medical Research andDevelopment (AMED).
Followings are some research results obtained at
our laboratory in 2021.
1) Monovalent follistatin-like-3 (mono-FSTL3)-Fcfusion protein increases muscle mass in mice.
Inhibition of some TGF-β family ligands, including
growth differentiation factor 8 (GDF8, also known as
myostatin) and activin A, is expected to induce muscle
growth in the elderly and in patients. We studied theeffects of an endogenous antagonist against TGF-βfamily ligands, follistatin-like 3 (FSTL3), which binds
and neutralizes activins, GDF8/myostatin, and GDF11,
but not TGF-βs or bone morphogenetic proteins(BMPs). Although bivalent human FSTL3 Fc-fusion
protein was rapidly cleared from mouse circulation,monovalent FSTL3-Fc (mono-FSTL3-Fc) generated
with the knobs-into-holes technology showedsignificantly longer serum half-life in mice. Systemic
administration of mono-FSTL3-Fc in mice induced
muscle fiber hypertrophy and increased muscle mass.
Our results thus suggest that the monovalent
FSTL3-based therapy overcomes the difficulties ofcurrent anti-GDF8 therapies (Ozawa et al. iScience2021).
2) Visualization of the cancer cell cycle bytissue-clearing technology using the Fucci reporter
system.
Tissue-clearing technology is an imaging techniquecurrently utilized not only in neuroscience research
but also in cancer research. In our previous studies, weused tissue-clearing methods for the detection ofmetastatic tumors. In the present study, we showedthat the cell cycles of primary and metastatic tumors
were visualized by tissue-clearing methods using

some cancer cell lines (human lung adenocarcinoma
A549 and mouse breast cancer 4T1), stably expressing
fluorescent ubiquitination-based cell cycle indicator(Fucci) reporter. Interestingly, fluorescence patterns of
the Fucci reporter of tumor colonies were different
between various organs, and even among colonies inthe same organs. The effects of anti-tumor drugs werealso analyzed using these Fucci reporter cells. We
found that, of the three anti-tumor drugs studied,
5-fluorouracil (5-FU) treatment on 4T1-Fucci cells
resulted in characteristic fluorescent patterns by the
induction of G2/M arrest in vitro as well as in vivo.
Thus, the combination of a tissue-clearing methodwith the Fucci reporter may be useful for analyzing
the mechanisms of cancer metastasis and drug
resistance (Takahashi et al. Cancer Sci 2021).
3) Suppression of anti-pyroptotic function of TGF-β bya synthetic dsRNA analogue in triple negative breast
cancer (TNBC) cells.
Transfection of polyI:C, a conventionally usedsynthetic double-stranded RNA (dsRNA) analogue,
activates retinoic acid-inducible gene-I (RIG-I)-likereceptors (RLRs), and has been evaluated in clinical
trials. However, mechanisms of tumor suppression by
RLRs, including interactions with other signaling
pathways, remain to be elucidated. We found thattransfection of polyI:C in cells suppressed TGF-βsignaling in an RLR-dependent manner. Suppressionof TGF-β signaling by polyI:C promoted cancer cell
death, which was attenuated by forced expression of
constitutively active Smad3. Interestingly, cell deathby polyI:C transfection exhibited characteristics ofpyroptosis, which is distinct from apoptosis.
Therapeutic efficacy of polyI:C transfection was also
confirmed using a mouse model. These findings
suggest that intratumor administration of polyI:C andrelated dsRNA analogues may be an interesting
strategy for treatment of TNBC through inhibition of
the anti-pyroptotic function of TGF-β (Tamura et al.
Mol Oncol 2021).
4) Heterogeneity of endoglin expression in clear cell
renal cell carcinoma (ccRCC) and its relationship to
the tumor microenvironment.
Intratumoral heterogeneity is a potential cause of drug
resistance and metastatic cancer progression.

49

Although endoglin (ENG, also known as CD105) has
been proposed as a marker for cancer-initiating cells
in ccRCC, we found that ENG-positive population did
not enrich other cancer-initiating cell markers or
induce the differentiation into the ENG-negative
population in our experimental systems. Mouse tumor
inoculation models revealed that the tumor-forming
capabilities of ENG-positive and ENG-negative cells
in vivo appeared to be dependent on the tumor
microenvironment, with the renal microenvironment
most preferable to ENG-positive cells. Thus, the renal
microenvironment, rather than the ENG-positivecell-centeredhierarchy,
maintains
cellularheterogeneity in ccRCC (Momoi et al. Cancer Sci
2021).

References
1.

2.

3.

4.

Takahashi, K., Ehata, S., Miyauchi, K., Morishita,Y., Miyazawa, K., and Miyazono, K. (2021)
Neurotensin receptor 1 signaling promotes
pancreatic cancer progression. Molecular
Oncology 15 (1), 151-166. doi: 10.1002/18780261.12815.
Kok, S.Y., Oshima, H., Takahashi, K., Nakayama,M., Murakami, K., Ueda, H.R., Miyazono, K.,
and Oshima, M. (2021) Malignant subclone
drivesmetastasisofgeneticallyandphenotypically heterogenous cell clusters throughfibrotic
niche
generation.
NatureCommunications 12 (1), 863. doi: 10.1038/
s41467-021-21160-0.
Kubota, S.I., Takahashi, K., Mano, T.,
Matsumoto, K., Katsumata, T., Shi, S., Tainaka,
K., Ueda, H.R., Ehata, S., and Miyazono, K.
(2021) Whole-organ analysis of TGF-β-mediatedremodelling of the tumour microenvironment by
tissue clearing. Communications Biology 4 (1),294. doi: 10. 1038/s42003-021-01786-y.
Sakamoto, K., Endo, K., Sakamoto, K.,
Kayamori, K., Ehata, S., Ichikawa, J., Ando, T.,
Nakamura, R., Kimura, Y., Yoshizawa, K.,
Masuyama, K., Kawataki, T., Miyake, K., Ishii,
H., Kawasaki, T., Miyazawa, K., and Saitoh, M.
(2021) EHF suppresses cancer progression by
inhibiting ETS1-mediated ZEB expression.

Oncogenesis 10 (3), 26. doi: 10.1038/s41389021-00313-2.
5. Katsuno, Y. and Derynck, R. (2021) Epithelial
plasticity, epithelial-mesenchymal transition, andthe TGF-β family. Developmental Cell 56 (6),726-746. doi: 10.1016/j.devcel.2021.02.028.
6. Tamura, Y., Morikawa, M., Tanabe, R., Miyazono,
K., and Koinuma, D. (2021) Anti-pyroptotic
function of TGF-β is suppressed by a synthetic
dsRNA analogue in triple negative breast cancer
cells. Molecular Oncology 15 (5), 1289-1307.
doi: 10.1002/1878-0261.12890.
7. Ozawa, T., Morikawa, M., Morishita, Y., Ogikubo,
K., Itoh, F., Koinuma, D., Nygren, P.Å., andMiyazono, K. (2021) Systemic administration ofmonovalent follistatin-like-3-Fc-fusion proteinincreases muscle mass in mice. iScience 24 (5),102488. doi: 10.1016/j.isci.2021.102488.
8. Yamamoto, H., Sakai, N., Ohte, S., Sato, T.,
Sekimata, K., Matsumoto, T., Nakamura, K.,
Watanabe, H., Mishima-Tsumagari, C., Tanaka,
A., Hashizume, Y., Honma, T., Katagiri, T.,
Miyazono, K., Tomoda, H., Shirouzu, M., andKoyama, H. (2021) Novel bicyclic pyrazoles aspotent ALK2 (R206H) inhibitors for thetreatment of fibrodysplasia ossificans progressiva.
Bioorganic & Medicinal Chemistry Letters 38,
127858. doi: 10.1016/j.bmcl.2021.127858.
9. Motizuki, M., Koinuma, D., Yokoyama, T., Itoh,Y., Omata, C., Miyazono, K., Saitoh, M., andMiyazawa, K. (2021) TGF-β-induced cell
motility requires down-regulation of ARHGAPs
to sustain Rac1 activity. Journal of Biological
Chemistry 296, 100545. doi: 10.1016/j.jbc.2021.
100545.
10. Fukuda, T., Fukuda, R., Miyazono, K., andHeldin, C.-H. (2021) Tumor promoting effect of
BMP signaling
inendometrial
cancer.
International Journal of Molecular Sciences 22(15), 7882. doi: 10.3390/ijms22157882.
11. Momoi, Y., Nishida, J., Miyakuni, K., Kuroda,
M., Kubota, S.I., Miyazono, K., and Ehata, S.
(2021) Heterogenous expression of endoglinmarks advanced renal cancer with distinct tumor
microenvironment fitness. Cancer Science 112(8), 3136-3149. doi: 10.1111/cas.15007.

50

12. Takahashi, K., Tanabe, R., Ehata, S., Kubota, S.I.,
Morishita, Y., Ueda, H.R., and Miyazono, K.
(2021) Visualization of the cancer cell cycle bytissue-clearing technology using the Fucci
reporter system. Cancer Science 112 (9),3796-3809. doi: 10.1111/cas.15034.
13. Fukuda, T., Fukuda, R., Koinuma, D., Moustakas,A., Miyazono, K., and Heldin, C.-H. (2021)
BMP2-inductionofFN14
promotes
protumorigenic signaling in gynecologic cancer
cells. Cellular Signalling 87, 100146. doi:
10.1016/j.cellsig.2021.110146.
14. Ozawa, T., Miyazono, K., and Morikawa, M.
(2021) Preparation of monovalent follistatin-like
3-Fc-fusion protein and evaluation of its effects
on muscle mass in mice. STAR Protocols 2 (4),100839. doi: 10.1016/j.xpro.2021.100839.

Pathology, Immunology andMicrobiology
2. Microbiology

52

Department of Microbiology
Professor
Masanori Hatakeyama, M.D.,Ph.D.

Lecturer
Naoko Kamiya, Ph.D.

Research Associate
Atsushi Kanemitsu, Ph.D., Takeru Hayashi, Ph.D.

Homepage

http://www.microbiol.m.u-tokyo.ac.jp/

Introduction and Organization
Professor emeritus Akio Nomoto who had been thechief of the Department retired in 2008 and moved to
Microbial Chemistry Research Foundation as the
Chairman of Board. From 2009, new Department ofMicrobiology started with Professor Masanori
Hatakeyama as the new chief. The present Department
consists of 16 members; 1 professor (Dr. Hatakeyama),
1 senior lecturer (Dr. Kamiya), 2 research associates(Drs. Kanemitsu and Hayashi), 3 post-doctoral fellows(Drs. Nishikawa, Kikuchi, and Ooki), 2 academic
assistants (Ms. Sakamoto and Komatsu), 7 graduate
school students (Mr. and Ms. Wada, Imai, Tahmina,
Wu, Priscillia, Del Valle Lazarte, Shrestha).

Education
In a series of lectures (totally 64 hr) and laboratory
courses (36 hr), the following subjects are covered.
1) Molecular biology of bacteria, phages, and animalviruses2) Mechanisms of microbial diseases
3) Laboratory diagnosis of pathogenic microbes
4) Infection control and biosafety
5) Application of microbial organisms for biotechnology
6) Socioeconomic impact of microbial diseases

Research
Gastric cancer is the third leading cause (10.4%) ofcancer death worldwide. It has now been wellestablished that infection with Helicobacter pylori (H.
pylori) is associated with the development of gastriccancer. Especially, infection with H. pylori strains
carrying a gene called cagA plays an essential role ingastric carcinogenesis. The cagA-positive H. pylori
delivers the cagA gene product, the CagA protein, into
the host gastric epithelial cells via the type IV
secretion system. Through a series of studies, we haveuncovered the molecular mechanisms by which
delivered CagA causes transformation of gastricepithelial cells.
East Asian countries such as Japan, Korea andChina, are known to show the highest incidence ofgastric cancer in the world. In Japan, for instance,
more than 40,000 peoples are killed by gastric cancer
each year. Thus, establishment of new strategies forprevention and treatment for gastric cancer is urgently
required. In our department, we are conducting
cutting-edge researches, ranging from molecular
structural biology to mouse genetics, to elucidate
oncogenic mechanisms of the bacterial CagA protein.
These researches will provide an opportunity todevelop molecular-targeting methods that effectively
prevent the development of gastric cancer. We madesubstantial progress in the following research during
the current year.

53

1. Helicobacter pylori CagA elicits BRCAness to
induce genome instability that may underlie
bacterial gastric carcinogenesis
Chronic infection with cagA-positive H. pylori plays acritical role in the development of gastric cancer.
However, once established, H. pylori is not required
for the maintenance of cancer cells, indicating that
CagA-dependent carcinogenesis proceeds through a“hit-and-run” mechanism.
The CagA protein, encoded by the cagA gene, isdirectly injected into gastric epithelial cells throughthe type IV secretion system (T4SS). Inside the hostcells, CagA binds and inhibits the polarity-regulating
serine/threonine kinase PAR1b (also known as
MARK2) via CM motif, thereby causing junctional
and polarity defects. In this study, we found that CagA
impairs nuclear accumulation of BRCA1 in a CM
motif-dependent manner. Mechanistically, CagA/
PAR1b interaction inactivates PAR1b and thereby
inhibits PAR1b-dependent phosphorylation of BRCA1
on Ser616 that is required for cytoplasmic-to-nuclear
translocation of BRCA1. The breast/ovarian tumor
suppressor BRCA1 that has essential functions inhomologous recombination (HR), a high-fidelity
mechanism to repair DNA double-strand breaks(DSBs), is also important in the protection of stalled
replication forks. CagA-induced shortage of nuclear
BRCA1 causes replication fork instability leading to
DSBs that are repaired through error-prone pathways
such as non-homologous end joining (NHEJ). The
CagA/PAR1b interaction also stimulates Hippo
signaling and thereby circumvents DSB-triggered
apoptosis. However, despite successful escape from
apoptosis, CagA-induced DSBs activate p53-p21Cip1
axis to inhibit cell proliferation. It has been reported
that TP53 is the most frequently mutated gene ingastric cancer. Indeed, p53 inactivation allows theproliferation of CagA-delivered cells. Furthermore,intermittent expression of CagA in TP53-mutant cells,
which mimics CagA delivery in the H. pyloricolonized human stomach, induces somatic mutations
with BRCAness-associated COSMIC signatures, AC3
and ID6, indicating that CagA elicits transient
BRCAness. Genome instability caused by CagAinduced transient BRCAness may promote acquisitionof additional driver gene mutations that confer H.
pylori-independence interms of neoplastictransformation. This study revealed the molecularmechanism by which H. pylori CagA promotes“hit-and-run” gastric carcinogenesis.
2. Mouse gastric epithelial cells resist CagA
delivery by the Helicobacter pylori typeIV secretion
systemMost if not all human gastric cancers are caused bychronic infection of the stomach lining with H. pylori
strains that possess the cagA gene. Inside the hostcells, CagA undergoes tyrosine phosphorylation by
Src family kinases (SFKs) or c-Abl kinase.
Tyrosine-phosphorylated CagA binds to and aberrantly activates pro-oncogenic tyrosine phosphatase
SHP2, thereby causing aberrant activation of the
RAS-ERK kinase signaling pathway. CagA-dependent
SHP2 deregulation and PAR1b inhibition contribute to
the neoplastic transformation of CagA-delivered
gastric epithelial cells.
Mice have been used in many studies for H.
pylori-dependent gastric diseases. Infection of micewith cagA-positive H. pylori strains induced more
severe gastritis than infection with cagA-negative
strains did. However, even long-term infection of micewith cagA-positive strains did not induce gastriccancer. In contrast, transgenic expression of CagA inmice gave rise to spontaneous gastrointestinal andhematological malignancies. These findings raise thepossibility that cagA-positive H. pylori cannot
efficiently deliver CagA into mouse gastric epithelial
cells.
The initial step in H. pylori infection is adherenceof H. pylori to the human gastric epithelial cells. H.
pylori exploits the interaction of bacterial adhesin
protein HopQ with human epithelial CEACAMs(CEACAM1, 5, and 6) to stably adhere to gastricepithelial cells, which is necessary for delivery of
the H. pylori CagA oncoprotein into the epithelial
cells via a type IV secretion system. In contrast tohuman CEACAMs, however, HopQ does not interact
with Ceacam1 (mouse CEACAM1) in vitro or in CHO
cells ectopically expressing Ceacam1. Since themouse genome lacks Ceacam5 and Ceacam6, no
significant HopQ-Ceacam interaction may occur inmouse gastric epithelial cells. Here, we found that themouse stomach has a much lower expression level of
Ceacam1 than the expression level of CEACAM1 in54

the human stomach using a public database (NCBI
Gene). Consistently, mouse gastric epithelial cells
resist CagA delivery by cagA-positive H. pylori. We
established human CEACAM (CEACAM1, 5, or6)-expressing mouse gastric epithelial cells. CagA
delivery was restored by ectopic expression of human
CEACAM1 or CEACAM5 in mouse gastric epithelial
cells. In contrast, despite sufficient expression ofhuman CEACAM6 on the mouse gastric epithelial
cells, there was no evidence for CagA delivery. Thus,
although mice are routinely used for H. pylori
infection studies, a low expression level of Ceacam1in the mouse stomach together with the loss or greatly
reduced interaction of HopQ with Ceacams make themouse an inappropriate model for studying the role ofH. pylori-delivered CagA in gastric pathogenesis,
including the development of gastric cancer.

Publications
1.

2.

3.

4.

5.

Tahmina, K., Hikawa, N., Takahashi-Kanemitsu,
A., Knight, C.T., Sato, K., Itoh, F., Hatakeyama,
M. Transgenically expressed Helicobacter pylori
CagA in vascular endothelial cells accelerates
arteriosclerosis in mice. Biochem. Biophys. Res.
Commun. in press.
Nishikawa, H., Christiany, P., Hayashi, T., Iizasa,
H., Yoshiyama, H., Hatakeyama, M. Kinase
activity of PAR1b, which mediates nuclear
translocalization of the BRCA1 tumor suppressor,
is potentiated by nucleic acid-mediated PAR1b
multimerization. Int. J. Mol. Sci. in press.
Murata-Kamiya,
N.,
Hatakeyama,
M.
Helicobacter pylori-induced DNA doublestranded break in the development of gastriccancer. Cancer Sci. in press.
Shrestha, R., Murata-Kamiya, N., Imai, S.,
Yamamoto, M., Tsukamoto, T., Nomura, S.,
Hatakeyama, M. Mouse gastric epithelial cells
resist CagA delivery by the Helicobacter pylori
type IV secretion system. Int. J. Mol. Sci. 23(5):2492 (2021)
Kolinjivadi, A.M., Sankar, H., Choudhary, R.,
Tay, L.S., Tan, T.Z., Murata-Kamiya, N., Voon,
D.C., Kappei, D., Hatakeyama, M., Krishnan, V.,
Ito, Y. The H. pylori CagA oncoprotein induces
DNA double strand breaks through Fanconi

6.

7.

Anemia pathway downregulation and replication
fork collapse. Int. J. Mol. Sci. 23(3): 1661 (2021)
Imai, S., Ooki, T., Murata-Kamiya, N., Komura,D., Tahmina, K., Wu, W., Takahashi-Kanemitsu,
A., Knight, C.T., Kunita, A., Suzuki, N., Tsuboi,
M., Hata, M., Hayakawa, Y., Ohnishi, N., Ueda,
K., Fukayama, M., Ushiku, T., Ishikawa, S.,
Hatakeyama, M. Helicobacter pylori CagA elicits
BRCAness to induce genome instability that may
underlie bacterial gastric carcinogenesis. Cell
Host Microbe, 29(6): 941-958 (2021)
Ooki, T., Hatakeyama, M. Protocol for
visualizing conditional interaction between
transmembrane and cytoplasmic proteins. STAR
Protocols 2: 100430 (2021)

55

Department of Infection Control
and Prevention
Professor
Kyoji Moriya, M.D., Ph.D.

Lecturer
Sohei Harada, M,D., Ph.D.

Project Lecturer
Nobuhiko Satoh, M.D., Ph.D.
Kazuya Okushin, M.D., Ph.D.

Research Associate
Mayo Tsuboi, MD., Ph.D.
Daisuke Ohki, MD., Ph.D.
Ryu Yoneda, MD., Ph.D.

Homepage

http://square.umin.ac.jp/ut-ict/

Introduction and Organization
The Department of Infection Control and Prevention
started at first as the Division of Hospital Infection
Control Services on January 23, 1991. This divisiondeveloped into the Division of Infection Control andPrevention on September l, 1993 and the present
department on June 4, 1994. Currently, our faculty
consists of one professor, one lecturer, five research
associates, 12 laboratory technicians, and two officeassistants. For isolation and identification of
microorganisms from clinical specimens, we
amalgamated the microbiology unit from the
Department of Clinical Laboratory in 2001.

Clinical activities
Our daily activities are as follows:
1) Surveillance and control of hospital-acquired
infection, such as infection or colonization ofmethicillin-resistant Staphylococcus aureus andother drug-resistant microbes.

2) Investigation of trends in weekly bases andmonthly reports to all departments; Screening ofcolonization; monitoring of appropriate use ofantibiotics.
3) Microbiological investigation of wards andenvironment.
4) Detection, investigation, intervention and controlof the hospital infection outbreak.
5) Offering of information and advice on HIVinfected patients’ management.
6) Direct inquiries and advises on management ofpatients with various infections through ward
rounds every week.

Education
We have been charged for education of undergraduate
students on the course of medicine (lectures andpractical exercises on the infection control for the 4th
grade students). These lectures and exercises contain
subjects not only on the hospital infection but also on
clinical microbiology. We are also engaged in the

56

education of graduate students as well as hospital
staff.
For postgraduate education, we have been committed
to the guidance for new postgraduates and residents on
the hospital and occupational infection control. We
have been also offering our information and techniqueon occasions of request.

Research
We have been mainly studying on following subjects:
Several studies are now going with the members of
department of pharmacy and of surgery.
1) Development of preemptive strategies for thecontrol of healthcare-associated infection2) Development of new methods in infection control
and treatment of viral hepatitis
3) Molecular pathogenesis of hepatocellular carcinoma in HCV infection4) Pathogenesis of progression of HIV infection5) Molecular pathogenesis of the mitochondrial
disturbances in viral infections
6) Molecular pathogenesis of hepatitis B viral infection7) Host defenses to microorganisms
8) Molecular analysis of innate immunity in microorganism infection
9) New detection method and pathogenesis of opportunistic cytomegaloviral infection10) Mechanisms and molecular epidemiology ofmulti-drug resistant microorganisms11) Epidemiology of Clostridioides difficile infection
12)
Clinicalcharacteristics
andmolecular
epidemiologyofhypervirulent
Klebsiellapnemoniae infection

Publications
1.

2.

Ito H, Okamoto K, Yamamoto S, Yamashita M,
Kanno Y, Jubishi D, Ikeda M, Harada S,
Okugawa S, Moriya K. Incidence and Risk
Factors for Inappropriate Use of Non-CultureBased Fungal Assays: Implication for Diagnostic
Stewardship. Open Forum Infect Dis. 2021 Dec
6;9(1):ofab601.
Yokoyama R, Kurano M, Nakano Y, Morita Y,
Ohmiya H, Kishi Y, Okada J, Qian C, Xia F, He
F, Zheng L, Yu Y, Mizoguchi M, Higurashi Y,

3.

4.

5.

6.

7.

Harada S, Jubishi D, Okamoto K, Moriya K,
Kodama T, Yatomi Y. Association of the Serum
Levels of the Nucleocapsid Antigen of SARSCoV-2 With the Diagnosis, Disease Severity, andAntibody Titers in Patients With COVID-19: A
Retrospective Cross-Sectional Study. Front
Microbiol. 2021 Dec 9;12:791489.
Kobayashi T, Ikeda M, Okada Y, Higurashi Y,
Okugawa S, Moriya K. Clinical andMicrobiological Characteristics of Recurrent
Escherichia coli Bacteremia. Microbiol Spectr.
2021 Dec 22;9(3):e0139921.
Nomura Y, Okamoto K, Ohama Y, Higurashi Y,
Harada S, Moriya K. Tenosynovitis caused by
Mycobacterium marseillense, initially identified
as Mycobacterium avium complex using
AccuProbe and COBAS TaqMan. BMC InfectDis. 2021 Oct 23;21(1):1092.
Ohama Y, Aoki K, Harada S, Nagasawa T,
Sawabe T, Nonaka L, Moriya K, Ishii Y,
Tateda K. Genetic Environment Surrounding
blaOXA-55-like in Clinical Isolates of Shewanella
algae Clade and Enhanced Expression of
blaOXA-55-like in a Carbapenem-Resistant Isolate.
mSphere. 2021 Oct 27;6(5):e0059321.
Kobayashi T, Ikeda M, Ohama Y, Murono K,
Ikeuchi K, Kitaura S, Okamoto K, Okugawa S,
Ishihara S, Moriya K. First human case ofcatheter-related blood stream infection caused by
Staphylococcus schleiferi subspecies coagulans:a case report and literature review. Ann Clin
Microbiol Antimicrob. 2021 Sep 25;20(1):68.
Minami T, Tateishi R, Fujiwara N, Nakagomi R,
Nakatsuka T, Sato M, Uchino K, Enooku K,
Nakagawa H, Fujinaga H, Izumiya M, Hanajiri K,
Asaoka Y, Kondo Y, Tanaka Y, Otsuka M, Ohki
T, Arai M, Tanaka A, Yasuda K, Miura H, Ogata
I, Kamoshida T, Inoue K, Koike Y, Akamatsu M,
Mitsui H, Fujie H, Ogura K, Yoshida H, Wada T,
Kurai K, Maekawa H, Obi S, Teratani T, Masaki
N, Nagashima K, Ishikawa T, Kato N, Moriya K,
Yotsuyanagi H, Koike K. Impact of Obesity andHeavy Alcohol Consumption on Hepatocellular
Carcinoma Development after HCV Eradication
with Antivirals. Liver Cancer. 2021 Jul;10(4):309-319.

57

8.

9.

10.

11.

12.

13.

Shinohara T, Okamoto K, Koyano S, Otani A,
Yamashita M, Wakimoto Y, Jubishi D,
Hashimoto H, Ikeda M, Harada S, Okugawa S,
Moriya K. Plesiomonas shigelloides Septic
Shock Following Ingestion of Dojo Nabe (Loach
Hotpot). Open Forum Infect Dis. 2021 Jul 26;
8(8):ofab401.
Kurokawa R, Inui S, Gonoi W, Nakai Y, Ishida
M, Watanabe Y, Kubo T, Amano Y, Okamoto K,
Kage H, Harada S, Tanaka G, Kawahara T,
Nagase T, Moriya K, Abe O. Standardized
reporting systems of chest computed tomography
in a population with low coronavirus disease2019 prevalence: A retrospective comparative
study. Heliyon. 2021 Aug;7(8):e07743.
Sato Y, Atarashi K, Plichta DR, Arai Y, Sasajima
S, Kearney SM, Suda W, Takeshita K, Sasaki T,
Okamoto S, Skelly AN, Okamura Y, Vlamakis H,
Li Y, Tanoue T, Takei H, Nittono H, Narushima
S, Irie J, Itoh H, Moriya K, Sugiura Y, Suematsu
M, Moritoki N, Shibata S, Littman DR,
Fischbach MA, Uwamino Y, Inoue T, Honda A,
Hattori M, Murai T, Xavier RJ, Hirose N, Honda
K. Novel bile acid biosynthetic pathways areenriched in the microbiome of centenarians.
Nature. 2021 Nov;599(7885):458-464.
Shimura T, Kurano M, Okamoto K, Jubishi D,
Kano K, Igarashi K, Shimamoto S, Aoki J,
Moriya K, Yatomi Y. Increase in serum levels ofphosphatidylserine-specific phospholipase A 1 in
COVID-19 patients. Cell Mol Immunol. 2021
Sep;18(9):2275-2277.
Hangai S, Kawamura T, Kimura Y, Chang CY,
Hibino S, Yamamoto D, Nakai Y, Tateishi R,
Oshima M, Oshima H, Kodama T, Moriya K,
Koike K, Yanai H, Taniguchi T. Orchestration of
myeloid-derived suppressor cells in the tumor
microenvironment by ubiquitous cellular protein
TCTP released by tumor cells. Nat Immunol.
2021 Aug;22(8):947-957.
Mizoguchi M, Harada S, Okamoto K, Higurashi
Y, Ikeda M, Moriya K. Comparative performanceand cycle threshold values of 10 nucleic acidamplification tests for SARS-CoV-2 on clinicalsamples. PLoS One. 2021 Jun 23;16(6):e0252757.

14. Nishikawa H, Shiraki M, Hiramatsu A, Hara N,
Moriya K, Hino K, Koike K. Reduced handgrip
strength predicts poorer survival in chronic liverdiseases: A large multicenter study in Japan.
Hepatol Res. 2021 Sep;51(9):957-967.
15. Ikeda M, Wakabayashi Y, Okamoto K,
Yanagimoto S, Okugawa S, Moriya K. Changing
trends in lipid profile and biomarkers of renal
function and bone metabolism before and afterswitching from tenofovir disoproxil fumarate to
tenofovir alafenamide: a prospective observational study. AIDS Res Ther. 2021 May 27;18(1):30.
16. Hirano J, Yoshio S, Sakai Y, Songling L, Suzuki
T, Itoh Y, Zhang H, Chen DV, Haga S, Oomori H,
Kodama T, Maeda Y, Ono Y, Takahashi Y,
Standley DM, Yamamoto M, Moriishi K, Moriya
K, Kanto T, Takehara T, Koike K, Matsuura Y,
Okamoto T. Hepatitis C virus modulates signal
peptide peptidase to alter host protein processing.
Proc Natl Acad Sci U S A. 2021 Jun 1;118(22):e2026184118.
17. Ikeda M, Kobayashi T, Fujimoto F, Okada Y,
Higurashi Y, Tatsuno K, Okugawa S, Moriya K.
The prevalence of the iutA and ibeA genes in
Escherichia coli isolates from severe andnon-severe patients with bacteremic acute biliary
tract infection is significantly different. Gut
Pathog. 2021 May 18;13(1):32.
18. Okushin K, Suzuki R, Tsutsumi T, Okamoto K,
Ikeuchi K, Kado A, Minatsuki C, MinamiKobayashi Y, Satoh N, Ikeda M, Harada S,
Enooku K, Fujinaga H, Yotsuyanagi H, Koike K,
Moriya K. Change in hepatitis C virus positivity
among needle-stick injury source patients: a
10-year experience in a Japanese tertiary hospital.
BMC Infect Dis. 2021 Apr 30;21(1):399.
19. Amano Y, Kage H, Tanaka G, Gonoi W, Nakai Y,
Kurokawa R, Inui S, Okamoto K, Harada S,
Iwabu M, Morizaki Y, Abe O, Moriya K, Nagase
T. Diagnostic prediction of COVID-19 based onclinical and radiological findings in a relatively
low COVID-19 prevalence area. Respir Investig.
2021 Jul;59(4):446-453.
20. Oyama Y, Yasunaga M, Honda A, Maki H,
Masamoto Y, Kobayashi T, Wakabayashi Y,
Okugawa S, Moriya K, Kurokawa M. Severe
cellulitis caused by Achromobacter xylosoxidans

58

21.

22.

23.

24.

25.

26.

27.

after allogeneic hematopoietic stem celltransplantation. J Infect Chemother. 2021 May;27(5):770-772.
Ikeuchi K, Okamoto K, Inoue N, Okugawa S,
Moriya K. Chronic Disseminated Gonococcal
Infection in a Japanese Man with Novel C5 Gene
Mutation. J Clin Immunol. 2021 Apr;41(3):691693.
Ishihara Y, Okamoto K, Shimosaka H, Ono Y,
Kanno Y, Ikeda M, Harada S, Kurano M,
Okugawa S, Moriya K, Yatomi Y. Prevalence
and clinical characteristics of patients withbiologicallyfalse-positive
reactionswithserological syphilis testing in contemporary
practice: 10-year experience at a tertiary
academic hospital. Sex Transm Infect. 2021 Sep;
97(6):397-401.
Osawa I, Okamoto K, Ikeda M, Otani A,
Wakimoto Y, Yamashita M, Shinohara T, Kanno
Y, Jubishi D, Kurano M, Harada S, Okugawa S,
Yatomi Y, Moriya K. Dynamic changes infibrinogen and D-dimer levels in COVID-19
patients on nafamostat mesylate. J Thromb
Thrombolysis. 2021 Apr;51(3):649-656.
Shimura T, Kurano M, Kanno Y, Ikeda M,
Okamoto K, Jubishi D, Harada S, Okugawa S,
Moriya K, Yatomi Y. Clot waveform of APTT
has abnormal patterns in subjects with
COVID-19. Sci Rep. 2021 Mar 4;11(1):5190.
Yokoyama R, Kurano M, Morita Y, Shimura T,
Nakano Y, Qian C, Xia F, He F, Kishi Y, Okada
J, Yoshikawa N, Nagura Y, Okazaki H, Moriya K,
Seto Y, Kodama T, Yatomi Y. Validation of a
new automated chemiluminescent anti-SARSCoV-2 IgM and IgG antibody assay system
detecting both N and S proteins in Japan. PLoS
One. 2021 Mar 4;16(3):e0247711.
Nakano Y, Kurano M, Morita Y, Shimura T,
Yokoyama R, Qian C, Xia F, He F, Kishi Y,
Okada J, Yoshikawa N, Nagura Y, Okazaki H,
Moriya K, Seto Y, Kodama T, Yatomi Y. Timecourse of the sensitivity and specificity ofanti-SARS-CoV-2 IgM and IgG antibodies for
symptomatic COVID-19 in Japan. Sci Rep. 2021
Feb 2;11(1):2776.
Kobayashi T, Nakajima K, Oshima Y, Ikeda M,
Kitaura S, Ikeuchi K, Okamoto K, Okada Y,

28.

29.

30.

31.

32.

33.

34.

Ohama Y, Higurashi Y, Okugawa S, Moriya K.
First Reported Human Case of Spondylodiscitis
by Staphylococcus condimenti: A Case Reportand Literature Review. Intern Med. 2021 Feb 15;
60(4):635-637.
Yamamoto S, Ikeda M, Kanno Y, Okamoto K,
Okugawa S, Moriya K. Microbiological analysis
of infectious lymphocele: Case series andliterature review. J Infect Chemother. 2021 Feb;
27(2):172-178.
Harada S, Suzuki M, Sasaki T, Sakurai A, Inaba
M, Takuya H, Wakuda M, Doi Y. Transmission
of NDM-5-Producing and OXA-48-Producing
Escherichia coli Sequence Type 648 byInternational Visitors without Previous Medical
Exposure. Microbiol Spectr. 2021 Dec 22;9(3):e0182721.
Nakamura K, Nomoto H, Harada S, Suzuki M,
Yomono K, Yokochi R, Hagino N, Nakamoto T,
Moriyama Y, Yamamoto K, Kutsuna S,
Ohmagari N. Infection with capsular genotype
K1-ST23 hypervirulent Klebsiella pneumoniae
isolates in Japan after a stay in East Asia: Twocases and a literature review. J Infect Chemother.
2021 Oct;27(10):1508-1512.
Takeda K, Harada S, Hayama B, Hoashi K,
Enokida T, Sasaki T, Okamoto K, Nakano K,
Ohkushi D. Clinical characteristics and risk
factors associated with Pneumocystis jirovecii
infection in patients with solid tumors: study ofthirteen-year medical records of a large cancer
center. BMC Cancer. 2021 Sep 3;21(1):987.
Harada S, Aoki K, Ohkushi D, Okamoto K,
Takehana K, Akatsuchi T, Ida K, Shoji D, Ishii Y,
Doi Y, Moriya K, Hayama B. Institutional
outbreakinvolving
multiplecladesofIMP-producing Enterobacter cloacae complex
sequence type 78 at a cancer center in Tokyo,
Japan. BMC Infect Dis. 2021 Mar 22;21(1):289.
Hosoda T, Harada S, Okamoto K, Ishino S,
Kaneko M, Suzuki M, Ito R, Mizoguchi M.
COVID-19 and Fatal Sepsis Caused byHypervirulent Klebsiella pneumoniae, Japan,
2020. Emerg Infect Dis. 2021 Feb;27(2):556-559.
Kubota Y, Ishioka H, Harada S, Suzuki M,
Shiotsuka J, Lefor AK, Sanui M. Septic shockwithemphysematouscholecystitis
and

59

disseminated infection caused by hypervirulent
Klebsiella pneumoniae capsular genotype
K2-ST65 in a Japanese man with diabetes
mellitus: A case report. J Infect Chemother. 2021
Feb;27(2):350-353.

Pathology, Immunology andMicrobiology
3. Immunology

61

Department of Immunology
Professor
Hiroshi Takayanagi, M.D., Ph.D.

Associate Professor
Takeshi Nitta, Ph.D.

Assistant Professor
Noriko Komatsu, Ph.D.; Hiroyuki Takaba, Ph.D.

Homepage

http://www.osteoimmunology.com/

Introduction and Organization
The history of the Department of Immunology,
formerly the Department of Serology, dates back to1918. The department adopted its present name when
Dr. Tomio Tada took his position as professor andchair in 1977. Through his innovative research andgreat contributions to the international community of
immunologists, Dr. Tada raised the stature of thedepartment to a world-renowned status. After Dr.
Tada’s retirement in 1994, Dr. Tadatsugu Taniguchi,
presently the project professor of the Department of
Molecular Immunology at the Research Center for
Advanced Science and Technology, the University ofTokyo, performed cutting-edge, internationallyrecognized research in the field of immunology
especially cytokine systems in the context of theregulation of immunity and oncogenesis. Dr.
Taniguchi’s major achievements were the discovery ofinterferon-β and a new family of transcription factors,
termed interferon regulatory factors (IRFs).
On May 2012, Dr. Hiroshi Takayanagi started the
new laboratory aiming to shed light on two major
questions; First, why self-tolerance are broken in
autoimmune diseases? Second, what is the immune
network among multiple organs including bone andneuron?

Teaching activities
All members of our department take very seriously
their responsibilities to teach and train the next

generation of scientists. Undergraduate students of thefaculty take part in departmental class work throughlectures on immunobiology, immunochemistry andmolecular immunology as well as practical training by
way of laboratory courses on basic immunology
experimental techniques. The education of graduate
students is based on weekly seminars where students
present the progress of their own research projects,
discuss the future directions of their research and theresearch of others, and are exposed to the latest
cutting-edge questions confronting the research fieldof immunology. We also offer a special training course(called ‘free quarter’) of basic and advanced
biological and immunological techniques to medical
students. We are also accepting undergraduate
students as Medical Scientist Training Program infaculty of medicine. In fiscal year 2020, special
lectures for undergraduate students were given byinternationally recognized scientists, Dr. Shimon
Sakaguchi (Osaka Univ.), Dr. Hitoshi Sakano (Fukui
Univ.), Dr. Hiroshi Kawamoto (Kyoto Univ.), and Dr.
Tadatsugu Taniguchi (The Univ. of Tokyo).

Research activities
We aim to achieve further understanding of themechanisms controlling the immune system, focusing
on the development and function of tissue
microenvironments in lymphoid organs, such as bone
and thymus, and molecular basis for lymphocyte
development and activation. The final goal of our62

study is to develop epoch-making strategies for thetreatment of immune disorders such as autoimmune
diseases and severe infectious diseases.
1) Osteoimmunology
The bone and immune systems share a variety ofmolecules and interact with each other underphysiological and pathological conditions, constituting
the “osteoimmune system” which functions as alocomotor organ and a mineral reservoir as well as a
primary lymphoid organ (Tsukasaki & Takayanagi.
Nat Rev Immunol., 2019). The bone marrow is a
primary lymphoid organ that plays a critical role inimmune cell development. The crucial stromal cell
types that support hematopoietic cell development in
the bone marrow have not been clarified. We reported
the crucial role of osteoblasts in supporting lymphoidlineage development within the bone marrow microenvironment (Terashima et al., Immunity, 2016). The
mice genetically ablated for osteoblasts exhibited amarked reduction of the number of common lymphoidprogenitor cells in the bone marrow and mature
lymphocytes in the periphery. Our results showed that
osteoblasts play a pivotal role in maintenance ofcommon lymphoid progenitors through the productionof IL-7. Furthermore, using a mouse model of sepsis,
we showed that sepsis rapidly ablated osteoblasts,
which reduced the common lymphoid progenitor
number and thereby resulted in peripheral
lymphopenia. This study demonstrates a reciprocalinteraction between the immune and bone systems, inwhich acute inflammation induces a defect in bone
cells
resultinginlymphopenia-associatedimmunodeficiency, suggesting that osteoblasts are apotential therapeutic target of the treatment ofinflammatory diseases.
Osteoclasts are polynuclear cells derived from themonocyte/macrophage lineage, which are responsible
for bone resorption. Aberrant osteoclast function anddevelopment is involved in the pathogenesis of several
diseases such as the inflammatory bone destruction
observed in rheumatoid arthritis as well as postmenopausal osteoporosis and osteopetrosis. Osteoclast
development is dependent on TNF family cytokine
receptor activator of nuclear factor kappa-B ligand(RANKL). We studied the receptor signal transduction
pathway for RANKL and identified nuclear factor of

activated T cells c1 (NFATc1) as a master regulator for
osteoclast differentiation (Takayanagi et al., Dev Cell,
2002; Asagiri et al., J. Exp. Med., 2005). We also
identified an ITAM-harboring co-receptor for RANK
(Koga et al., Nature, 2004) and the importance ofbridging signal cascade between RANK and ITAM
via Btk for RANK dependent osteoclastogenesis(Shinohara et al., Cell, 2008; Shinohara et al., Bone,2014). Our recent proteomic analysis identified
multiple target proteins phosphorylated upon
differentiation of osteoclasts (Sumiya et al., Biochem
Biophys Res Commun., 2015).
Furthermore, we have revealed the roles of
Semaphorin4D on osteoblast differentiation (NegishiKoga et al., Nature Med. 2011) and Semaphorin3A on
inhibition of bone resorption as well as promotion ofbone formation (Hayashi et al., Nature, 2012; Hayashi
et al., Cell Metab., 2019). We also found that immune
complexes in serum activate osteoclastogenesis andcause bone loss through binding to Fcγ receptors(Negishi-Koga et al., Nat Commun., 2015). To
understand the precise mechanisms underlying cellfate specification during osteoclast differentiation, we
performed single-cell RNA sequencing (scRNA-seq)
analysis on the in vitro osteoclast culture system, andprovided a comprehensive picture of molecular
processes underlying osteoclastogenesis (Tsukasaki etal., Nat Metab., 2020). We also reported that, using abone-fracture model in mouse, the cytokine IL-17
promotes bone fracture healing via osteoblastic boneformation and that γδT cells are the major source of
IL-17 produced in the bone injury site (Ono et al., Nat
Commun., 2016). Although it has been known that
IL-17 enhances osteoclastic bone resorption in certain
pathological situations, our current results clearlyshow the promoting effect of IL-17 on boneformation,
Most recently, we found that oral bacteria promote
the conversion of Foxp3+T cells into Th17 cells(exFoxp3Th17 cells) in periodontitis which is one of
the most common infectious diseases. exFoxp3Th17
cells were found to be the most potent bone-damaging
T cells. Interestingly, these bone-damaging
exFoxp3Th17 cells protect against oral bacteria in two
different ways. First, they elicit mucosal immune
responses mainly by the production of anti-bacterial
products. Second, they inhibit bacterial dissemination

63

by removing the tooth. Thus, exFoxp3Th17 cells playa beneficial role in the host defense against oral
bacteria. This investigation highlighted the notion that
T-cell-mediated bone damage, which was considered
to be an adverse consequence of inflammation, may
have developed to contribute to host defense against
oral bacteria (Tsukasaki et al., Nat Commun., 2018).
An anti-RANKL neutralizing antibody has been
introduced for the treatment of osteoporosis,
skeletal-related events by bone metastasis and bone
destruction in rheumatoid arthritis. We havedemonstrated that oral administration of the novel
small-molecule inhibitor against RANKL suppressedbone metastasis using the mouse models, indicating
the great efficacy of RANKL inhibition with asmall-molecule compound in bone metastasis (Nakai
et al., Bone Res., 2019). RANKL is synthesized asmembrane-bound molecule, and cleaved into its
soluble form by proteases. We have reported thatsoluble RANKL is dispensable for physiologicalregulation of bone and immune systems, but has adistinct and pivotal role in the promotion of bonemetastasis (Asano et al., Nat Metab., 2019). TheRANKL system plays a central role in bone andimmune homeostasis, but the source of OPG, thedecoy receptor for RANKL, has long been unknown.
We generated OPG-floxed mice and showed that
locally produced OPG, but not circulating OPG, has a
crucial function in the thymus, bone, and intestine(Tsukasaki et al., Cell Rep., 2020). These findings
provided a new paradigm for physiological interaction
between bone and immune system.
2) Lymphocyte development and lymphoid tissue
microenvironment
Thymus is the primary lymphoid organ that
supports development of useful T cells (positive
selection)

andeliminates

self-reactive

T

cells

(negative selection). The microenvironment of thethymus is mainly composed of thymic epithelial cells
that regulate selections of developing T cells.
Recently, we focused on thymic fibroblasts, astromal cell type with uncharacterized function in thethymus, and established a method to isolate the thymic
fibroblast subsets, capsular fibroblasts and medullary

fibroblasts. Our results demonstrated that medullary
fibroblasts contribute to the induction of T cell
self-tolerancebyproducingauniquesetofself-antigens (Nitta et al, Nat Immunol., 2020; Nitta etal, Immunol Rev., 2021). Fibroblasts have been
attracting much attention in recent years due to theirfunctional diversity in different organs and theirability to control various biological responses throughinteractions with immune cells. It is expected that ourfindings contribute to the elucidation of the functionsof various types of fibroblasts in vivo. In addition, we
reported that the transcription factor Sox4 is required
for the development of thymic tuft cells, a subset ofterminally differentiated medullary thymic epithelial
cells (mTECs). Our findings suggest that mTECs
employ the same transcription programs as peripheral
epithelial cells to ‘project’ an immunological self
within the thymus for the establishment of central
self-tolerance.
We have reported that the genetic variations ofhuman PSMB11 gene, which encodes β5t, a thymusspecific proteasome subunit, affected the MHC class
I-bound peptide repertoire in the thymus and positive
selection of CD8 T cells (Nitta et al., Sci Immunol.,2017). One of the PSMB11 polymorphisms, G49S,
detected in the Japanese population at a highfrequency, was associated with a higher risk of
Sjögren’s syndrome. These results suggested that, in
addition to the MHC haplotype, genetic variations ofproteasome influence T cell repertoire selection andsusceptibility to autoimmunity. Elucidation of theprinciples of T-cell repertoire selection is one of mostimportant issues in immunology. We have been
continuing our research efforts including a recent
release of updated protocols for gene transduction
method optimized for T-cell repertoire analysis (Muroet al, Methods Mol Biol., 2020).
We have also been studying on thymic developmentof γδT cells. We showed that the γδTCR signal
mediated by the Syk-PI3K pathway is essential forthymic development of IL-17-producing γδT cells(Muro et al., J Clin Invest., 2018). These findings
suggest that the Syk-PI3K pathway might be a64therapeutic target of inflammatory diseases. Recently,
we generated mutant mice lacing all of the Skint
family genes (Skint1-11) that encode candidate thymic
factors for regulation of γδT cell development (Narita
et al., Int Immunol., 2018). These mice exhibited amarked reduction of Vγ5Vδ1 γδT cells in the thymus
and skin, but had normal development of other γδTcell subsets and leukocytes. This study indicates an
exclusive function of Skint family genes in thedevelopment of Vγ5Vδ1 γδT cells and provides auseful animal model to analyze the mechanism forthymic education of γδT cells.
Much attention has been paid to the development
and function of the gut-associated lymphoid tissues(GALTs) and the symbiotic relationship between thegut microbiota and host immune system. We
identified a previously unrecognized subset ofmesenchymal cells in the subepithelial dome of
GALTs (Nagashima et al., Nat Immunol., 2017).
These cells expressed high levels of RANKL anddirectly interacted with the gut epithelium to induce
microfold (M) cell differentiation and CCL20
expression. The deletion of RANKL in mesenchymal
cells impaired M cell-dependent antigen sampling,which resulted in a reduction in IgA production and adecrease in microbial diversity, indicating thatsubepithelial RANKL-expressing mesenchymal cells(M cell inducer (MCi) cells) are key players in themaintenance of host-microbe symbiosis. Furthermore,
we reported that Col6a1-Cre driver mice are useful tostudy the function of MCi cells (Nagashima et al.,Biochem Biophys Res Commun., 2017). Manipulationof MCi cells may provide a molecular basis for novel
treatments of intestinal diseases such as inflammatory
bowel disorders and infectious diseases.
We have recently found that protein arginine
methylation, a post-translational modification, is an
essential regulator of T cell maintenance. T
cell-specificdeficiency
ofthearginine
methyltransferase PRMT5 led to a decrease in thenumber of peripheral CD4, CD8 and regulatory T cells,
and an almost complete loss of iNKT cells.
PRMT5-mediated arginine methylation was essential
for the expression of the cytokine-signal-transducing
components, the common cytokine receptor γ-chain(γc) and JAK3, which are required for thedevelopment of iNKT cells and the proliferation andsurvival of peripheral T cells. PRMT5 induced thearginine methylation of the spliceosomal component
SmD3 that promoted the splicing of pre-mRNA
encoding γc and JAK3. In recent years, Jak inhibitors
have attracted attention as potential agents for the
autoimmune diseases such as rheumatoid arthritis.
This study presented an entirely new regulatory
mechanism governing γc family cytokine-Jak3
signaling in T cells (Inoue et al., Nat Immunol., 2018).
3) Mechanism of autoimmune disease
The IL-17 producing helper T cell subset (Th17cell) plays critical roles in several autoimmune diseasemodels such as collagen induced arthritis (CIA) andexperimental encephalomyelitis (EAE). We haveidentified IκBζ as an indispensable transcription
factor for Th17 cell differentiation (Okamoto et al.,Nature, 2010). However, in both RA and EAE models,effector mechanisms of Th17 cells have been unclear.
Recently, we identified a subset of Th17 cells thatrobustly produces IL-17 and RANKL and exacerbates
both inflammation and bone destruction in CIA mice.
Interestingly these Th17 cells are the progeny of CD4
T cells expressing Foxp3, a master regulator for
immunosuppressive Treg cells (Komatsu et al., Nat
Med., 2014). We also reported that RANKL producedby synovial fibroblasts is primarily responsible for theformation of bone-destructive osteoclasts in inflammatory arthritis (Danks et al., Ann Rheum Dis., 2016).
Periarticular bone loss is one of the earliest indices ofRA, often preceding the onset of clinical symptoms
via largely unknown mechanisms. We found that bonemarrow plasma cells promote periarticular bone loss
as RANKL-expressing osteoclast inducer cells(Komatsu et al., J Clin Invest., 2021). These results
show that the targeting these cells and/or molecules
could be effective in preventing bone destruction inRA.
To elucidate a role of RANKL on T cells, we
generated T cell-specific RANKL-deficient mice.
These mice were protected from EAE, a mouse modelof multiple sclerosis, due to an impairment of
infiltration of pathogenic T cells into the central
nervous system (CNS). RANKL on T cells stimulates
the chemokine production by astrocytes, leading to thechronic inflammation in the CNS. Pharmacologicalinhibition of RANKL prevented the development of

65

EAE, indicating that RANKL is a potential therapeutictarget for treatment of multiple sclerosis (Guerrini etal., Immunity, 2015).
We have also been studying the mechanism of T
cell tolerance induction, because a breakdown of T
cell tolerance induces autoimmune diseases. Selftolerance of T cells is primarily established during
their development in the thymic medulla, wheremTECs
ectopically
expressavarietyoftissue-restricted antigens (TRAs) and thereby
TRA-reactive immature T cells are deleted. It has
been known that expression of a set of TRAs isregulated by the transcriptional regulator Aire,although how the remaining TRAs are regulated has
been unclear. We identified a novel key transcription
factor Fezf2, which is highly expressed in mTECs andcontrols the expression of a large fraction of
Aire-independent TRAs (Takaba et al., Cell, 2015).
Mice lacking Fezf2 in mTECs exhibited severe
autoimmune disorders in peripheral organs, and thespectrum of autoimmunity in Fezf2-deficient micediffered from that in Aire-deficient mice. These
results indicate that two independent factors, Fezf2
and Aire, play non-redundant and mutually complementary roles in the TRA expression to ensure T cell
tolerance induction. In addition, we identified Chd4 as
chromatin remodeler interacting with Fezf2. Chd4
works with not only Fezf2 but Aire to promote
promiscuous TRA expression in mTECs, mediating
central immune tolerance (Tomofuji et al., Nat
Immunol., 2020). Thus, these studies represented
important advance in our understanding of themechanisms underlying the immune tolerance andautoimmune diseases.

References
1.

2.

3.

Tsukasaki M, Takayanagi H. Osteoimmunology:
evolving concepts in bone-immune interactions inhealth and disease. Nat Rev Immunol., 19: 626-642(2019)
Tsukasaki et al., Stepwise cell fate decision
pathways during osteoclastogenesis at single-cellresolution. Nat Metab., 2: 1382–1390 (2020)
Tsukasaki et al., OPG Production Matters Where
It Happened. Cell Rep., 2: 1382–1390 (2020)

4.

5.

6.

7.

8.

9.

Nitta et al., Fibroblasts as a source ofself-antigens for central immune tolerance. Nat
Immunol., 21: 1172–1180 (2020)
Nitta et al., The fibroblast: an emerging key
player in thymic T cell selection. Immunol Rev,
302: 68-85 (2021)
Muro R, Takayanagi H, Nitta T. Retroviral genetransduction into T-cell progenitors for analysis
of T cell development in the thymus. Methods
Mol Biol., 2111, 193-203 (2020)
Mino et al., The Transcription Factor Sox4 is
Required for Thymic Tuft Cell Development. Int
Immunol., 34: 45-52 (2022)
Komatsu et al., Plasma cells promoteosteoclastogenesis and periarticular bone loss in
autoimmune arthritis. J Clin Invest., 131:
e143060 (2021)
Tomofuji et al., Chd4 choreographs self-antigen
expression for central immune tolerance. Nat
Immunol., 21: 892–901 (2020)

Radiology and Biomedical
Engineering
1. Radiology

67

Department of Radiology
Professor
Osamu Abe, M.D., Ph.D.

Associate Professor
Hideomi Yamashita, M.D., Ph.D., Hidemasa Takao, M.D., Ph.D.,
Takeyuki Watadani, M.D., Ph.D.

Lecturer
Shouhei Hanaoka, M.D., Ph.D., Shiori Amemiya, M.D., Ph.D., Atsuto Katano, M.D., Ph.D.

Project Lecturer
Naotoshi Ishida, M.D., Ph.D.

Assistant Professor
Nawa Yobu, Ph.D., Mami Ogita, M.D., Soichiro Miki, M.D., Ph.D.
Ryousuke Takenaka, M.D., Ph.D., Eisuke Shibata, M.D., Ph.D., Koichiro Yasaka, M.D.,
Ph.D., Yusuke Watanabe, M.D., Ph.D., Yudai Nakai, M.D., Ph.D., Takatoshi Kubo, M.D.,
Ph.D., Subaru Sawayanagi, M.D., Ph.D., Ryu Miyagawa, Ph.D.

Project Assistant Professor
Fumio Suzuki, M.D., Ph.D., Yuta Ohtake, M.D. Takeshi Ohta, R.T., Ph.D., Hisaichi Shibata,Ph.D., Tomomi Takenaga, R.T., Ph.D., Yuki Nozawa, M.Sc.

Homepage

http://www.ut-radiology.umin.jp/

Introduction and Organization
Department of Radiology was established in
1932. Radiology covers three major fields that are,Diagnostic Radiology (imaging and intervention),
Radiation Oncology (radiotherapy), and Nuclear
Medicine. The clinical, educational and research
activities of our department are being carried out incooperation with Department of Radiology in The
Research Institute of Medical Science, which has
three (1 associate professor, 1 lecturer, and 1 assistant professor) positions. In addition, Department ofRadiology mainly takes care of radiation protection
and radiation safety in the hospital.

Clinical activities
Clinical services on Diagnostic Radiology,
Nuclear Medicine, and Radiation Oncology areprovided in the centralized Clinical Radiology
Service Department in cooperation with radiology
technologists and nurses.
In the section of Diagnostic Radiology, all CT
and MRI examinations are monitored and reported
by diagnostic radiologists. Diagnostic radiologists,
gastroenterologists, cardiologists, and neurosurgeons mainly perform interventional procedures.
In the section of Nuclear Medicine, twocyclotrons and several remote or processorcontrolled automated devices are installed, whichfacilitate standardized procedures in the PET tracer
production and the implementation of GMP in
PET-related work. There are two SPECT rooms and
two PET rooms. These nuclear imaging procedures
are chiefly performed and reported by diagnostic
radiologists and cardiologists.

68

Each year, over 700 new patients receive
radiation therapy in the Radiation Oncology section.
Highly accurate 3D radiation therapy is the mostoutstanding feature. Stereotactic radiation therapy
for small lung or liver tumors has been carried out.
In the 9th floor of the new inpatient building,there are 12 beds in the Radiology ward, which areusually used for oncology patients receiving
radiation therapy and chemotherapy. Some of them
are sometimes used for patients receiving invasive
diagnostic procedures such as interventional
radiology (IVR), angiography and myelography.
There are two special beds for radionuclide (RN)
therapy in the same floor. In addition, four beds areallotted to terminal care ward located in the 14th
floor.

Education
Lectures are given to the fourth-, fifth- and sixthyear students to provide fundamental knowledge ofdiagnostic radiology, radiation oncology, andnuclear medicine. Professor, associate professors
and lecturers as well as specialists assigned as parttime lecturers take part in the education. A series oflectures about fundamentals of radiology andrelated sciences are given to the fourth-year
students. As bed-side-learning (Clinical Clerkship,CC) curriculum, small groups of the sixth-year
students are taking part in mini-lectures andpractice to learn basics of diagnostic radiology,
advanced medical techniques of Radiation
Oncology and Nuclear Medicine. They will learn
detailed principles of image constructions invarious kinds of imaging modalities and technology
in radiation therapy against cancer. Postgraduate
students are also welcome to each of subspecialties
of radiology according to their interests.

ResearchResearch activities in our department include
clinical research, animal experiments, and development of instruments as well as computer-based newtechnology
including
artificial
intelligence.
Diagnostic Radiology group in the department
promotes research activities aiming at efficacy
improvement of diagnostic imaging and expansionof its application. Multi-row detector helicalcomputed tomography (MDCT) enables us to taketomographic images in a three-dimensional (3D)fashion. Using the data acquired by MDCT, various
kinds of diseases in almost all parts of the body,from cerebral diseases to musculoskeletal diseases,
can be displayed in 3D images. New 3D softwaredeveloped in our departments is now widely used in
the field of the gastrointestinal tract, lung, andcentral nervous system. In addition, we haveopened a new laboratory section named Image
Computing and Analysis Laboratory with invitationof a new staff from the Faculty of Engineering, theUniversity of Tokyo. This section will contribute todevelopment of novel software including
convolutional neural network to abstract clinicallyuseful information from the 3D imaging data moresophisticatedly. In the field of magnetic resonance(MR) imaging, MR digital subtraction angiography,
perfusion imaging, and diffusion imaging are thefoci of research. These techniques are aggressively
applied to the investigation of vascular andneoplastic diseases of the brain.
Radiation oncology group promotes research
projects in two major fields; one is physicalengineering such as the optimization of dose
distribution in the radiation therapy (RT) and theother is reduction of injuries due to radiation
exposure in vitro and in vivo. This group pushes
forward studies mainly on a brain tumor, head andneck cancer, esophageal cancer, uterine cervicalcancer, prostate cancer in conformity with recent
EBM in the clinical study, and is active in studies ofthe physical engineering traditionally and plays amain role in the highly precise radiation therapy ofour country until now. With the purpose ofachieving precise external irradiation, a new linear
accelerator with multileaf collimator systems wasdeveloped and installed, which is utilized mainly
for non-coplanar radiation therapy in many patients
especially with brain tumor or head and neck tumor.
Dynamic conical conformal radiotherapy formetastatic brain tumors using the accelerator isunder evaluation. In addition to gamma knife
radiosurgery, this new accelerator based stereotactic
radiotherapy for brain diseases has been undergone,and stereotactic radiotherapy (SRT) for body tumors,

69

such as head and neck cancer, prostate cancer, rectal
cancer and lung cancer, has been investigated(intensity modulation radiation therapy; IMRT) for
the reduction of the adverse radiation damage. A
new technology to track mobile tumors, represented
by lung tumors, is under investigation incollaboration with accelerator makers.
Nuclear Medicine group promotes clinicalresearch on functional imaging by the application ofradioisotope-labeled tracer technology, combinedwith molecular biology. In particular, emission
tomography (PET and SPECT) is applied for theevaluation of cerebral blood flow and metabolism
in patients with dementia, epilepsy, and cerebrovascular diseases. Cerebral blood flow, glucose
metabolism, and neural synaptic functions aremeasured for the understanding of normal andpathophysiological states of CNS disorders, using avariety of positron-emitter radiotracer, such as[F-18] FDG,. The study of dementia using SPECTand the standard brain atlas has made it possible tocategorize the type of dementia. Evaluation of
dopaminergic function by SPECT is very importantin the differential diagnosis of Parkinsonism.
Cardiac PET and SPECT are also active fields.
Myocardial viability, vascular reserve, andsympathetic nerve denervation in the ischemic heartdisease are evaluated with [F-18] FDG, Tl-201 and[I-123] MIBG. Higher brain functions such as
reading, speech, and thinking have been studied
with PET by comparing blood flow and receptor
binding potential (BP) under various tasks and atrest. For the precise localization of activated brain
function, computer processing and reconstruction ofcomposite images of function and anatomy is an
essential subject for investigation. At present, wholebody FDG-PET is one of the most effective tool for
exploring metastatic lesions of cancer patients.
Combination display of SPECT/PET with CT/MRI
would be a routine job and anatomo-functional
images would play an important role in the clinicalmanagement of the patients.

Publications
One hundred and thirty seven, 83, and 98 English
original articles have been published from ourdepartment in 2021, 2020, and 2019. respectively.
Pleaserefertoourhomepage,
http://www.ut-radiology.umin.jp/publication/2021.html.

Radiology and Biomedical
Engineering
2. Biomedical Engineering

71

Department of System Physiology
Professor (Concurrent)
Kiyoshi Miyagawa, M.D., Ph.D.

Associate Professor
Kimiko Yamamoto, M.D., Ph.D.

Homepagehttps://square.umin.ac.jp/bme/research_Eng.html

Introduction and Organization

Research activities

Our department originated from the department of
Basic Medical Science, the Institute of Medical
Electronics, established in 1961. In 1997, as a result of
the shift to the chair system of the Graduate School of
Medicine, the Institute was replaced with three departments of Biomedical Engineering: System Physiology,
Bioimaging and Biomagnetics, and Biosystem
Construction and Control. The Department of System
Physiology consists of a Professor (concurrent) and an
Associate Professor.

This laboratory has been pursuing the study ofbiomechanics dealing with mechanical phenomena in
the human body, especially focusing on cellularsensing and response mechanisms to mechanicalstimuli. The main theme of our work is the relationships between shear stress or cyclic strain, which arehemodynamic forces generated by blood flow, andtheir target cells, vascular endothelial cells (ECs). This
would be of benefit not only to understanding blood
flow-mediated regulation of vascular functions but
also to the elucidation of clinically important
problems such as angiogenesis, vascular remodeling,atherogenesis, and development of cerebral aneurysm
which occur in a blood flow-dependent manner.
Original biomedical engineering methods have been
applied, in which cultured ECs are exposed tocontrolled levels of shear stress or cyclic strain in a
fluid–dynamic flow apparatus and whose responses
are analyzed at the cellular and molecular levels.
Microcirculatory hemodynamics and oxygen transportof genetically modified mice are studied by employing
opto-electronics technology. The results of theseexperiments are listed below.

Teaching activities
We give lectures of “Early Exposure to Medicine”
for first year students, “Basic Principles of Biomedical
Engineering” for second and third year students,“Introduction to Biomedical Engineering” for postgraduate students, “Introduction to Medical Science:
Mechanobiology” for master’s students, in the facultyof Medicine, and “Principles of Medicine” forpostgraduate students in the faculty of Engineering.
We offer practical training of biomedical engineeringresearch to third- and fourth-year students of undergraduate medical school. A weekly seminar is held in
our laboratory bringing together staff and research
fellows to discuss journal articles and give updates on
experiments. Our aim is to enhance the research skillsof students.

1. Cell responses to hemodynamic forces
2. Hemodynamic force-mediated gene regulation
3. Hemodynamic force-induced cell differentiation
4. Mechanosensing and mechanotransduction
5. Shear stress-induced mitochondria oxidative
Phosphorylation
6. Hemodynamic force-induced changes in plasma
membrane cholesterol levels

72

1. Cell responses to hemodynamic forces
Our studies have demonstrated that ECs havefunctional responses to hemodynamic forces, shear
stress and cyclic strain. When a cultured EC
monolayer was partially denuded, surrounding cells
migrated and proliferated in the denuded area, andcovered the denuded area. Shear stress enhanced theregenerative functions of ECs. Shear stress increased
the production of nitric oxide, a potent vasodilator, in
ECs in a dose-dependent manner. Shear stress also
increased the expression of thrombomodulin, an
antithrombotic molecule, in ECs. In contrast, it
decreased the expression of vascular cell adhesion,
which leads to the inhibition of leukocyte adhesion tovascular cell adhesion molecule-1 (VCAM-1). It was
shown that shear stress increases the levels of
adrenomedulin and C-type natriuretic peptide mRNA
which have vasodilating effects in addition to nitricoxide, and that it also augmented the expression oflectin like low density lipoprotein receptor (LOX-1) at
the protein and mRNA level.

2. Hemodynamic force-mediated gene regulation
We have demonstrated that shear stress regulates
endothelial gene expression transcriptionally and/or
posttranscriptionally. Shear stress downregulates
VCAM-1 gene transcription via the double AP-1
binding element (TGACTCA) in the promoter whichfunctions as a shear stress-responsive element. Shearstress has also been shown to increase the expression
level of granulocyte/macrophage-colony stimulating
factor (GM-CSF) via mRNA stabilization. Differential
display and DNA microarray analysis showed thataround 600 known and unknown transcripts were upor down-regulated in human umbilical vein ECs
exposed to a shear stress. From these shear stressresponsive genes, a cDNA encoding an unknown
G-protein coupled receptor was cloned. We showedthat the transcription factor SP1 is involved in theshear stress-induced down-regulation of P2X4 (anATP-gated cation channel) gene expression in ECs.
We also revealed that endothelial genes aredifferentially regulated by laminar and turbulent shear
stress. Laminar shear stress decreases the gene
expression of urokinase plasminogen activator (uPA),which plays a role in fibrinolysis and vascular remodeling, via both GATA6-mediated down-regulationof gene transcription and an acceleration of mRNAdegradation, while turbulent shear stress increases theuPA gene expression through mRNA stabilization. We
demonstrated that shear stress up-regulates the gene
expression of plasminogen activator inhibitor-1(PAI-1) through activation of transcription factors
Sp-1 and Ets-1 in human hepatocytes. We developed acompliant tube-type flow-loading device that allows
simultaneous application of physiological levels ofshear stress and cyclic strain to cultured cells andobserved that the response of endothelial genes toshear stress or cyclic strain depends on whether thetwo forces are applied separately or together.

3.
Hemodynamic
differentiation

force-inducedcell

We have revealed that endothelial progenitor cells(EPCs) circulating in human peripheral blood
proliferate and differentiate into mature ECs in
response to shear stress, thereby forming tube-likestructures in collagen gel. Moreover, we revealed thatshear stress increased the gene expression of thearterial EC marker ephrinB2 in EPCs, while itdecreased the gene expression of the venous EC
marker EphB4, suggesting that shear stress affects
arterial-venous differentiation of EPCs.
Embryonic stem (ES) cells have the potential todifferentiate into every cell type in the body, andattracting interest as a promising source of cells foruse in regenerative medicine. Embryonic cells are
exposed to fluid-mechanical forces, including shear
stress and the cyclic strain generated by beating heart
during the process of embryonic development. We
found that shear stress induces the differentiation ofmurine ES cells into vascular EC lineage in vitro;
cyclic strain induces the differentiation into vascularsmooth muscle cell (SMC) lineage. Differentiation
into the EC lineage and differentiation into SMC
lineage are mediated by ligand-independent
phosphorylation of vascular endothelial growth factor
receptor 2 (VEGFR2) and platelet derived growth
factor receptor (PDGFR), respectively. Moreover, ourstudy has shown that shear stress increases expressionof ephrinB2 in murine ES cells via the VEGF-Notch
signaling pathways, suggesting that shear stress canalso affect the arterial-venous differentiation of ES
cells. Based on these findings, in a collaborative study,

73

a new hybrid type of artificial blood vessel, in which
ES cells were cultured on the surface of polymer tubes
and exposed to pulsatile shear stress and cyclic strain,
was developed.

4. Mechanosensing and mechanotransduction
We were the first to show that Ca2+ signaling plays
an important role in the mechanism by which ECs
recognize the shear stress signal and transmit it into
the cell interior. Strong shearing forces induced by
dragging ECs with a balloon causes an increase incytoplasmic Ca2+ concentrations. A relatively weak
shearing force like shear stress generated by fluid flowneeds the presence of extracellular ATP to induce Ca2+
response, and at several hundred nanomolar of ATP,intracellular Ca2+ concentrations increase in a shear
stress-dependent manner. Generally, flow-induced
Ca2+ responses are initiated at a locus at the cell edge
and propagate throughout the entire cell in the form ofa Ca2+ wave. The initiation locus corresponded
precisely to caveolae rich cell edges. We found that a
subtype of ATP-gated cation channel, the P2X4
receptor, is expressed in human vascular ECs and that
P2X4 receptors play a crucial role in the shear stressdependent Ca2+ response. Endogenously released ATP
by shear stress is involved in the P2X4-mediated Ca2+
responses. We produced P2X4-deficient mice andobserved that the P2X4-deficent mice have impaired
flow-dependent control of vascular tone and remodeling, indicating that shear stress signal transduction via
P2X4 plays a critical role in the regulation of circulatory functions.
Our study revealed that cell surface ATP synthase
localized in caveolae/lipid rafts are involved in theshear-stress-induced ATP release by ECs. Recently, wedemonstrate that the cellular mitochondria play a
critical role in this process. Cultured humanpulmonary artery ECs were exposed to controlledlevels of shear stress in a flow-loading device and thechanges in the mitochondrial ATP levels were
examined by real-time imaging using a fluorescenceresonance energy transfer-based ATP biosensor.
Immediately upon the exposure of the cells to flow,
the mitochondrial ATP levels increased, which wasboth reversible and dependent on the shear stressintensity. Inhibitors of the mitochondrial electrontransport chain and ATP synthase, as well as

knockdown of caveolin-1, a major structural protein of
the caveolae, abolished the shear-stress-induced
mitochondrial ATP generation, resulting in the loss of
the ATP release and influx of Ca2+ into the cells. These
results suggest the novel role of the mitochondria intransducing the shear stress into ATP generation: theATP generation leads to ATP release in the caveolae,
triggering purinergic Ca2+ signaling. Thus, exposureof ECs to shear stress seems to activate mitochondrial
ATP generation through caveola- or caveolin-1mediated mechanisms.
Moreover, we report that the plasma membrane
itself differentiates between shear stress and stretch byundergoing transitions in its lipid phases. Shear stressdecreased the lipid order of human pulmonary artery
EC plasma membranes, thereby causing a transition
from the liquid-ordered phase to the liquid-disorderedphase in some areas, along with an increase inmembrane fluidity. In contrast, uniaxial stretching andhypotonic swelling increased the membrane lipid
order and decreased membrane fluidity. A similar
increase in lipid order occurred when the artificial
lipid bilayer membranes of giant unilamellar vesicles
were stimulated by shear stress by using aflow-loading apparatus or stretched by hypotonic
swelling, indicating that mechanical force-mediatedresponses of lipid membranes are physical phenomena.
The cholesterol content of EC plasma membranes
significantly decreased in response to shear stress but
clearly increased in response to stretch. Blocking
these changes in the membrane lipid order bydepleting membrane cholesterol with methylβ-cyclodextrin or by adding cholesterol resulted in amarked inhibition of the EC response specific to shear
stress and stretch, i.e., phosphorylation of VEGFR2
and phosphorylation of PDGFR, respectively. Thesefindings indicate that EC plasma membranes
differently respond to shear stress and stretch bychanging their lipid order, fluidity, and cholesterol
content in opposite directions and that these changes
in membrane physical properties are involved in themechanosensing mechanisms and the mechanotransduction that activates membrane receptors
specific to each force.

5. Shear stress-induced mitochondria oxidative
phosphorylation

74

Vascular endothelial cells (ECs) sense and respondto hemodynamic shear stress, which is critical for
circulatory homeostasis and the pathophysiology ofvascular diseases. The mechanisms of shear stressmechanotransduction, however, remain elusive. We
previously demonstrated a direct role of mitochondria
in the purinergic signaling of shear stress: shear stressincreases mitochondrial ATP production, triggering
ATP release and Ca2+ signaling via EC purinoceptors.
Here, we showed that shear stress rapidly decreases
cholesterol in the plasma membrane, thereby
activating mitochondrial ATP production. Imaging
using D4 mutant-derived cholesterol biosensors
showed that the application of shear stress to cultured
ECs markedly decreased cholesterol levels in both theouter and inner plasma membrane bilayers. Flowcytometry showed that the cholesterol levels in theouter bilayer began to decrease within 3 min after the
onset of shear stress, reached a minimum (around 60%of the control level) at 10 min, and plateaued
thereafter. After the shear stress ceased, the decreasedcholesterol levels returned to those seen in the control.
A biochemical analysis showed that shear stresscaused both the efflux and the internalization ofplasma membrane cholesterol. ATP biosensor imaging
demonstrated that shear stress significantly increased
mitochondrial ATP production. Similarly, thetreatment of cells with methyl-β-cyclodextrin(MβCD), a membrane-cholesterol-depleting agent,increased mitochondrial ATP production. The additionof cholesterol to cells inhibited the increasing effects
of both shear stress and MβCD on mitochondrial ATP
production in a dose-dependent manner. Thesefindings indicate that plasma membrane cholesterol
dynamics are closely coupled to mitochondrial
oxidative phosphorylation in ECs.

6. Hemodynamic force-induced changes
plasma membrane cholesterol levels

ATP release and Ca2+ signaling via EC purinoceptors.
Here, we showed that shear stress rapidly decreases
cholesterol in the plasma membrane, thereby
activating mitochondrial ATP production. Imaging
using D4 mutant-derived cholesterol biosensors
showed that the application of shear stress to cultured
ECs markedly decreased cholesterol levels in both theouter and inner plasma membrane bilayers. Flowcytometry showed that the cholesterol levels in theouter bilayer decreased rapidly after the onset of shear
stress, reached a minimum (around 60% of the control
level) at 10 min, and plateaued thereafter. After the
shear stress ceased, the decreased cholesterol levels
returned to those seen in the control. A biochemical
analysis showed that shear stress caused both theefflux and the internalization of plasma membranecholesterol. ATP biosensor imaging demonstrated thatshear stress significantly increased mitochondrial ATP
production. Similarly, the treatment of cells withmethyl-β-cyclodextrin(MβCD),amembrane-cholesterol-depleting agent, increased
mitochondrial ATP production. The addition ofcholesterol to cells inhibited the increasing effects ofboth shear stress and MβCD on mitochondrial ATP
production in a dose-dependent manner. Thesefindings indicate that plasma membrane cholesterol
dynamics are closely coupled to mitochondrial
oxidative phosphorylation in ECs.

References
1.

in

Vascular endothelial cells (ECs) sense and respond tohemodynamic shear stress, which is critical for
circulatory homeostasis and the pathophysiology ofvascular diseases. The mechanisms of shear stressmechanotransduction, however, remain elusive. We
previously demonstrated a direct role of mitochondria
in the purinergic signaling of shear stress: shear stressincreases mitochondrial ATP production, triggering

2.

H. Tani, B. Li, T. Kusu, R. Okumura, J. Nishimura, D. Okuzaki, D. Motooka, S. Nakamura,
S-H. Tsai, Y. Furuta, M. Muneta, K. Yamamoto,H. Yagita, H. Kayama, and K. Takeda. The
ATP-hydrolyzing ectoenzyme E-NTPD8 attenuates colitis through modulation of P2X4 receptor-dependent metabolism in myeloid cells.
Proc. Natl. Acad. Sci. USA. 118 (39):e2100594118, 2021.
T. Hirata, K. Yamamoto, K. Ikeda, and M. Arita.
Functional lipidomics of vascular endothelial
cells in response to laminar shear stress. FASEB
J. 35: 1-13 (e21301), 2021.

75

Department of Chemical Biology
and Molecular Imaging
Professor
Yasuteru Urano, Ph.D.

Associate Professor
Mako Kamiya, Ph.D.

Assistant Professor
Ryosuke Kojima, Ph.D.

Webpage

http://cbmi.m.u-tokyo.ac.jp/

Introduction and Organization
The Laboratory of Chemical Biology and Molecular
Imaging is one of the laboratories in the department ofRadiology and Biomedical Engineering. Ourlaboratory is located in the annex of the medicalbuilding 3. Our lab members consist of 1 postdoctoral
researcher, 8 PhD students, one master course students,
one technical staff, as of FY2020.

Teaching activities
As for under-graduate education, our laboratory
takes part in medical engineering lectures for the 3rdyear medical students. As for PhD course education,
our laboratory delivers the lecture of fluorescenceimaging for both master and doctor course students.

Research activities
Our lab aims at developing novel fluorescenceprobes and applying these molecules to biology andmedicine. So far, we have succeeded in establishingrational design strategies of fluorescence probes basedon several mechanisms including intramolecularspirocyclization. In FY2020, we have developed a
coumarin-hemicyanine hybrid fluorescent probe forhydrases, a fluorescent probe for super-resolution
microscopy that blinks by the reaction withintracellular glutathione, a γ-glutamyltranspeptidase(GGT)-detecting fluorescence probe with high cellularretention, fluorescence probes for glycosidases todetect breast cancers, and Activatable Raman Probes
for Simultaneous Detection of Plural Enzyme
Activities. The details are described below.
Coumarin-hemicyanine fluorophores (CHCs) haveunique properties such as fluorescence in the redregion, large Stokes shift, and compatibility withratiometricmeasurement.
By
incorporating
intramolecular spirocyclization as a switchingmechanism, we have succeeded in developing a new
fluorescent probe that reacts with GGT and esterases
to significantly change their fluorescence properties.
(Reference [1])Single-molecule localization microscopy (SMLM)
is a powerful technique for super-resolution imaging,but its implementation has generally been limited by
the need for intense laser irradiation and additives toforce molecular blinking. We have succeeded indeveloping new fluorescent probes that spontaneously
blink in response to intracellular glutathione, and usedthem to perform super-resolution imaging of
microtubules and mitochondria in living cells.
(Reference [2])Hydroxymethyl rhodamine (HMR) derivatives arefluorophores that enable the development of various
fluorogenic and super-resolution fluorescent imaging

76probes by appropriately controlling the intramolecularspirocyclization equilibrium (equilibrium between
open and closed forms) and the lifetime of the open
form. On the other hand, the development offluorescent probes with optimized properties required
a time-consuming and labor-intensive process ofsynthesizing various derivatives to identify
fluorescent probes bearing the desired properties. We
have developed a quantum chemical calculation
method to accurately predict the properties of these
fluorescent probes in silico, enabling us to develop
fluorescent probes with desired properties with highprobability by rational design without synthesizing alarge number of derivatives. In addition, this has
enabled us to develop multicolor cancer imaging
fluorescent probes and super-resolution fluorescentimaging probes (Ref. [3, 4]).
Although fluorescent probes that detect GGTactivity are extremely useful for cancer visualization,
conventional probes have the disadvantage of leaking
from the cells after prolonged imaging and fixation
processes. We have succeeded in developing a probethat reacts with GGT followed by nucleophilic attackby intracellular nucleophiles including proteins andglutathione, enabling the fluorescent product to be
trapped inside the cells. By using a patient-derived
xenograft model, we have shown that this probe isindeed resistant to fixation and immunostaining.
(Reference [5])Fluorescent probes to detect breast cancer are
extremely useful tools for fluorescence-guided surgeryof breast cancer, but conventional probes have shownconsiderable background fluorescence even in normal
tissues. We focused on glycosidase activity, which ishighly expressed in breast cancer, and developed alibrary of fluorescent probes containing various sugars.
As a result, we found that the fluorescent probe with
α-mannose showed good results and that the target
enzyme was α-mannosidase 2C1. We also found thatsimultaneous multicolor imaging with a probetargeting GGT can distinguish between malignant andbenign tumors. (Reference [6])Alkyne- and nitrile-tagged Raman probes are
extremely useful for multiplex imaging, but it has
been difficult to develop activatable Raman probesthat visualize enzyme activity. By applying ouraccumulated knowledge of the properties of xanthenedyes, we have succeeded in developing a general
strategy to prepare activatable Raman probes thatshow enhanced Raman signals due to electronic
preresonance (EPR) upon reaction with enzymes
under physiological conditions. By using the probes,
we succeeded in visualizing multiple enzyme
activities simultaneously in living cells. (Reference[7], collaborative research with Ozeki Laboratory,
Graduate School of Engineering, the University ofTokyo).
We also performed several collaborative works(Reference 8-12).

References[1] H. Fujioka, S.N. Uno, M. Kamiya, R. Kojima, K.
Johnsson, Y. Urano, Activatable fluorescentprobes for hydrolase enzymes based on
coumarin-hemicyanine hybrid fluorophores withlarge Stokes shifts, Chem. Commun. 56 (2020)
5617-5620.
[2] A. Morozumi, M. Kamiya, S.N. Uno, K.
Umezawa, R. Kojima, T. Yoshihara, S. Tobita, Y.
Urano, Spontaneously Blinking Fluorophores
Based on Nucleophilic Addition/Dissociation of
Intracellular Glutathione for Live-Cell Superresolution Imaging, J. Am. Chem. Soc. 142(2020) 9625-9633.
[3] R. Tachibana, M. Kamiya, A. Morozumi, Y.
Miyazaki, H. Fujioka, A. Nanjo, R. Kojima, T.
Komatsu, T. Ueno, K. Hanaoka, T. Yoshihara, S.
Tobita, Y. Urano, Design of spontaneously
blinking fluorophores for live-cell superresolution imaging based on quantum-chemical
calculations, Chem. Commun. 56 (2020) 1317313176.
[4] R. Tachibana, M. Kamiya, S. Suzuki, K.
Morokuma, A. Nanjo, Y. Urano, Molecular
design strategy of fluorogenic probes based on
quantum chemical prediction of intramolecularspirocyclization, Commun. Chem. 3 (2020) 82.
[5] R. Obara, M. Kamiya, Y. Tanaka, A. Abe, R.
Kojima, T. Kawaguchi, M. Sugawara, A.
Takahashi, T. Noda, Y. Urano, gammaGlutamyltranspeptidase(GGT)-Activatable
Fluorescence Probe for Durable Tumor Imaging,
Angew. Chem. Int. Ed. 60 (2021) 2125-2129.

77[6] K. Fujita, M. Kamiya, T. Yoshioka, A. Ogasawara,
R. Hino, R. Kojima, H. Ueo, Y. Urano, Rapid andAccurate Visualization of Breast Tumors with a
Fluorescent Probe Targeting alpha-Mannosidase
2C1, ACS Cent. Sci. 6 (2020) 2217-2227.
[7] H. Fujioka, J. Shou, R. Kojima, Y. Urano, Y.
Ozeki, M. Kamiya, Multicolor Activatable
Raman Probes for Simultaneous Detection of
Plural Enzyme Activities, J. Am. Chem. Soc. 142(2020) 20701-20707.
[8] T. Akashi, H. Isomoto, K. Matsushima, M.
Kamiya, T. Kanda, M. Nakano, T. Onoyama, M.
Fujii, J. Akada, Y. Akazawa, K. Ohnita, F.
Takeshima, K. Nakao, Y. Urano, A novel method
for rapid detection of a Helicobacter pylori
infection using a gamma-glutamyltranspeptidaseactivatable fluorescent probe, Sci. Rep. 9 (2019)9467.
[9] T. Asano, Y. Nagayo, S. Tsuda, A. Ito, W.
Kobayashi, K. Fujita, K. Sato, K.M. Nishiguchi,
H. Kunikata, H. Fujioka, M. Kamiya, Y. Urano, T.
Nakazawa, Companion Diagnosis for Retinal
Neuroprotective Treatment by Real-Time
Imaging of Calpain Activation Using a Novel
Fluorescent Probe, Bioconjugate Chem. 31(2020) 2241-2251.
[10] S. Kawashima, T. Yoshioka, H. Hino, K. Kitano,
K. Nagayama, M. Sato, R. Kojima, M. Kamiya,
Y. Urano, J. Nakajima, & x264; -glutamylhydroxymethyl rhodamine green fluorescence asa prognostic indicator for lung cancer, Gen.
Thorac. Cardiovas. 68 (2020) 1418-1424.
[11] Y. Kono, T. Ishizawa, N. Kokudo, Y. Kuriki, R.J.
Iwatate, M. Kamiya, Y. Urano, A. Kumagai, H.
Kurokawa, A. Miyawaki, K. Hasegawa, On-Site
Monitoring of Postoperative Bile Leakage Using
Bilirubin-Inducible Fluorescent Protein, World J.
Surg. 44 (2020) 4245-4253.
[12] K. Yamamoto, S. Ohnishi, T. Mizushima, J.
Kodaira, M. Ono, Y. Hatanaka, K.C. Hatanaka, Y.
Kuriki, M. Kamiya, N. Ehira, K. Shinada, H.
Takahashi, Y. Shimizu, Y. Urano, N. Sakamoto,Detection of early adenocarcinoma of theesophagogastric junction by spraying an
enzyme-activatable fluorescent probe targeting
Dipeptidyl peptidase-IV, BMC Cancer, 20 (2020)
64.

78

Department of Biosystem
Construction & Control
Lecturer
Takashi Isoyama, Ph.D.

Homepage

http://www.bme.gr.jp/bme_E/

Introduction and Organization
As the first research institute for medical engineeringin Japan, Institute of Medical Electronics wasestablished in 1963. Department of Clinical Medicine
in the Institute of Medical Electronics was started in1964 for research and development of advanced
diagnostic and therapeutic medical engineering technologies. To date, medical engineering has grown up
not only to a very important academic discipline but
also to a very important means for clinical medicine.
With the structural reformation of Faculty of Medicine,
Institute of Medical Electronics has been shifted to
Graduate School of Medicine, and Department ofClinical Medicine in the Institute of Medical
Electronics has been reformed to the present department since April 1, 1997.
The current members include a lecturer, one graduate
student, a senior technical specialist, and a project
academic support staff.
Since our research covers wide area of interdisciplinary and comprehensive research fields basedon the advanced medical and engineering technologies,
we are cooperating with various laboratories.

Teaching activities
We take a part in systematic lectures for the 3rd year
medical students. We also provide practice in the “freequarter” course for the 2nd year medical students. In
systematic lectures, we teach an introduction of theadvanced diagnostic and therapeutic medical
engineering technologies. The lectures for artificialorgan technologies are included.

For post-graduate education, we provide lectures forthe master course students, and we take a part in seriesof lectures for the doctor course students. For the
master course students, we offer lectures on artificialorgan technologies. For the doctor course students, weoffer lectures on advanced medical engineering
technologies.
The educational practice of the post-graduate students
is performed mainly by on-the-job training method in
the daily research works. Through the development
and animal experiments of the artificial hearts,
research strategy, methods of in-vitro, ex-vivo andin-vivo studies, design and fabrication techniques,machining technique, pre-operative management,
anesthesia, surgery, post-operative management,
measurement, data processing, ethical factor, andother important knowledge, techniques and experiences are acquired. In the practice, we give the mastercourse students several assignments from the field of
the artificial organs as a subject of their research. The
doctor course students have to find the subject of theirresearch by themselves. The research subject of thedoctor course students is not limited to the field of theartificial organs but is found from the wide area ofadvanced medical and engineering technologies.
Students must attend research and development
meeting. They can learn how to perform the research
work and how to report it through the meeting.
The education to train the leaders of medical
engineers and clinical engineers is another importantrole of our laboratory.

79

Research activities
Our research field covers advanced diagnostic andtherapeutic medical engineering technologies forclinical medicine. The main subjects are artificialorgans (artificial hearts, assist circulations, artificial
lungs, artificial valves, tissue engineered artificialorgans, regenerative artificial organs, etc.). Especially,
the artificial heart is our world famous research
project having a long history since 1959. Concerning the artificial heart, almost all the researches anddevelopments for driving mechanisms, energy
converters, blood pumps, biomaterials, power transmissions, measurement techniques, control methods,
anatomical fitting, blood compatibility, tissuecompatibility, computational fluid dynamics (CFD)
analysis, physiology, pathology, and so on, have beenstudied. All the stuffs and students are in part
participating in the artificial heart project. In 1995,
we succeeded to survive a goat for 532 days with theparacorporeal total artificial heart (TAH) with noanticoagulant, which is still the longest surviving
record of TAH animals in the world.
Our artificial heart research at present is to develop a
totally implantable TAH with high performance, goodanatomical fitting, high durability, high reliability,
high efficiency, good controllability, and excellent
biological compatibility, which can be implanted in
the body of small stature like Japanese. To meet the
purpose, we had been developing the TAH using
undulation pumps, named undulation pump TAH(UPTAH). The undulation pump is our original bloodpump invented in 1992. The UPTAH revealed to havean excellent performance and the goat whose heart
was replaced with the UPTAH survived for 153 days.
However, the UPTAH had a problem in the durabilityof the complex drive shaft mechanism. To improve theproblem of the UPTAH, a new blood pump, named thehelical flow pump (HFP), was invented in ourlaboratory in 2005. The HFP is a novel blood pumphaving a hydrodynamic levitating impeller, which
promises high durability. The animal experiment of
the helical flow TAH (HFTAH) had started in 2011.
The HFTAH could be implanted in the goatsuccessfully with good anatomical fitting. To date, thegoat whose heart was replaced with the HFTAH
survived for 100 days. We are expecting to develop an

ideal TAH that surpass the outcome of the hearttransplantation with combination of the technologiesof the physiological control and hybrid materials
described later.
How to control the output of a TAH is primary interest.
We have developed our original physiological control
method of the TAH, named 1/R control. The 1/R
control was developed with a conductance (1/R:
reciprocal of a resistance) parallel circuit model. Withthe 1/R control, the particular problems of a TAH suchas venous hypertension, slight anemia, low thyroid
hormone level and so on, were not observed and theoutput changed in accordance with a metabolic
demand of the animal.
The problem of the 1/R control was a mismatching of
the time constants between the control systems of thedevice and the body. As a consequence, the 1/R
control occasionally diverged in the animal experiment of the UPTAH and HFTAH. To improve theproblem of instability in the 1/R control, a new control
method based on the fluctuation of arterial and venous
pressures (named ΔP control) was developed byreforming the 1/R control function. At present, ΔP
control is tested with the animal experiment.
On the other hand, the 1/R control was applied to the
UPTAH and HFTAH to perform a physiological study
with a nonpulsatile TAH by changing the drive mode
from pulsatile to nonpulsatile in a single goat. The
result showed that, for a period of several weeks, the
1/R control could be promising not only with apulsatile flow, but also with a nonpulsatile flow. The
general conditions and organ functions were notchanged by the application of the nonpulsatile flow.
The cardiac output and the arterial pressure changed
with the condition of the goat in the pulsatile and also
nonpulsatile flow, which seemed almost identical.
However, under the physiological atrial pressure, thesucking effect of atria was more significant in the
nonpulsatile flow than the pulsatile flow. Therefore,
the nonpulsatile TAH with the 1/R control was
considered to be inadequate, unless some pulsatility
would be introduced to avoid the sucking effect for
ensuring sufficient inflow condition.
Concerning the materials, we have been developing a
new method to develop hybrid materials. In general, it
is not easy to develop mechanical parts for complex
artificial organs such as artificial hearts from the80components of living tissue because these components
have insufficient strength and durability, even though
they have excellent tissue compatibility. To overcome
these problems, an insert molding method, which iscommonly used for resin molding in the industrial
field, was introduced. In this method, the mold, inwhich an artificial material was inserted, was
implanted in the animal, and the tissue grew into themold to make a hybrid material. The method was first
applied to the Jellyfish valve that was originally apolymer valve for the artificial hearts. The hybrid
Jellyfish valve demonstrated a good result. Then, we
started to develop the hybrid conduit of the inflow
cannula for the left ventricular assist device (LVAD).
The conduit is inserted into the apex of the left
ventricle where the thrombus often formed. In thismethod, the mold in which the core of the conduit wasinserted was implanted under the skin of a goat. Afterseveral months, the hybrid conduit was extirpated, andthen freeze-dried, sterilized and used. The experimentof the LVAD using the hybrid conduit is going on witha goat. This hybrid technique will be an important
technology for developing the next generation
artificial organs.
A project of the novel gas-exchange system forbridging to lung transplantation has been performed in
an AMED project. The device consists of a blood
pump, an oxygenator, a drive and control unit, and abattery unit. To realize several-months support, theleft side blood pump of helical flow TAH has been
employed. This system is expected to offer more
opportunities and safer surgical interventions to those
who are waiting for lung transplants. In case of highafterload, the sequential flow pump (SFP) would beapplied. The SFP in which fluid is given centrifugal
force sequentially twice in a pump was invented in ourlaboratory in 2013. This sequential pressurization
mechanism enables high-pressure output without highimpeller speed, which can reduce the sheer stress ofthe blood. To realize integration of the pump with theartificial lung, inlet and outlet ports are located atlateral side and center of the pump, respectively,
which is the reverse configuration of conventional
centrifugal pumps.

References
1. Yusuke INOUE, Ayaka TASHIRO, Yukino
KAWASE, Takashi ISOYAMA, Itsuro SAITO,
Toshiya ONO, Shintaro HARA, Kohei ISHII,
Terumi YURIMOTO, Yasuyuki SHIRAISHI,
Akihiro YAMADA, Tomoyuki YAMBE, Yusuke
ABE, Optimum Sterilization Methods ofBiocompatible Hybrid Material for Artificial
Organs. Advanced Biomedical Engineering 9:2020 83-92,2020

81

Division of Integrative Genomics
Professor
Katsutoshi Oda, M.D., Ph.D.

Associate Professor
Aya Ushiku, M.D., Ph.D.

Organization
The division of Integrative Genomics wasestablished in January 2020 to comprehensively
promote genomic research both clinically andbasically. The activity of this division is linked to
the Department of Clinical Genomics and Genomic
Research Support Center, as well as the Departmentof Next-Generation Precision Medicine Development
Laboratory. We focus on both basic research andtranslational research in the field of genomics(especially genomic medicine in cancer).

Activities
Basic Research(1) Genome-wide analysis of cancer
a. Whole-genome sequencing, whole-exome
sequencing, Comprehensive Genomic Profilingb. Multi-omics (Copy Number Variation Analysis,RNA-sequencing, Methylation Array, etc)
c. Liquid biopsy (with circulating tumor cells,
cell-free tumor DNA, DNA from ascites, etc)
d. Analysis of hereditary cancer syndromes(Genetic
testing
andNGS-based
comprehensive analysis)(2) Development of a novel NGS-based cancer
genomic profiling panel (Todai OncoPanel2)
a. Analysis of quality of DNA and RNA fromFFPE (formalin-fixed paraffin-embedded)
specimens.
b. Prospective analysis of various cancers forclinical application.
c. Evaluation of microsatellite instability andgenomic instability(3) Exploration of biomarkers for molecular-targeteddrugs
a. Evaluation of homologous recombination
deficiency by using mutational signatures
b. Biomarkers for immune checkpoint inhibitorsc. Classification by expression signatured. Drug sensitivity screening by using patientderived models
Translational Research(1) Todai OncoPanel and Genomic Medicine inCancerTrial of a multiplex genomic testing by "Todai
OncoPanel" for Geneprofiling of malignant solid
tumors as Advanced Medical Care Category B was
performed in 200 cancer patients (from 2018 to2020).
UMIN000033647
Todai OncoPanel (TOP) has been originallyestablished at the University of Tokyo (by Professor
Hiroyuki Mano (currently Director of National
Cancer Center Research Institute) and Professor
Hiroyuki Aburatani et al), which is composed of
DNA panel (version 3: 464 genes) and RNA panel(version 4: 463 genes). We reported the usefulness of
TOP panel, especially in detecting gene fusions,
including ALK, ROS1, and NTRK.
(2) Investigator-Initiated Clinical Trial using a PARP
inhibitor, entitled “A multi-center, phase II study of
Olaparib maintenance therapy in patients with highgrade ovarian cancer, combined with translational

82

research by integrated genome-wide analysis”
This study assesses the efficacy of olaparib
maintenance monotherapy in high-grade and stage
IIIC/IV ovarian cancer patients (including patientswith primary peritoneal and / or fallopian tube
cancer) with “BRCA-related biomarker” that ispredicted by whole-exome sequencing of freshfrozen tumor samples.
(3) Enrollment to the prospective trial of patientproposed healthcare services with multiple targeted
agent based on the result of gene profiling by
multigene panel test. (BELIEVE): jRCTs031190104
Clinical activities are described in the section of“Department of Clinical Genomics”.

Publications
1.

2.

3.

4.

Iwasaki A, Shinozaki-Ushiku A, Kunita A,
Yamazawa S, Sato Y, Yamashita H, Fukayama
M, Seto Y, Ushiku T: Human Leukocyte
Antigen Class I Deficiency in Gastric
Carcinoma: An Adaptive Immune Evasion
Strategy Most Common in Microsatellite
Instable Tumors. Am J Surg Pathol 45:12131220,2021.
Nagano M, Kohsaka S, Hayashi T, Ueno T,
Kojima S, Shinozaki-Ushiku A, Morita S, Tsuda
M, Tanaka S, Shinohara T, Omori Y, Sugaya F,
Kato H, Narita Y, Nakajima J, Suzuki K,
Takamochi K, Mano H: Comprehensive
molecular profiling of pulmonary pleomorphic
carcinoma. NPJ Precis Oncol 5:57,2021.
Sasaki K, Honda A, Shinozaki-Ushiku A,
Fujioka Y, Maki H, Toyama K, Ushiku T,
Kurokawa M: A case of transplantationassociated thrombotic microangiopathy with
autopsy-proven fatal myocardial ischemia after
allogeneic hematopoietic stem cell transplantation. Ann Hematol 100:1621-1622,2021.
Sato A, Tanabe M, Tsuboi Y, Niwa T,
Shinozaki-Ushiku A, Seto Y, Murakami Y:
Circulating Tumor DNA Harboring the
BRAF(V600E) Mutation May Predict Poor
Outcomes of Primary Papillary Thyroid Cancer
Patients. Thyroid 31:1822-1828,2021.

5.

Yoshioka K, Kurokawa R, Amemiya S,
Koyamaa H, Matsuda K, Honda A, Kurokawa
M, Shinozaki-Ushiku A, Abe O: Rapidly
progressing blastic plasmacytoid dendritic cell
neoplasm causing diffuse skin thickening: A
case report with sequential computed
tomography examinations. Radiol Case Rep
16:2929-2933,2021.
6. Tsuzuki S, Komai T, Terada K, Tsuchida Y,
Tanaka M, Tateishi Y, Shinozaki-Ushiku A,
Shoda H, Fujio K: Nailfold capillaroscopic
abnormalities in angioedema with eosinophilia.
Allergol Int 70:501-503,2021.
7. Tanaka R, Kaburaki T, Taoka K, Karakawa A,
Tsuji H, Nishikawa M, Yatomi Y, ShinozakiUshiku A, Ushiku T, Araki F: More Accurate
Diagnosis of Vitreoretinal Lymphoma Using a
Combination of Diagnostic Test Results: A
Prospective
Observational
Study.
Ocul
Immunol Inflamm Apr 1; 1-7,2021.
8. Kato S, Kubota Y, Sekiguchi M, Watanabe K,
Shinozaki-Ushiku A, Takita J, Hiwatari M:
KMT2A-rearranged
diffuselarge
B-celllymphoma in a child: a case report andmolecular characterization. Pediatr Hematol
Oncol 38:281-289,2021.
9. Kobayashi H, Makise N, Shinozaki-Ushiku A,
Ishibashi Y, Ikegami M, Kohsaka S, Ushiku T,
Oda K, Miyagawa K, Aburatani H, Mano H,
Tanaka S: Scapular Angiomatoid Fibrous
Histiocytoma with EWSR1-CREB1 Fusion in an
Adult Patient. Case Rep Orthop:9434222,2021.
10. Ikeda Y, Adachi K, Tomio K, Eguchi-Kojima S,
Tsuruga T, Uchino-Mori M, Taguchi A,
Komatsu A, Nagamatsu T, Oda K, KawanaTachikawa A, Uemura Y, Igimi S, Osuga Y,
Fujii T, Kawana K: A Placebo-Controlled,
Double-Blind Randomized (Phase IIB) Trial of
Oral Administration with HPV16 E7-Expressing
Lactobacillus, GLBL101c, for the Treatment ofCervical Intraepithelial Neoplasia Grade 2(CIN2). Vaccines (Basel) 9:329,2021.
11. Yamaguchi K, Matsumoto Y, Suzuki R, Nishida
H, Omata D, Inaba H, Kukita A, Tanikawa M,
Sone K, Oda K, Osuga Y, Maruyama K, Fujii T:
Enhanced antitumor activity of combined lipid
bubble ultrasound and anticancer drugs in

83

12.

13.

14.

15.

16.

gynecological cervical cancers. Cancer Sci 112:2493-2503,2021.
Takahashi Y, Sone K, Noda K, Yoshida K,
Toyohara Y, Kato K, Inoue F, Kukita A,
Taguchi A, Nishida H, Miyamoto Y, Tanikawa
M, Tsuruga T, Iriyama T, Nagasaka K,
Matsumoto Y, Hirota Y, Hiraike-Wada O, Oda
K, Maruyama M, Osuga Y, Fujii T: Automatedsystem for diagnosing endometrial cancer byadopting
deep-learningtechnology
inhysteroscopy. PLoS One 16:e0248526,2021.
Kawata A, Taguchi A, Baba S, Miyamoto Y,
Tanikawa M, Sone K, Tsuruga T, Mori M, Oda
K, Kawana K, Osuga Y, Fujii T: A low
preoperative albumin-to-globulin ratio is anegative prognostic factor in patients withsurgically treated cervical cancer. Int J Clin
Oncol 26:980-985,2021.
Halimi SA, Maeda D, Ushiku-Shinozaki A,
Goto A, Oda K, Osuga Y, Fujii T, Ushiku T,
Fukayama
M:
Comprehensive
immunohistochemical
analysisofthegastrointestinal and Mullerian phenotypes of
139 ovarian mucinous cystadenomas. Hum
Pathol 109:21-30,2021.
Naito Y, Aburatani H, Amano T, Baba E,
Furukawa T, Hayashida T, Hiyama E, Ikeda S,
Kanai M, Kato M, Kinoshita I, Kiyota N, Kohno
T, Kohsaka S, Komine K, Matsumura I, Miura
Y, Nakamura Y, Natsume A, Nishio K, Oda K,
Oda N, Okita N, Oseto K, Sunami K, Takahashi
H, Takeda M, Tashiro S, Toyooka S, Ueno H,
Yachida S, Yoshino T, Tsuchihara K: Clinicalpractice
guidancefornext-generation
sequencing in cancer diagnosis and treatment(edition 2.1). Int J Clin Oncol 26:233-283,2021.
Matsuo K, Matsuzaki S, Nusbaum DJ, Maoz A,
Oda K, Klar M, Roman LD, Sood AK: Possible
candidate population for neoadjuvant chemotherapy in women with advanced ovarian cancer.
Gynecol Oncol 160:32-39,2021.

Neuroscience
1. Basic Neuroscience85

Department of Neuropathology
Professor
Takeshi Iwatsubo, M.D.

Lecturer
Tomoki Kuwahara, Ph.D.

Associate
Kaoru Yamada, Ph.D.
Kenichiro Sato, M.D., Ph.D.

Homepage

http://www.neuropathology.m.u-tokyo.ac.jp/

Dr. Iwatsubo’s research group has been pursuing
the pathogenesis of Alzheimer’s disease (AD) andrelated neurodegenerative conditions (especially,
dementia with Lewy bodies; DLB) by multidisciplinary approaches, based on histopathology andprotein biochemistry of postmortem human brains.
They then extended the knowledge derived from thehuman studies in a way to establish cellular models
and to elucidate the key steps in the pathologicalcascade of neurodegeneration. Thus, Dr. Iwatsubo’sgroup has been addressing the pathogenesis ofneurodegenerative disorders from the downstream (i.e.,analysis of aggregated proteins) as well as from the
upstream (i.e., pathogenic effects of pathogenic genes),
covering a number of crucial proteins/genes related to
AD and DLB, i.e., β-amyloid (including its binding
protein CLAC), presenilin/γ-secretase and α-synuclein.
In this way Dr. Iwatsubo’s group has contributed
much to the widely accepted notion that abnormal
misfolding of brain proteins is the common cause of avariety of neurodegenerative disorders including AD.
Furthermore, Dr. Iwatsubo’s group is currently
working hard to translate the basic findings into theclinical application of mechanism-based, diseasemodifying therapies for AD through the world-wide
ADNI project, in which Dr. Iwatsubo serves as the PI
of Japanese ADNI.
1. Research on β-amyloid and presenilins

Using C-terminal specific monoclonal antibodies
that discriminate amyloid β peptides (Aβ) ending at
40th or 42nd residues (Aβ40 and Aβ42, respectively),
Dr. Iwatsubo has performed a systematic immunohistochemical studies on autopsied brain tissues frompatients with AD, Down syndrome and familial AD,
and demonstrated that Aβ42, that most readily form
amyloid fibrils in vitro, is the initially andpredominantly deposited species in human cerebral
β-amyloidosis (Iwatsubo et al. Neuron 1994, Ann
Neurol 1995). Dr. Iwatsubo’s group then establishedcelllar models expressing mutant forms of presenilin(PS) genes linked to familial AD (FAD), and using
their original highly-sensitive ELISA quantitation
system, his group has clearly shown that an increasein the production of Aβ42 is the pathogenic
mechanism leading to FAD (Tomita et al. Proc Natl
Acad Sci USA, 1997). These findings have provided afirm basis for the currently prevailing β-amyloid
hypothesis. They then focused on the mechanisms ofγ-secretase complex that cleaves the C terminus of Aβ,
and set out to cell biological studies using RNAinterference on the formation and function of theγ-secretase complex harboring PS as the catalytic
center, associated with three additional membraneproteins. They demonstrated that APH-1 and Nicastrin
serve as the “stabilizing” co-factor of PS, whereas
PEN-2 is the component that confers proteolytic
activity to this complex. They also showed that PS,

86

APH-1, nicastrin and PEN-2 are the essential set ofproteins that comprise the γ-secretase complex(Takasugi et al. Nature, 2003). This study ishighlighted as a milestone work that elucidated themechanistic roles of protein cofactors in the formationand function of γ-secretase (see reviews; Iwatsubo
Mol Psychiatr, 2004; Curr Opin Neurobiol, 2004). His
group has established an elegant strategy to analyze
the structure-function relationship within the catalytic
structure of γ-secretase complex by cystein chemistry,and demonstrated that γ-secretase harbors a waterpermeable catalytic pore (Sato et al. J Neurosci, 2006),
and that substrate proteins enter the catalytic porethrough the lateral gate located at the C terminal sideof PS (Sato et al. J Neurosci, 2008). Thus, Dr.
Iwatsubo’s group started from an elegant immunohistochemical analysis of Aβ deposits in AD brains
and extended it to a contemporary molecular/cellularbiology of PS, that proved to play a key role in“intramembrane proteolysis”.
2. Identification and characterization of α-synuclein
as a major component of Lewy bodies.
Using cortical Lewy bodies purified frompostmortem brains of patients with dementia with
Lewy bodies (DLB) by his original method (Iwatsubo
et al. Am J Pathol 1996) as immunogens, Dr.
Iwatsubo’s group, in collaboration with Drs. Virginia
Lee and John Trojanowski at Univ. Penn, performed
an extensive immunochemical search for componentsof Lewy bodies. They have demonstrated by raising a
specific monoclonal antibody that α-synuclein, thatproved to be a product of pathogenic gene for familial
form of Parkinson’s disease, is one of the major
constituent of Lewy bodies in sporadic Parkinson’s
disease and DLB (Baba et al. Am J Pathol 1998). His
group then purified aggregated α-synuclein from DLB
cortices using fine biochemical techniques, purified it
to near homogeneity, and demonstrated using mass
spectrometry and specific antibodies that α-synuclein
deposited in synucleinopathy lesions is highly
phosphorylated at a specific serine residue (Fujiwara
et al. Nature Cell Biol 2002). This finding led to arange of studies focusing on the role of synuclein
phosphorylation in neurodegeneration. Also, thephospho-specific α-synuclein antibody is widely usedas the most sensitive marker for α-synucleinopathy

lesions, and has characterized a wide spectrum of
α-synuclein
pathologies
inneurodegenerative
disorders.
3. Identification of a non-Aβ Alzheimer amyloid plaquecomponent CLAC, and its precursor CLAC-P
The major component of Alzheimer’s amyloid
plaques is Aβ, although there are a number of non-Aβ
components that potentially affect fibrillization anddegradation of amyloid deposits. Among these, there
has been an enigmatic “missing piece” protein ofmolecular masses of 50/100 kDa. Dr. Iwatsubo’sgroup raised a monoclonal antibody against amyloid
fraction that recognizes this protein, and using thisantibody as a probe, they conducted a thoroughbiochemical purification of these antigens and finallycloned a cDNA coding for the precursor of this protein.
This protein turned out to be a novel class ofmembrane-bound collagen, which was named CLAC
(collagen-like Alzheimer amyloid plaque component)
and its precursor CLAC-P (Hashimoto et al. EMBO J
2002). This finding had an immense impact both on
fields of AD research as well as on general biology as
a first discovery of neuron-specific collagen harboringa unique membrane-spanning structure. CLAC has
been highlighted as a protein that may affectfibrillization of Aβ and contribute to amyloid plaqueformation. Indeed, he has recently shown that CLACpositive senile plaques constitute a unique subset ofplaques distinct from the classical, β-sheet-richamyloid deposits, underscoring the pathobiologicalrole of CLAC in amyloid formation, and that CLAC
inhibits fibrillization of Aβ in vitro. Knockout micestudies have confirmed the role of CLAC inneuromuscular development (Tanaka et al. J Neurosci,2014).
4. Glymphatic system and tau clearance
Accumulation of tau has been implicated invariousneurodegenerative
diseasestermedtauopathies. Tau is a microtubule-associated protein
but is also actively released into the extracellular
fluids including brain interstitial fluid andcerebrospinal fluid (CSF). However, it remained
elusive whether clearance of extracellular tau impacts
tau-associated neurodegeneration. We showed thataquaporin-4 (AQP4), a major driver of the glymphatic
clearance system, facilitates the elimination of

87

extracellular tau from brain to CSF and subsequently
to deep cervical lymph nodes. Strikingly, deletion of
AQP4 not only elevated tau in CSF but also markedly
exacerbated phosphorylated tau deposition andassociated neurodegeneration in the brains oftransgenic mice expressing P301S mutant tau. We thus
identified the clearance pathway of extracellular tau in
the central nervous system, suggesting that glymphatic
clearance of extracellular tau is a novel regulatory
mechanism whose impairment contributes to tau
aggregation and neurodegeneration.
5. Japanese ADNI: clinical studies for the identification of surrogate imaging and biomarkers of AD
Basic studies on the pathomechanism of AD haveboosted the development of mechanism-based drugs
for AD, whereas the bottleneck has been the lack ofsurrogate biomarkers that represent the progression of
AD pathology and are useful in the clinical trial of
disease-modifying drugs. In close collaboration with
Drs. Mike Weiner and Ron Petersen of US-ADNI, Dr.
Iwatsubo has initiated the Japanese ADNI as theprincipal investigator on 2006, recruiting 38 clinicalsites nationwide, and preparing all the infrastructures
required for the large-scale clinical study. The J-ADNI
group recruit 537 individuals in total, and all the data
derived from the J-ADNI study have been made inpublic from the National Bioscience Database Center
for research use. Recently, the J-ADNI group has
demonstrated the similarity between MCI due to AD
in Asian and Caucasian populations by comparing theclinical and biomarker features of J-ADNI and ADNI
participants, supporting the feasibility of global
clinical trials of disease-modifying therapies for AD.
Recently, his group is leading the “Japanese
Trial-Ready cohort for prevention of AD (J-TRC).

3)

4)

5)

6)

7)

References
1)

2)

Matsukawa K, Kukharsky, Park S-K, Park S,
Iwatsubo T, Hashimoto T, Liebman S, Shelkovnikova T: Long non-coding RNA NEAT1 ameliorates TDP-43 toxicity in in vivo models of
TDP-43 proteinopathy. RNA Biol 1-9, 2021
Sato K, Ihara R, Suzuki K, Niimi Y, Toda T,
Jimenez-Maggiora G, Langford O, Donohue MC,
Raman R, Aisen PS, Sperling RA, Iwata A,
Iwatsubo T: Predicting amyloid risk by machine8)

learning algorithms based on the A4 screen data:application to the Japanese Trial-Ready Cohort
study. Alzheimers Dementia: Translational Research & Clinical Interventions 7:e12135, 2021
Levine SZ, Goldberg Y, Yoshida K, Samara M,
Cipriani A, Iwatsubo T, Leucht S, Furuwaka TA:
Quantifying the heterogeneity of cognitive functioning in Alzheimer's disease to extend the placebo-treatment dichotomy: latent class analysis
of individual-participant data from Five pivotal
randomized clinical trials of donepezil. European Psychiatr 64: e16, 2021
Levine SZ, Yoshida K, Goldberg Y, Samara M,
Cipriani A, Efthimiou O, Iwatsubo T, Leucht S,
Furukawa TA: Linking the Mini-Mental State
Examination, the Alzheimer's Disease Assessment Scale-Cognitive Subscale and the Severe
Impairment Battery: Evidence from five randomized clinical trials. Evid Based Ment Health
24:56-61, 2021
Sato K, Niimi Y, Ihara R, Suzuki K, Toda T, Iwata A, Iwatsubo T: Efficacy and cost-effectivenessof multiple promotion methods to recruit participants to online screening registry for the facilitation of Alzheimer’s disease prevention trials. J
Med Internet Res 23:e26284, 2021
Mano T, Sato K, Ikeuchi T, Toda T, Iwatsubo T,
Iwata A: Peripheral blood BRCA1 methylation
positively correlates with major Alzheimer’s disease risk factors. J Prev Alzheimers Dis 8:477482, 2021
Ochiai T, Nagayama T, Matsui K, Amano K,
Sano T, Wakabayashi T, Iwatsubo T: Tauroursodeoxycholic acid attenuates diet-induced andage-related peripheral endoplasmic reticulum
stress and cerebral amyloid pathology in a mousemodel of Alzheimer’s disease. J Prev Alzheimers
Dis 4:483-494, 2021
Senda M, Ishii K, Ito K, Ikeuchi T, Matsuda H,
Iwatsubo T, Iwata A, Ihara R, Suzuki K, Kasuga
K, Ikari Y, Niimi Y, Arai H, Tamaoka A, Arahata
Y, Itoh Y, Tachibana H, Ichimiya Y, Washizuka S,
Odawara T, Ishii K, Ono K, Yokota T, Nakanishi
A, Matsubara E, Mori H, Shimada H: A Japanesemulticenter study on PET and other biomarkers
for subjects with potential preclinical and pro-

88

dromal Alzheimer’s disease. J Prev Alzheimers
Dis 8:495-502, 2021
9) Sato K, Mano T, Ihara R, Suzuki K, Toda T,
Iwatsubo T, Iwata A: Cohort-specific optimization of models predicting preclinical Alzheimer’s
disease, to enhance screening performance in the
middle of preclinical Alzheimer’s disease clinicalstudies. J Prev Alzheimers Dis 8:503-512, 2021
10) Sato K, Mano T, Niimi Y, Toda T, Iwata A,
Iwatsubo T: Facial nerve palsy following the administration of mRNA COVID-19 vaccines. Int J
Infect Dis 111:310-312, 2021
11) Ochiai T, Sano T, Kubota N, Kadowaki T, Wakabayashi T, Iwatsubo T: Differential involvementof insulin receptor substrate (IRS)-1 and IRS-2 inbrain insulin signaling is associated with the effects of their deficiency on amyloid pathology in
Alzheimer's disease. Neurobiol Dis 159:105510,
2021
12) Samara MT, Levine SZ, Yoshida K, Goldberg Y,
Clipriani A, Efthimiou O, Iwatsubo T, Leucht S,
Furukawa TA: Linking the clinical dementia rating scale-sum of boxes, the clinician’s interview-based impression plus caregiver input andthe clinical global impression scale: Evidence
based on individual participant data from fiverandomized clinical trials of donepezil. J Alz Dis
82:1075-1084, 2021
13) Sato K, Mano T, Niimi Y, Iwata A, Toda T,
Iwatsubo T: The impact of COVID-19 pandemic
on the provision of ambulatory care for patientswith chronic neurological diseases in Japan:
evaluation of an administrative claims database.
BioScience Trends 15:219-230, 2021
14) Koh HS, Lee SJ, Lee HJ, Min J-W, Iwatsubo T,
Teunissen CE, Cho H-J, Ryu J-H: Targeting microRNA-485-3p blocks Alzheimer’s disease progression. Int J Mol Sci 22:13136, 2021
15) Komaki K, Takano T, Sato Y, Asada A, Ikeda S,
Yamada K, Wei R, Huo A, Saito T, Ando K, Murayama S, Araki W, Kametani F, Hasegawa M,
Iwatsubo T, Tomomura M, Fukuda M, Hisanaga
S-I: Lemur tail kinase 1 (LMTK1) regulates theendosomal localization of b-secretase BACE1. J
Biochem 170:729–738, 2021

89

Department of Neurochemistry
Professor and Head
Haruhiko Bito, M.D., Ph.D.

Lecturer
Hajime Fujii, Ph.D.

Assistant Professor
Ryang Kim, Ph.D., Keisuke Ota, Ph.D.

Homepage

http://www.neurochem.m.u-tokyo.ac.jp/Homepage.html

Introduction and Organization
Our Department’s primary goal is to elucidate thebasic signal transduction mechanisms which mediate
key processes underlying various brain functions, suchas learning, memory or emotion. A fundamental
question is how an ensemble behavior of 10~100
billion neurons can possibly give rise to a coherent
and integrated “brain” that controls the whole humanorganism for a period of more than eighty years. Our
central nervous system is physically wired andorganized based on evolutionary and developmental
principles that are primarily encoded into the genome
and that are highly conserved in mammals fromrodents to primates. This neural network, however, isable to recognize and memorize external and internal
events as they occur. And furthermore, brain function,
especially human’s, stands out by its intrinsic capacity
to extract patterns and rules from these events, and to
consciously associate them with abstract meaning andaffective valence, while also unconsciously
facilitating coordinated body responses.
Neurochemistry once used to be a relatively dull
discipline consisting of analyzing substances that form
the brain. However, it has recently become a field of
excitement where we are now (almost) able tomeasure changes in cellular messengers or modifications in signaling molecules in critical parts of theneurons such as the dendritic spines or the axon
terminals, as the neurons summate synaptic potentials
or fire action potentials.

What are the precise nature and the whole
spectrum of the molecular changes in the neurons that
undergo heavy or patterned electrical activity? What
are the molecular rules that govern these local andglobal changes, both electrical and chemical? How arethese events, in turn, converted into more profoundmodifications of the synaptic wiring mechanisms?
And finally do these alterations genuinely underlie
certain kinds of information processing and storage?
To address these issues, this Department currently focuses its resources into two basic aims:
1) Molecular investigation (including identification,
characterization and real-time visualization) of
signaling molecules involved in calcium-dependent
synaptic modification, especially during signalingfrom synapse-to-nucleus, and back from nucleusto-synapses.
2) Understanding molecular mechanisms controlling
cytoskeletal dynamics and remodeling on both sidesof the synapses, in the dendritic spines and in axon
terminals.
Following the retirement of Professor Tatsuya
Haga (who became the President of Life Sciences
Institute at the Faculty of Science at Gakushuin
Univisersity) in March 2001, and the departure of
Associate Professor David Saffen to initially University of Minnesota and then to Ohio State University inAugust 2001, Associate Professor Haruhiko Bito was
appointed as Head of Department since January 2003.
The Department is located on the 6th floor, in the West90

wing of the third building of the Medical School. The
Department currently enrolls one professor, one
lecturer, two assistant professors, two postdoctoral
scholars, one technical staff, eight Ph.D. graduate
students, one technical assistant and three administrative assistants.

Teaching activities
The Department’s teaching activities include:
1) Introductory Neuroscience coursework provided to
pre-medical students in the Komaba campus (onehour);
2) Neurochemistry lectures to medical students as partof the “Biochemistry- Molecular BiologyNutrition” core curriculum (two hours);3) Introductory Molecular and Cellular Neuroscience,
and Basic Neurochemistry lectures to first-year
master degree students (three hours);
4) Organization of the lecture course: “Basic Neuroscience” (Molecular and Cellular Neuroscience) (alecture series with fifteen lectures from outstanding
neuroscientists from all over Japan).
Additionally, Neurochemistry Seminars are
frequently and regularly organized that enables direct
exposure of Ph.D. graduate students and postdocs toboth young promising researchers and establishedinvestigators from all over the world.

Research activities
The Department of Neurochemistry currently
focuses its resources into two core projects:
1) Molecular investigation (including identification,
characterization and real-time visualization) of
signaling molecules involved in calcium-dependent
synaptic modification, especially during signalingfrom synapse-to-nucleus, and back from nucleus-tosynapses.
Changes in efficacy of synaptic transmission
have been shown to strongly correlate with functional
plasticity of many brain circuits including the
hippocampus, the amygdala, the striatum, theneocortex, the cerebellum or the spinal cord. An earlyphase of long-term synaptic plasticity is induced byvirtue of specific post- and/or presynaptic modifications of the biochemical machinery dedicated tosynaptic release and neurotransmitter recognition. It
then is expressed by bistable mechanisms that arestrongly governed and dictated by the pattern ofsynaptic calcium influxes experienced during theinitial conditioning period. While the molecular
identity of the involved synaptic proteins is now(almost) being solved (or is becoming much lesscontroversial than before), several essential questions
remain unanswered.
The “Old” question was: What are the moleculardeterminants that enable these plastic changes to be
induced and maintained locally? Yet, related issues ofcritical importance that still remain wide open
questions are:1) What are the full-range of calcium-triggered
molecular signaling cascades which are activated atand near the potentiated/depressed synapses? And
how do they influence plasticity per se?
2) What is the contribution of activity-dependent gene
expression in prolongation and consolidation ofsuch synapse-restricted changes?
In order to begin to address these issues, we havebeen investigating in particular the role of several
calcium-calmodulin dependent protein kinases.
We previously showed the critical importanceof a CaMKK/CaMKIV cascade in triggering
synaptically-stimulated nuclear CREB phosphorylation in hippocampal neurons. The extreme
biochemical efficacy and the relative poor frequencydependence of this signaling cascade, in combination
with the robust correlation between prolonged pCREB
response and downstream gene expression led us topropose that CaMKK/CaMKIV/pCREB cascade was
likely to act as a critical temporal integrator for
activity-dependent gene expression in excitatoryneurons (Bito et al., Cell, 1996; Bito et al., Curr. Opin.
Neurobiol., 1997; Bito, Cell Calcium, 1998). Thishypothesis has now been critically tested in various
brain systems and indeed pCREB immunofluorescence is now considered as a universal marker
for integrated synaptic activity that is more sensitive
than that of c-Fos (Nonaka, J. Neurosci. 2009). The
critical function of CaMKK/CaMKIV/pCREB cascadein the expression of long-term synaptic plasticity was
also validated in long-term potentiation in the
hippocampus (Redondo et al., J Neurosci. 2010).
Furthermore,
CaMKIV-KO,
CaMKK-KOand91

CaMKIV-dominant negative transgenic studies bymany laboratories have confirmed the critical role for
CaMKIV as synaptic activity-triggered CREB kinase.
We subsequently also showed that CaMKIV inthe cerebellar granule cells played a critical role intuning the pCREB response necessary for
depolarization-mediated neuronal survival, and that infact CaMKIV stability was actively maintained bydepolarization. Loss of depolarizing signal led to a
caspase-mediated proteolytic degradation of CaMKIV.
This in turn severely impaired CREB phosphorylation,
facilitating apoptosis, and conversely rescuing pCREB
by overexpressing an active form of CaMKIV was
sufficient to prevent apoptosis (See et al., FASEB J.,
2001). Consistent with our observation that subtle
CREB regulation may underlie the neuronal cell
survival, CREB-dependent gene expression mechanisms, especially CBP regulation, have actually been
proposed to be affected in one way or another in manyneurodegenerative disorders such as hereditary
polyglutamine diseases. We thus speculated that if
CREB-opathies (or various defects in CREB-mediatedgene activation mechanisms) were critical determinants in exacerbating neurodegeneration, certain
disease forms may actually accompany deficit in
CaMKIV / pCREB signaling (Bito and TakemotoKimura, Cell Calcium 2003). We also identified
kinase/phosphatase signaling responsible for activitydependent nuclear trafficking of CRTC1, a key
cofactor of CREB, and demonstrated its roles in
CREB-dependent transcription and contextual fear
memory in amygdala (Nonaka et al., Neuron 2014).
To elucidate the significance of the genes
regulated downstream of CREB during learning andmemory, we set out to uncover the most elementary
regulatory element required and sufficient to trigger
robust activity-dependent gene induction of theimmediate early gene Arc, whose expression in many
brain areas have been invariably associated with key
cognitive activities mediated by these areas. We
discovered a fundamentally novel synaptic activityresponsive element (SARE) which was present as a
distal regulatory promoter element and was conserved
across most mammalian species (Kawashima et al.,PNAS 2009; Kim et al., Nature 2010; Inoue et al.,Commun. Integr. Biol. 2010). Surprisingly, SARE
contained juxtaposed binding elements for all three

activity-regulated transcription factors, CREB, MEF2
and SRF. The identification of SARE enables us tobuild reporter virus and mouse lines that are expected
to be useful to map the extent of neuronal circuit
activation during various kinds of cognitive activities(Kawashima et al., Nat. Methods 2013). In addition
to the transcriptional regulation, we are currently
investigating about the physiological function and its
molecular mechanism of Arc, which is thought to be a
key player that contributes activity dependentneuronal plasticity at post synaptic sites (Okuno et al.,Cell 2012).
One parallel branch of CaMK signaling that has
not been widely studied is the CaMKK/CaMKI
pathway. During the search for potential CaMKIV-like
CREB regulatory kinases (CLICKs) (Ohmae et al., J.
Biol. Chem. 2006), we identified a novel CaMKI
isoform that contained a C-terminal CAAX lipid
modification motif (Takemoto-Kimura et al., J. Biol.
Chem., 2003; Takemoto-Kimura et al., Neuron 2007).
This novel membrane-bound CaMK (CLICK-III/
CaMKIγ) is most expressed in the central nucleus of
the amygdala and in the ventral medial hypothalamus,
while also being present at a much weaker amount inmost central neurons. Biochemical and cell biologicalstudies indicated a critical role for lipidification of thiskinase to be properly sorted into specific lipidrestricted membrane microdomains. The function
played by this lipidified, membrane-inserted CaMK in
circuitry formation and maturation was scrutinizedusing RNA interference. Along with the identificationof the critical lipid-modifying enzyme that controls
lipid-anchoring of this kinase, we discovered a novel
activity-regulated mechanism whereby CLICK-III/
CaMKIγ is actively sorted into dendritic lipid rafts,
where it specifically regulates Rac-mediated actin
remodeling that is required for BDNF-stimulated
dendritogenesis (Takemoto-Kimura et al., Neuron,
2007; Takemoto-Kimura et al. Eur. J. Neurosci. 2010).
Similar studies in axonal growth also suggest theactive contribution of CaMKK cascade in this process(Ageta-Ishihara et al., J. Neurosci. 2009; TakemotoKimura et al., Eur. J. Neurosci. 2010). Using amembrane-tethered genetically encoded calcium
indicator, we successfully recorded spontaneous regenerative calcium transients (SRCaTs) in developing
mouse excitatory cortical neurons and discovered that

92

L-type VGCCs play critical roles in neuraldevelopment and corticogenesis (Kamijo et al., J.
Neurosci. 2018).
How do these multiple Ca2+-dependent signaling
molecules process each pattern of intracellular Ca2+
dynamics to induce a cellular response? Recently, we
have developed a method named dFOMA (dual FRET
imaging with optical manipulation) to simultaneously
measure activities of two distinct signaling moleculesin living neurons. Applying originally developed
FRET probes to dFOMA method enabled us tomeasure activities of CaMKII, calcineurin and Ca2+,
when a neuron received various frequencies ofsynaptic inputs. These experiments provided evidence
that CaMKIIα and calcineurin are fine-tuned to uniquebandwidths and compute input variables in an
asymmetric manner (Fujii et al., Cell Reports 2013).
In line with the visualization of neuronal activity
and Ca2+ signaling, we have developed R-CaMP2, a
red genetically-encoded Ca2+ indicator that has singleaction-potential sensitivity based on rational designthat takes advantage of our long-standing effort andknowledge about CaMKK-CaMKIV signaling. By
combining R-CaMP2 with green Ca2+ indicator
G-CaMP, distinct activity patterns between excitatory
and inhibitory neurons in somatosensory cortex was
revealed (Inoue et al., Nat. Methods 2015).
Furthermore, we have advanced our visualization
probe technology to developed ultra-fast, ultrasensitive Ca2+ indicators XCaMP-B/G/Y/R, whichallowed imaging in blue, green, yellow, and red, andsimultaneously tracked activities of high-frequency
firing parvalbumin (PV)-positive cells, as well asactivities of three different neuronal cell types(excitatory pyramidal cells, PV-positive andsomatostatin (SST)-positive cells) (Inoue et al., Cell,2019).
One further important topic that we have been
focusing for a number of years is the role of gene
expression in prolongation / consolidation of synapsespecific local changes. Neurons undergoing various
stimulus patterns have been followed up in time andthe amount of newly synthesized proteins and the
local distribution of induced gene products have beenmonitored. Using state-of-the-art multi-wavelength
fluorescence imaging techniques, we are now quantitatively assessing how local distribution of these

newly synthesized gene products affect synaptic
protein complexes (Okuno and Bito, AfCS/Nature
Mol. Pages 2006).
2) Understanding molecular mechanisms controlling
cytoskeletal dynamics and remodeling on both sidesof the synapses, in the dendritic spines and in axon
terminals.
Both synaptic maturation and synaptic plasticity
have been shown to include a morphological component that is directed by the dynamics of actin
cytoskeleton, a major cytoskeletal component both in
the dendritic spines and at the very proximity ofboutons in the axon terminals. Few studies in the past,
however, had directly addressed what moleculardeterminants regulate actin dynamics in living central
neurons undergoing synaptic activity. This was in part
because actin filament assembly and disassembly wereclassically studied mostly at the moving edges oflamellipodia of large growth cones in large-size
neurons from either mollusc or peripheral nerve cells.
Such visualization turned out to be much moredifficult in seemingly far less mobile spine structures
tightly apposed to presynaptic active zones.
We (and others) used GFP-actin imaging to try tounderstand how neuronal actin cytoskeleton in
hippocampal neurons was organized and reorganizedby exposure to synaptic activity. In our dissociatedculture system, virtually all spines contained a highamount of GFP-actin and most of them with few
exceptions were apposed to FM4-64-positive active
presynaptic termini. In these cultures, increases insynaptic glutamatergic transmission by repeated burstsof high-frequency synaptic activity clearly induced
several distinct kinds of activity-dependent actin
mobilization, including a slow but sustained synaptic
delivery of GFP-actin in a non-negligible number ofactivated spines and a massive but transientenhancement in cortical actin at the somatic periphery.
The former was entirely dependent on NMDAdependent Ca2+-influx while the latter was likely to be
mediated at least in part by L-type voltage-gated Ca2+
channel activity. Thus, distinct patterns and sources of
Ca2+ influx were likely to trigger a complex spatiallysegregated patterns of actin cytoskeletal reorganization, with variable impact on either neuronalmorphology and/or synaptic protein assembly93(Furuyashiki et al., PNAS, 2002).
Similar studies are now ongoing in cerebellar
Purkinje neurons, where spinogenesis is also subject
to complex regulation during development, and where
calcium dynamics is key to pre- and postsynaptic
plasticity.
What are the key signaling pathways controlling
actin dynamics in central neurons? We were especiallykeen to resolve the contribution of the small GTPase
Rho and its downstream effectors, initially in thecontext of developmentally regulated neuronalmorphogenesis. We first established in a model cellline N1E-115 that neurite retraction was directly
linked to Rho/ROCK activity (Hirose et al., J. Cell
Biol., 1998). We subsequently revealed that in central
neurons, in addition to its essential role in regulating
growth cone motility, Rho/ROCK activity in fact acted
as a negative gate that tightly controls the timing withwhich the first processes are initiated out from theround cell soma (Bito et al., Neuron, 2000).
Disruption of Rho/ROCK activity was sufficient toimmediately initiate neuritogenesis. This indicatedthat endogenous Rho activators, by titrating ROCK
activity, continuously antagonized process/ branchformation and that local gradient of Rho activators
might play a crucial role in shaping the timing and theextent of process formation (Bito, J. Biochem., 2003).
Consistent with this idea, we found that in cerebellar
granule cells, a chemokine SDF-1α released from thepia mater was likely to be a predominant Rho
activator via stimulation of a cognate and specific
GPCR CXCR4 (Arakawa et al., J. Cell Biol., 2003).
While a true gradient in SDF-1α still remains to be
demonstrated in vivo, it is intriguing to note that mostactive axonal process formation and elongation
actually occur in the inner zone of EGL that is
opposite and most distant from the interface with the
pia mater (Bito, J. Biochem., 2003). Most strikingly,
we demonstrated that axon elongation could actively
occur in an intermediate Rho activity range thatenables ROCK to be weakened enough while allowing
another Rho effector mDia1 to actively mediate its
effect on actin nucleation and polymerization(Arakawa et al., J. Cell Biol. 2003).
Whether similar or distinct mechanisms also
operate during spinogenesis and spine maturation
remains to be determined, though a role for Rho andROCK has already been postulated in control of spinecomplexity and spine stability. However, multiple
small GTPase signaling cascades clearly seem tocontribute together, in a tightly coordinated manner, tospine regulation, since many distinct classes of GEFs
and GAPs have now been shown to be localized in thedendritic spines. We ourselves initially reported thefirst two direct examples for PSD localization for such
Rho small GTPases interacting proteins, Citron(Furuyashiki et al., J. Neurosci., 1999) and Cupidin/
Homer2 (Shiraishi et al., J. Neurosci., 1999).
In an attempt to pin down molecular mechanismsthat link PSD complexes and spine formation, wequantitatively examined the effect of deleting thebinding capacity of single PDZ domains of PSD-95,
one by one, and in combination, by structure-based
amino acid replacements rather than domain deletion.
Such a second-generation structure-function relation
study surprisingly revealed that a quantitative binding
between PSD-95 and synGAP tightly controlled thedegree of PSD protein clustering in a manner that was
inversely correlated with the distance from the spine
head to the shaft. Thus, these results suggest theexistence of a tight coordination between the state of
PSD complex and the morphogenetic activity of eachspine (Nonaka et al. J. Neurosci., 2006).
In parallel with this work, we and others
determined that protein-protein interaction was key todetermining the physical distance between thesynaptic vesicles in the active zone and the voltagegated calcium channels in its vicinity, the opening of
which triggers their release (Kiyonaka et al., Nat.
Neurosci. 2007).

Publications by lab members(January 2021- December 2021)
1.

Ueda S, Hosokawa M, Arikawa K, Takahashi K,
Fujiwara M, Kakita M, Fukada T, Koyama H,
Horigane SI, Itoi K, Kakeyama M, Matsunaga H,
Takeyama H, Bito H, Takemoto-Kimura S.
Distinctive Regulation of Emotional Behaviors
and Fear-Related Gene Expression Responses in
Two Extended Amygdala Subnuclei With Similar
Molecular Profiles. Front Mol Neurosci. 2021
Sep 3, 14:741895. Doi: 10.3389/fnmol.2021.
741895.

94

2.

3.

4.

5.

Ohnishi T, Kiyama Y, Arima-Yoshida F, Kadota
M, Ichikawa T, Yamada K, Watanabe A, Ohba H,
Tanaka K, Nakaya A, Horiuchi Y, Iwayama Y,
Toyoshima M, Ogawa I, Shimamoto-Mitsuyama
C, Maekawa M, Balan S, Arai M, Miyashita M,
Toriumi K, Nozaki Y, Kurokawa R, Suzuki K,
Yoshikawa A, Toyota T, Hosoya T, Okuno H,
Bito H, Itokawa M, Kuraku S, Manabe T,
Yoshikawa T. Cooperation of LIM domainbinding 2 (LDB2) with EGR in the pathogenesisof schizophrenia. EMBO Mol Med. 2021 Apr 9,
13(4):e12574. Doi: 10.15252/emmm.202012574.
Sulistomo HW, Nemoto T, Kage Y, Fujii H,
Uchida T, Takamiya K, Sumimoto H, Kataoka H,
Bito H, Takeya R. Fhod3 Controls the Dendritic
Spine Morphology of Specific Subpopulations ofPyramidal Neurons in the Mouse Cerebral Cortex.
Cereb Cortex. 2021 Mar 5, 31(4):2205-2219.
Doi: 10.1093/cercor/bhaa355.
Horigane SI, Hamada S, Kamijo S, Yamada H,
Yamasaki M, Watanabe M, Bito H, Ohtsuka T,
Takemoto-Kimura S. Development of an L-type
Ca2+ channel-dependent Ca2+ transient during
the radial migration of cortical excitatory neurons.
Neurosci Res. 2021 Aug, 169:17-26. Doi: 10.
1016/j.neures.2020.06.003.
Benner S, Aoki Y, Watanabe T, Endo N, Abe O,
Kuroda M, Kuwabara H, Kawakubo Y, Takao H,
Kunimatsu A, Kasai K, Bito H, Kakeyama M,
Yamasue H. Neurochemical evidence fordifferential effects of acute and repeated oxytocin
administration. Mol Psychiatry. 2021 Feb, 26(2):710-720. doi: 10.1038/s41380-018-0249-4.

Neuroscience
2. Integrative Medical Neuroscience96

Department of Child
Neuropsychiatry
Associate Professor
Yukiko Kano, M.D., Ph.D.

Assistant professor
Yosuke Eriguchi, M.D., Ph.D.

Homepage

http://childpsy.umin.jp/

Introduction and Organization

improvement.

Recently, mental problems of child and adolescent or
problems of mental development are continuously
increasing, and serious deficiency of specialists suchas child psychiatrists and necessity of their development are emphasized. Especially, as Japan falls far
behind other nations in research and education systemof child psychiatry, development of specialists who
can promote research by themselves and improve
quality of diagnosis and treatment based on their own
research are strongly demanded. In response to theseneeds, Department of Child Neuropsychiatry,
Graduate School of Medicine was established in April
2010. This is believed to be the first Japanese
department which works as an actual department ofchild psychiatry managed by child psychiatrist. Basedon experience of clinical-based research as well as
medical care and training of clinicians for decades inchild psychiatry division of Department of Neuropsychiatry and Department of Child Psychiatry sinceApril 2005, we are developing new activities.
Professors are administrating Department of Child
Psychiatry, the University Hospital also, and trying toutilize its clinical activities for research more
effectively.

Research activities

Teaching activities
In the year of 2021, we had 6 graduate students (1 inmaster course and 6 in doctor course). In addition toresearch training, educational program includingcase conference was implemented with further

Main subjects of our research are Autism Spectrum
Disorder (ASD), Attention-Deficit/Hyperactivity
Disorder (ADHD), Tourette syndrome which is asevere and chronic tic disorder, and child & adolescentobsessive-compulsive disorder (OCD). We are trying
to combine scientific analysis of objective mental andbehavioral indicators with neuropsychological, brainimaging, and genetic studies into comprehensive andmultidimensional approach to problems in development of brain and mind. We are applying this comprehensive approach to intervention studies including
pharmacotherapy.
Major research projects with full or preliminary
performance in 2021 are as follows:・ Epidemiological, behavior phenotype, neuropsychological, and treatment study of Tourette
syndrome and child & adolescent OCD
・ Brain-imaging study of ASD, ADHD and Tourette
syndrome by structural-MRI, functional-MRI andnear-infrared spectroscopy (NIRS)
・ Development of predictor of parent training for
ADHD
・ Effectiveness study of early intervention for
autistic preschoolers and group cognitive behavior
therapy for adults with high-functioning ASD
・ Investigation on clinical evaluation and psychological education for adults with developmental
disorders97

References
1.

2.

3.

4.

5.

6.

7.

Yagi T, Ando S, Usami S, Yamasaki S, Morita M,
Kiyono T, Hayashi N, Endo K, Iijima Y,
Morimoto Y, Kanata S, Fujikawa S, Koike S,
Kano Y, Hiraiwa-Hasegawa M, Nishida A, Kasai
K. Longitudinal Bidirectional Relationships Between Maternal Depressive/Anxious Symptoms
and Children's Tic Frequency in Early
Adolescence.Front Psychiatry, 12: 767571, 2021.
Kaji N, Ando S, Nishida A, Yamasaki S,
Kuwabara H, Kanehara A, Satomura Y, Jinde S,
Kano Y, Hiraiwa-Hasegawa M, Igarashi T, Kasai
K. Children with special health care needs andmothers' anxiety/depression: Findings from theTokyo Teen Cohort study. Psychiatry Clin
Neurosci.,75(12): 394-400, 2021.
Eriguchi Y, Gu X, Aoki N, Nonaka M, Goto R,
Kuwabara H, Kano Y, Kasai K. A 2-year
longitudinal follow-up of quantitative assessment
neck tics in Tourette's syndrome. PLoS One,
16(12): e0261560, 2021.
Okada N, Yamamoto Y, Yahata N, Morita S,
Koshiyama D, Morita K, Sawada K, Kanata S,
Fujikawa S, Sugimoto N, Toriyama R, Masaoka
M, Koike S, Araki T, KanoY, Endo K, Yamasaki
S, Ando S, Nishida A, Hiraiwa-Hasegawa M,
Yokoyama C, Kasai K, Birth order andprosociality in the early adolescent brain. Sci Rep,
11(1): 21806, 2021.
Kimura Y, Iijima K, Takayama Y, Yokosako S,
Kaneko Y, Omori M, Kaido T, Kano Y, Iwasaki
M. Deep Brain Stimulation for Refractory
Tourette Syndrome: Electrode Position andClinical Outcome. Neurol Med Chir (Tokyo),
61(1): 33-39, 2021.
Kato Y, Kuwabara H, Okada T, Munesue T,
Benner S, Kuroda M, Kojima M, Yassin W,
Eriguchi Y, Kameno Y, Murayama C, Nishimura
T, Tsuchiya K, Kasai K, Ozaki N, Kosaka H,
Yamasue H. Oxytocin-induced increase in
N,N-dimethylglycine and time course of changesin oxytocin efficacy for autism social core
symptoms. Mol Autism, 12(1):15, 2021.
Kuru Y, Nishiyama T, Sumi S, Suzuki F, Shiino T,
Kimura T, Hirai K, Kuroda M, Kamio Y, Kikuchi
S. Practical applications of brief screening

questionnaires for autism spectrum disorder in a
psychiatry outpatient setting. Int J Methods
Psychiatr Res, 30(2): e1857, 2021.

Neuroscience
3. Clinical Neuroscience99

Department of Neuropsychiatry
Professor
Kiyoto Kasai, M.D., Ph.D.

Associate Professor
Seiichiro Jinde, M.D., Ph.D.

Shuntaro Ando, M.D., Ph.D.

Lecturer
Eisuke Sakakibara, M.D., Ph.D.

Research Associate
Shinsuke Kondo, M.D.

Kayo Ichihashi, M.D.

Taiki Johse, M.D.

Oji Tomoatsu, MD.

Shinya Fujikawa, M.D., Ph.D.

Mariko Tada, M.D., Ph.D.

Tenpei Ikegame, M.D., Ph.D.

Daisuke Koshiyama, M.D., Ph.D.

Shintaro Kawakami, M.D., Ph.D.

Mao Fujoka, M.D., Ph.D.

Fumikazu Hiyoshi, MD

Homepage

http://npsy.umin.jp/

Introduction and Organization
The Department of Neuropsychiatry is the oldest
department of psychiatry in Japan which wasestablished in 1886. "Anti-Psychiatry" movement in
the last 3 decades had brought highly negative impacts
on the progress of all aspects of our activities.
However, in 1994, our department has been normalized and restarted to play a leading role in psychiatryin Japan. Since 2005, we have launched the new
department of child neuropsychiatry to focus on basic
and clinical neuroscience in the developmental
disorders including autism spectrum disorder (ASD).
Dr. Kiyoto Kasai has been serving as a professor since2008. Now the Department of Neuropsychiatry is
dedicated to high quality clinical services, excellent
training, education for students and innovative
research.

Clinical activities
For our clinical services, we have more than 20

staff psychiatrists, 5 clinical psychologists and 2 psychiatric social workers. In 2020, approximately 450
new patients visited our outpatient clinic, and the total
visits per day were about 100.
In our inpatient wards, the secluded ward has 27
beds including 3 seclusion rooms, as well as 21 beds
for the open general ward. Approximately 330 patientswith various psychiatric disorders were admitted in2020. Recently, the number of inpatients who werereferred from the emergency unit is increasing. Mean
hospitalization is 30 day long, and the age of patientsis from teenager to senior. The majority of the patientsare schizophrenia, mood disorder and the psychosis
based on the somatic diseases. Modified electroconvulsive therapy was performed for approximately
400 patients per year.
We established the day care unit for outpatientswith schizophrenia in 1974, and the patients areengaged in rehabilitation and re-work programs.

100

Education

Publications

For psychiatric residents, we have provided: 1)
clinical meetings on patients (every morning); 2) caseconferences on inpatients (every week); 3) a series oflectures by teaching staffs on various aspects ofpsychiatry. For undergraduates, we have provided
neuropsychiatry comprehensive lectures (for 2nd year
students), and clinical clerkship (for 3rd year students).
For postgraduate, currently more than 10 neuropsychiatry Ph.D. students are studying.

1.

2.

Research
Our mission in research is to clarify the pathophysiology of the mental illness to develop better
treatment approach.
1) Neuroimaging
Our research plays a leading role in psychiatricneuroimaging in Japan and aims at multi-modality
neuroimaging (structural and functional MRI, MR
spectroscopy, EEG, MEG, near-infrared spectroscopy(NIRS)) in schizophrenia, mood disorders and autism
spectrum disorders.
2) Molecular/cellular neuroscience
The goal of the molecular/cellular neuroscience groupis to build causal bridges among the molecular,
cellular, neural systems, and behavior on the rodent
model of neuropsychiatric disorders. We employ
integrated multidisciplinary techniques including
genetics, cell biology, biochemistry, histology,
electrophysiology, imaging and behavioral analysis
for elucidating molecular pathophysiology of rodent
models of neuropsychiatric disorder. We have focusedon schizophrenia and hippocampal neuronal circuits.
3) Genetic and Epidemiology research
The Genetic Research Group of the department isinvestigating genetic as well as environmental
mechanism of psychiatric disorders. A major focus of
the studies is exploration of susceptibility genes of thedisorders including schizophrenia, autism, theirspectrum disorders and anxiety disorder (mainly panic
disorder).

3.

4.

5.

6.

7.

Echizen K, Sakakibara E, Suga M, Kasai K:
Improvements in obsessive-compulsive disorderand schizophrenia after left putaminal hemorrhage. Psychiatry Clin Neurosci. 2021 Nov;
75(11):354-355.
ENIGMA Clinical High Risk for Psychosis
Working Group,: Association of structural
magnetic resonance imaging measures withpsychosis onset in individuals at clinical high riskfor developing psychosis: An ENIGMA Working
Group mega-analysis. JAMA Psychiatry 78: 753766, 2021. (Jul)
Furukawa Y, Saito H, Hasegawa K, Ichikawa M.
Assessing the quality of cancer screening leaflets
using the International Patient Decision Aids
Standards instrument: A cross-sectional content
analysis. Patient Educ Couns. 2021;104(12):3100-3103. doi:10.1016/j.pec.2021.03.034
Ikegame T, Hidaka Y, Nakachi Y, Murata Y,
Watanabe R, Sugawara H, Asai T, Kiyota E,
Saito T, Ikeda M, Sasaki T, Hashimoto M,
Ishikawa T, Takebayashi M, Iwata N, Kakiuchi C,
Kato T, Kasai K, Bundo M, Iwamoto K:
Identification and functional characterization of
the extremely long allele of the serotonintransporter-linked polymorphic region. Transl
Psychiatry 11: 119, 2021 (Feb).
Kaji N, Ando S, Nishida A, Yamasaki S,
Kuwabara H, Kanehara A, Satomura Y, Jinde S,
Kano Y, Hiraiwa-Hasegawa M, Igarashi T, Kasai
K: Children with special health care needs andmothers' anxiety/depression: findings from theTokyo Teen Cohort study. Psychiatry Clin
Neurosci. 2021 Sep 22.
Kanehara A, Koike H, Fujieda Y, Yajima S,
Kabumoto A, Kumakura Y, Morita K, Miyamoto
Y, Nochi M, Kasai K: Culture-dependent andUniversal Constructs and Promoting Factors for
the Process of Personal Recovery in users ofMental Health Services: Qualitative Findings
from Japan. BMC Psychiatry, 2022 Feb 10;22(1):105.
Koike S, Fujioka M, Satomura Y, Koshiyama D,
Tada M, Sakakibara E, Okada N, Takano Y,
Iwashiro N, Natsubori T, Zhu Y, Abe O, Kirihara

101

8.

9.

10.

11.

12.

13.

K, Yamasue H, Kasai K: Surface area in theinsula was associated with 28-month functional
outcome in first-episode psychosis. NPJ
Schizophr. 2021 Nov 29;7(1):56.
Koike S, Fujioka M, Takano Y, Iwashiro N,
Satomura Y, Nagai T, Koshiyama D, Tada M,
Natsubori T, Okada N, Abe O, Kirihara K,
Yamasue H, Suga M, Kasai K: Neurocognitive
Deficits Mediate the Relationship Between
Structural Abnormalities and Clinical Outcomesin Individuals With Ultrahigh Risk for Psychosis:
A Multimodal Neuroimaging and Longitudinal
Neurocognitive Study. Schizophrenia Bulletin
Open 2, January 2021.
Koike S, Tanaka SC, Okada T, Aso T, Yamashita
A, Yamashita O, Asano M, Maikusa N, Morita K,
Okada N, Fukunaga M, Uematsu A, Togo H,
Miyazaki A, Murata K, Urushibata Y, Autio J,
Ose T, Yoshimoto J, Araki T, Glasser MF, Van
Essen DC, Maruyama M, Sadato N, Kawato M,
Kasai K, Okamoto Y, Hanakawa T, Hayashi T;
Brain/MINDS Beyond Human Brain MRI Group.
Brain/MINDS beyond human brain MRI project:
A protocol for multi-level harmonization acrossbrain disorders throughout the lifespan.
Neuroimage Clin 30:102600, 2021. (Mar)Koshiyama D, Miyakoshi M, Joshi YB, Molina
JL, Tanaka-Koshiyama K, Sprock J, Braff DL,
Swerdlow NR, Light GA. Neural network
dynamics underlying gamma synchronization
deficits in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 107:110224, 2021.
Koshiyama D, Miyakoshi M, Joshi YB,
Nakanishi M, Tanaka-Koshiyama K, Sprock J,
Light GA. Source decomposition of thefrontocentral auditory steady-state gamma band
response in schizophrenia patients and healthy
subjects. Psychiatry Clin Neurosci 75: 172-279,
2021.
Koshiyama D, Miyakoshi M, Joshi YB,
Nakanishi M, Tanaka-Koshiyama K, Sprock J,
Light GA. Sources of the Frontocentral Mismatch
Negativity and P3a Responses in Schizophrenia
Patients and Healthy Comparison Subjects. Int J
Psychophysiol 161:76-85, 2021.
Koshiyama D, Miyakoshi M, Tanaka-Koshiyama
K, Joshi YB, Sprock J, Braff DL, Light GA.

14.

15.

16.

17.

18.

19.

Abnormal phase discontinuity of alpha- andtheta-frequency oscillations in schizophrenia.
Schizophr Res 231: 73-81, 2021.
Koshiyama D, Miyakoshi M, Thomas ML, Joshi
YB, Molina JL, Tanaka-Koshiyama K, Sprock J,
Braff DL, Swerdlow NR, Light GA. Uniquecontributions of sensory discrimination andgamma synchronization deficits to cognitive,
clinical, and psychosocial functional impairments
in schizophrenia. Schizophr Res 228:280-287,
2021.
Koshiyama D, Thomas ML, Miyakoshi M, Joshi
YB, Molina JL, Tanaka-Koshiyama K, Sprock J,
Braff DL, Swerdlow NR, Light GA. Hierarchicalpathways from sensory processing to cognitive,
clinical, and functional impairments inschizophrenia. Schizophr Bull 47: 373-385, 2021.
Morita M, Ando S, Kiyono T, Morishima R, Yagi
T, Kanata S, Fujikawa S, Yamasaki S, Nishida A,
KasaiK:
Bidirectional
relationshipofproblematic Internet use with hyperactivity/
inattention and depressive symptoms inadolescents: a population-based cohort study. Eur
Child Adolesc Psychiatry. 2021 May 22.
Nagaoka D, Tomoshige N, Ando S, Morita M,
Kiyono T, Kanata S, Fujikawa S, Endo K,
Yamasaki S, Fukuda M, Nishida A,
Hiraiwa-Hasegawa M, Kasai K: Being praisedfor prosocial behaviors longitudinally reduces
depressive symptoms in early adolescents: A
population-based cohort study. Front Psychiatry.
June 2021.
Okada N, Yamamoto Y, Yahata N, Morita S,
Koshiyama D, Morita K, Sawada K, Kanata S,
Fujikawa S, Sugimoto N, Toriyama R, Masaoka
M, Koike S, Araki T, Kano Y, Endo K, Yamasaki
S, Ando S, Nishida A, Hiraiwa-Hasegawa M,
Yokoyama C, Kasai K: Birth order andprosociality in the early adolescent brain. Sci Rep.
2021 Nov 8;11(1):21806.
Sakakibara E, Satomura Y, Matsuoka J, Koike S,
Okada N, Sakurada H, Yamagishi M, Kawakami
N, Kasai K: Abnormality of Resting-State
Functional Connectivity in Major Depressive
Disorder: A Study With Whole-Head NearInfrared Spectroscopy. Front Psychiatry 12:664859, 2021. (Apr)102

20. Tada M, Kirihara K, Ishishita Y, Takasago M,
Kunii N, Uka T, Shimada S, Ibayashi K, Kawai K,
Saito N, Koshiyama D, Fujioka M, Araki T,
Kasai K: Global and parallel cortical processing
based on auditory gamma oscillatory responses inhumans. Cereb Cortex. 2021 Apr 28:bhab103.

103

Department of Neurology
Professor
Tatsushi Toda, M.D., Ph.D.

Associate Professor
Wataru Satake, M.D., Ph.D.

Lecturer
Masashi Hamada, M.D., Ph.D.
Hiroyuki Ishiura, M.D., PhD.

Associate
Meiko Maeda, M.D., PhD., Akatsuki Kubota, M.D., Ph.D.,
Yu Nagashima, M.D., Ph.D., Takashi Matsukawa, M.D., PhD., Tatsuo Mano, M.D., PhD.,
Satoshi Kodama, M.D., Ph.D., Toshiyuki Kakumoto M.D., Ph.D.

Homepage

http://www.utokyo-neurology.org

Introduction and Organization
The Department of Neurology was established by
the founder Professor Yasuo Toyokura in 1964 as one
Department in the Brain Research Institute. The
Department of Neurology was succeeded byProfessors Toru Mannen, Ichiro Kanazawa, and Shoji
Tsuji. The organization of the Brain Research Institutewas reorganized as the Division of Neuroscience of
the Graduate School of Medicine in 1997.

Clinical activities
We offer clinical services in the field of
Neurology. We are putting our effort to provide thepatients with highly advanced clinical practice as wellas on clinical activities connected to postgraduate
education of Neurology.
We have outpatient clinics covering the broad
fields of Neurology. Furthermore, we also provide
clinics specialized to movement disorders anddementia (Dementia center).
In the in-patient ward, we offer programs forpostgraduate education including the program for the
first stage postgraduate education. We also offer the

excellent training program with the goal to get theboard of Neurologist. In 2005, we initiated deep brain
stimulation for the treatment of movement disorders incooperation with Department of Neurosurgery.

Teaching activities
As for under-graduate education, our Department
takes a part in lectures of Neurology for the 4th and5th grade medical students, and clinical clerkship forthe 5th grade medical students.
In the clinical clerkship we include small group
lectures including neurophysiology, and stroke care.
We are also putting our effort for Free Quarters where
we offer various opportunities for medical students to
be involved in research activities, and 2-3 medical
students are conducting their research activities in thelaboratories.
In postgraduate education we offer the integrated
program including Neurology as the part of the
program of Internal Medicine.
Regarding training for board-certified neurologists, we offer the excellent program including
patients’ care, training in Neurophysiology and Neuro-104

pathology, consultation for Neurology and supervisingof junior trainees. This program is integrated withclinical practice at the affiliated hospitals where richexperience is obtained for numerous cases in Clinical
Neurology.
In Graduate School, we offer highly advanced
research activities based on the interest of graduate
students.

Research activities
Our research field covers broad fields related toneurological diseases, with the goals to elucidate themechanisms of neurological diseases, and to eventually develop new therapeutic strategies. Our research
activities include molecular genetics, developmental
biology, cell biology, pharmacology, pathology, andphysiology. We aim to integrate these broad research
fields to better contribute to clinical neurology.
In the development of molecular therapeutics thatameliorate α-dystroglycan (α-DG)-associated diseases,
we identified the glycan unit ribitol 5-phosphate(Rbo5P) in α-DG and showed that enzyme activitiesof α-DG-associated diseases are involved in thesynthesis of tandem Rbo5P. We also found that FKTN
and FKRP can transfer GroP to O-mannosyl glycans
by using CDP-glycerol (CDP-Gro) as a donor
substrate. The analysis of mouse models of α-DGassociated diseases indicated that spatiotemporalpersistence of functionally glycosylated α-DG may be
crucial for brain development. These findings provide
insight into pathogenesis and therapeutic strategies in
α-DG-associated diseases. In addition, we have started
a plan to conduct a First In Human clinical trial of anovel
antisense
nucleicacidNS-035inFukuyama-type congenital muscular dystrophy, whichis common in Japan due to dystroglycanopathy. (Toda,
T., Kanagawa, M., Kobayashi, K., Sudo, A., Fujino,G., Kitamura, A., Takahashi, A.)
We perform case-control association studies in
Parkinson disease (PD) employing whole-exome
sequence analysis to discover rare PD susceptibility
variants. Employing a novel bioinformatics approach
using GWAS loci in PD along with in vitro functional
studies and MPTP mouse model analysis, we
identified a novel drug candidate for the prevention ofneurodegeneration in PD. We also identified genetic

factors responsible for the individual difference of theeffects of zonisamide by using GWAS andtranscriptome analysis. (Toda, T., Satake, W., Uenaka,
T., Cha, P.C., Fujino, G., Naito, T.)
In the field of molecular genetics, we havedeveloped the Genomic Medicine Research Support
Center, and introduced next-generation sequencers to
conduct comprehensive genome analyses to elucidate
molecular bases of various neurological diseases.
Regarding monogenic neurologic diseases, we
conduct pedigree analyses in various neurologicaldiseases including epilepsy, multiple system atrophy,
amyotrophic lateral sclerosis, hereditary spastic
paraplegia,
spinocerebellar
atrophy,andadrenoleukodystrophy. As for sporadic neurologic
diseases, we perform case-control association studies
in multiple system atrophy and amyotrophic lateralsclerosis to identify genetic factors underlying these
diseases. On the basis of the findings that mutations in
COQ2 are associated with familial as well as sporadic
multiple system atrophy, we are conducting an
investigator-initiated clinical trial using coenzyme
Q10 for patients with multiple system atrophy.
Genetic study on benign adult familial myoclonus
epilepsy (BAFME), neuronal intranuclear inclusion
disease (NIID), oculopharyngeal myopathy withleukoencephalopathy(OPML),
andoculopharyngodistal myopathy type 1 (OPDM1) are
performed, which have been revealed to be caused byexpasions of noncoding repeats at our department. We
reported safety and efficacy of hematopoietic stem
cell transplantation for adolescent-/adulthood-onset
cerebral form/cerebello-brainstem form of adrenoleukodystrophy. We are now studying a biomarker for
adrenoleukodystrophy. (Toda, T., Tsuji, S., Mitsui, J.,
Ishiura, H., Matsukawa, T., Naruse, H., Kakumoto, T.,
Nagasako, Y., Hao, A., Shinmi, J, Mitsue, A.,
Mitsutake, A., Yamaguchi, N., Almansour, M. A.,
Porto, K. J. L., Orimo, K.)
The human neurophysiology section specializes
in studying the physiology of the human motor andsensory systems in awake healthy volunteers and thepathophysiology of neurological disorders using
several non-invasive physiological methods, such as
TMS, EEG, MEG, fMRI, NIRS and EOG. Our final
goal is to devise new therapeutic techniques for
intractable neurological disorders. To this end, the105work extends from the study of spinal systems to basal
ganglia and cerebral cortex. We are interested inmismatch negativity changes in ataxic syndrome aswell as basalganglia disorders and entrainment ofneuronal oscillation by peripheral nerve stimulation,
sensor-oriented and sensor-free motion measurements
in Parkinson disease, network analysis in patient withepilepsy using MEG, fMRI of spinal cord andneuronal excitability changes in dystonic patients.
(Hamada, M., Shirota, Y., Kodama, S., Kainaga M,
Seto E, Katsuse K, Tokimura R, and Miyano R.)
In the field of neuromuscular diseases, we
provide pathological diagnosis of biopsied materials
from patients with myopathy or neuropathy. We also
provide autoantibody testing for anti-gangliosideantibodies, muscle specific antibodies and paraneoplastic neurological antibodies. In research field,
using biopsied muscles and collected serum samples,
we have been studying the mechanisms of inflammatory myopathies from the view points of pathological changes, myositis specific autoantibodies,
serum cytokines, and expression profiling of muscle
samples. Our aim is to increase understanding of the
etiology and pathogenesis of neuromuscular diseases.
(Shimizu, J., Kubota A., Maeda M.).
In the biochemistry laboratory, autopsy brain
analysis of Alzheimer's disease and Lewy bodydisease was performed, and a new gene involvement
was discovered. Chronic cerebral hypoperfusion
model mouse was created and its characteristics wereanalyzed, the technology was applied to analyze
amyloid β metabolism under chromic hypoperfusion.
On the other hand, we analyzed J-ADNI cohort data.
Comparison
with
US-ADNIdata
revealed
compatibility between the two cohorts. The influenceof sex difference and education level, and theinfluence of serum calcium level was discovered. We
analyzed the database of adverse drug reactions to
COVID-19 vaccine and dementia drugs. Other
activities include development of new imaging
techniques using Raman microspectroscopy. We
recently invented a novel high-sensitivity lipid
imaging methodology using delipidation technique forsample preconditioning before Raman observation,
which successfully determined spatial distribution ofminor lipid species in porcine nerve and muscle
tissues. We also developed a new optical sensor chip

detecting biomarkers for Alzheimer’s disease using
nanoimprint lithography (NIL)-based two-dimensional
photonic crystal (2D-PhC), which achieved thesensitivity surpassing ELISA. We newly developed adetection device for our sensor chip, realizing
automated, high-throughput measurement. (YuNagashima, Ryo Ohtomo, Tatsuo Mano, Taro Bannai,
Takeyuki Tsuchida, Kensuke Hamada, Kagari Mano,
Gaku Ohtomo, Kenichiro Sato, Masanori Kurihara)
Neuroimmunology section is focused onunderstanding inflammatory disease of the CNS:
namely multiple Sclerosis and neuromyelitis optica.
Through application of both conventional and more
contemporary immunological methods (FACS, ELISA,
cell culture and NGS analysis), we aim to reveal
disease-specificpatho-mechanisms
forbetterdiagnosis and treatment of immune-mediated CNS
inflammation. (Sakuishi K, Koguchi A, and Kawasaki
R)

Publication
1.

2.

Yau WY, Vandrovcova J, Sullivan R, Chen Z,
Zecchinelli A, Cilia R, Duga S, Murray M,
Carmona S; Genomics England ResearchConsortium, Chelban V, Ishiura H, Tsuji S,
Jaunmuktane Z, Turner C, Wood NW, Houlden H.
Low Prevalence of NOTCH2NLC GGC Repeat
Expansion in White Patients with Movement
Disorders. Mov Disord. 2021 Jan;36(1):251-255.
doi: 10.1002/mds.28302.
Watanabe M, Nakamura Y, Sato S, Niino M,
Fukaura H, Tanaka M, Ochi H, Kanda T,
Takeshita Y, Yokota T, Nishida Y, Matsui M,
Nagayama S, Kusunoki S, Miyamoto K, Mizuno
M, Kawachi I, Saji E, Ohashi T, Shimohama S,
Hisahara S, Nishiyama K, Iizuka T, Nakatsuji Y,
Okuno T, Ochi K, Suzumura A, Yamamoto K,
Kawano Y, Tsuji S, Hirata M, Sakate R, Kimura T,
Shimizu Y, Nagaishi A, Okada K, Hayashi F,
Sakoda A, Masaki K, Shinoda K, Isobe N,
Matsushita T, Kira JI. HLA genotype-clinicalphenotype correlations in multiple sclerosis andneuromyelitis optica spectrum disorders based onJapan MS/NMOSD Biobank data. Sci Rep. 2021
Jan 12;11(1):607. doi: 10.1038/s41598-02079833-7.

106

3.

4.

5.

6.

7.

8.

9.

Kawai M, Mano T, Naito T, Honda A, Nakai Y,
Toyama K, Fujioka Y, Makise N, Haesgawa H,
Sakuishi K, Kurokawa M, Toda T. Disseminatednecrotizing leukoencephalopathy after allogeneic
peripheral blood stem cell transplantation andmethotrexate administration. Neurol Clin
Neurosci. 2021 Jan;9(1): 155-156.
Koh K, Takaki R, Ishiura H, Tsuji S, Takiyama Y.
SPG9A with the new occurrence of an
ALDH18A1 mutation in a CMT1A family with
PMP22 duplication: case report. BMC Neurol.
2021 Feb 11;21(1):64. doi: 10.1186/s12883-02102087-x.
Naruse H, Ishiura H, Mitsui J, Takahashi Y,
Matsukawa T, Yoshimura J, Doi K, Morishita S,
Goto J, Toda T, Tsuji S. Loss-of-function
variants in NEK1 are associated with anincreased risk of sporadic ALS in the Japanese
population. J Hum Genet. 2021 Mar;66(3):237241. doi: 10.1038/ s10038-020-00830-9.
Song D, Dai Y, Chen X, Fu X, Chang X, Wang N,
Zhang C, Yan C, Zheng H, Wu L, Jiang L, Hua Y,
Yang H, Wang Z, Dai T, Zhu W, Han C, Yuan Y,
Kobayashi K, Toda T, Xiong H. Genetic
variations
andclinical
spectrumofdystroglycanopathy in a large cohort of Chinesepatients. Clin Genet. 2021 Mar;99(3):384-395.
doi: 10.1111/cge.13886.
Naruse H, Ishiura H, Mitsui J, Takahashi Y,
Matsukawa T, Sakuishi K, Nakamagoe K,
Miyake Z, Tamaoka A, Goto J, Yoshimura J, Doi
K, Morishita S, Toda T, Tsuji S. Splice-site
mutations in KIF5A in the Japanese case series ofamyotrophic lateral sclerosis. Neurogenetics.
2021Mar;22(1):11-17. doi: 10.1007/s10048-02000626-1.
Naito T, Suzuki K, Hirata J, Kamatani Y,
Matsuda K, Toda T, Okada Y. A deep learning
method for HLA imputation and trans-ethnic
MHC fine-mapping of type 1 diabetes. Nat Comn
2021 Mar.12; 12(1)1639 doi:10.1038/s41467021-21975-x.
Sato K, Ihara R, Suzuki K, Niimi Y, Toda T,
Jimenez-Maggiora G, Langford O, Donohue MC,
Raman R, Aisen PS, Sperling RA, Iwata A,
Iwatsubo T. Predicting amyloid risk by machinelearning algorithms based on the A4 screen data:

10.

11.

12.

13.

14.

15.

16.

Application to the Japanese Trial-Ready Cohort
study. Alzheimers Dement (N Y). 2021 Mar 24;
7(1):e12135. doi: 10.1002/trc2.12135.
Miyazawa A, Kanahara N, Nakata Y, Kodama S,
Kimura H, Kimura A, Oda Y, Watanabe H, Iyo M.
Clozapine Prolongs Cortical Silent Period in
Patients with Treatment-Resistant Schizophrenia.
Psychopharmacol Bull. 2021 Mar 16;51(2):20-30.
Taniguchi T, Ando M, Okamoto Y, Yoshimura A,
Higuchi Y, Hashiguchi A, Shiga K, Hayashida A,
Hatano T, Ishiura H, Mitsui J, Hattori N, Mizuno
T, Nakagawa M, Tsuji S, Takashima H. Genetic
spectrum of Charcot-Marie-Tooth diseaseassociated with myelin protein zero gene variants
in Japan. Clin Genet. 2021 Mar;99(3):359-375.
doi: 10.1111/cge.13881.
Okano A, Miyawaki S, Hongo H, Dofuku S,
Teranishi Y, Mitsui J, Tanaka M, Shin M,
Nakatomi H, Saito N. Associations ofpathological diagnosis and genetic abnormalities
in meningiomas with the embryological originsof the meninges. Sci Rep. 2021 Mar 26;11(1):6987. doi: 10.1038/s41598-021-86298-9.
Sato K, Mano T, Iwata A, Toda T.
Disproportionality by sex in the prescription ofdrugs capable of inducing parkinsonism for theelderly: A survey using statistics of Japanesenational health claims from 2014 to 2017.
Neurology and Clinical Neuroscience. 2021
May: 9(3):211-217. doi:10.1111/ncn3.12501
Ueha R, Sato T, Goto T, Yamauchi A,
Nativ-Zeltzer N, Mitsui J, Belafsky PC,
Yamasoba T. Esophageal Dysmotility is Common
in Patients With Multiple System Atrophy.
Laryngoscope. 2021 Apr; 131(4): 832-838. doi:
10.1002/lary. 28852.
Shibata Y, Matsushima M, Matsukawa T, Ishiura
H, Tsuji S, Yabe I. Adrenoleukodystrophy
siblings with a novel ABCD1 missense variant
presenting with phenotypic differences: a casereport and literature review. J Hum Genet. 2021
May; 66(5): 535-537. doi: 10.1038/s10038-02000866-x.
Hashimoto Y, Mitsui J, Ishiura H, Matsukawa T,
TodaT, Kakisu K, Hori Y,Nakagawa S, Toyono T,
Yoshida J, Usui T, Yamagami S, Aihara M, Miyai

107

T. A Case of Irreversible Corneal Edema
Associated with Dentatorubropallidoluysian
Atrophy Following Corneal Endothelial Transplantation.
SN
Comprehensive
ClinicalMedicine. 2021 June5; 3: 2029-2032. doi:10.
1007/s42399-021-00962-9
17. Mano T, Sato K, Ikeuchi T, Toda T, Iwatsubo T,
Iwata A. Peripheral Blood BRCA1 Methylation
Positively Correlates with Major Alzheimer's
Disease Risk Factors. J Prev Alzheimers Dis.
2021June9; 8(4): 477-482. doi: 10.14283/jpad.
2021.31.
18. Bonora E, Chakrabarty S, Kellaris G, Tsutsumi M,
Bianco F, Bergamini C, Ullah F, Isidori F, Liparulo
I, Diquigiovanni C, Masin L, Rizzardi N, Cratere
MG, Boschetti E, Papa V, Maresca A, Cenacchi G,
Casadio R, Martelli P, Matera I, Ceccherini I, Fato
R, Raiola G, Arrigo S, Signa S, Sementa AR,
Severino M, Striano P, Fiorillo C, Goto T, Uchino
S, Oyazato Y, Nakamura H, Mishra SK, Yeh YS,
Kato T, Nozu K, Tanboon J, Morioka I, Nishino I,
Toda T, Goto YI, Ohtake A, Kosaki K, Yamaguchi
Y, Nonaka I, Iijima K, Mimaki M, Kurahashi H,
Raams A, MacInnes A, Alders M, Engelen M,
Linthorst G, de Koning T, den Dunnen W, Dijkstra
G, van Spaendonck K, van Gent DC, Aronica EM,
Picco P, Carelli V, Seri M, Katsanis N, Duijkers
FAM, Taniguchi-Ikeda M, De Giorgio R. Biallelicvariants in LIG3 cause a novel mitochondrial
neurogastrointestinal encephalomyopathy. Brain.
2021 June 22; 144(5): 1451-1466. doi: 10.1093/
brain/ awab056.
19. Wiessner M, Maroofian R, Ni MY, Pedroni A,
Müller JS, Stucka R, Beetz C, Efthymiou S,
Santorelli FM, Alfares AA, Zhu C, Uhrova
Meszarosova A, Alehabib E, Bakhtiari S, Janecke
AR, Otero MG, Chen JYH, Peterson JT, StromTM, De Jonghe P, Deconinck T, De Ridder W, De
Winter J, Pasquariello R, Ricca I, Alfadhel M,
van de Warrenburg BP, Portier R, Bergmann C,
Ghasemi Firouzabadi S, Jin SC, Bilguvar K,
Hamed S, Abdelhameed M, Haridy NA, Maqbool
S, Rahman F, Anwar N, Carmichael J,
Pagnamenta A, Wood NW, Tran Mau-Them F,
Haack T; Genomics England ResearchConsortium, PREPARE network, Di Rocco M,
Ceccherini I, Iacomino M, Zara F, Salpietro V,

20.

21.

22.

23.

Scala M, Rusmini M, Xu Y, Wang Y, Suzuki Y,
Koh K, Nan H, Ishiura H, Tsuji S, Lambert L,
Schmitt E, Lacaze E, Küpper H, Dredge D,
Skraban C, Goldstein A, Willis MJH, Grand K,
Graham JM, Lewis RA, Millan F, Duman Ö,
Dündar N, Uyanik G, Schöls L, Nürnberg P,
Nürnberg G, Catala Bordes A, Seeman P, Kuchar
M, Darvish H, Rebelo A, Bouçanova F, Medard
JJ, Chrast R, Auer-Grumbach M, Alkuraya FS,
Shamseldin H, Al Tala S, Rezazadeh Varaghchi J,
Najafi M, Deschner S, Gläser D, Hüttel W, Kruer
MC, Kamsteeg EJ, Takiyama Y, Züchner S, Baets
J, Synofzik M, Schüle R, Horvath R, Houlden H,
Bartesaghi L, Lee HJ, Ampatzis K, Pierson TM,
Senderek J. Biallelic variants in HPDL cause
pure and complicated hereditary spastic
paraplegia. Brain. 2021 Jun 22;144(5):14221434. doi: 10. 1093/brain/awab041.
Seike N, Yokoseki A, Takeuchi R, Saito K,
Miyahara H, Miyashita A, Ikeda T, Aida I,
Nakajima T, Kanazawa M, Wakabayashi M,
Toyoshima Y, Takahashi H, Matsumoto R, Toda
T, Onodera O, Ishikawa A, Ikeuchi T, Kakita A.
Genetic Variations and Neuropathologic Featuresof Patients With PRKN Mutations. Mov Disord.
2021 Jul; 36(7): 1634-1643. doi: 10.1002/mds.
28521.
Sato K, Mano T, Iwata A, Toda T. Need of carein interpreting Google Trends-based COVID-19
infodemiological study results: potential risk offalse-positivity. BMC Med Res Methodol. 2021
Jul 18; 21(1):147. doi: 10.1186/s12874-02101338-2.
Sato K, Niimi Y, Ihara R, Suzuki K, Toda T,
Iwata
A,
Iwatsubo
T.
EfficacyandCost-effectiveness of Promotion Methods to
Recruit Participants to an Online Screening
Registry for Alzheimer Disease Prevention
Trials: Observational Study. J Med Internet Res.
2021 Jul 22;23(7):e26284. doi: 10.2196/26284.
Kumutpongpanich T, Ogasawara M, Ozaki A,
Ishiura H, Tsuji S, Minami N, Hayashi S,
Noguchi S, Iida A, Nishino I; OPDM_LRP12
Study Group, Mori-Yoshimura M, Oya Y, Ono K,
Shimizu T, Kawata A, Shimohama S, Toyooka K,
Endo K, Toru S, Sasaki O, Isahaya K, Takahashi
MP, Iwasa K, Kira JI, Yamamoto T, Kawamoto M,

108

24.

25.

26.

27.

28.

Hamano T, Sugie K, Eura N, Shiota T, Koide M,
Sekiya K, Kishi H, Hideyama T, Kawai S,
Yanagimoto S, Sato H, Arahata H, Murayama S,
Saito K, Hara H, Kanda T, Yaguchi H, Imai N,
Kawagashira Y, Sanada M, Obara K, Kaido M,
Furuta M, Kurashige T, Hara W, Kuzume D,
Yamamoto M, Tsugawa J, Kishida H, Ishizuka N,
Morimoto K, Tsuji Y, Tsuneyama A, Matsuno A,
Sasaki R, Tamakoshi D, Abe E, Yamada S,
Uzawa A. Clinicopathologic Features ofOculopharyngodistal Myopathy With LRP12CGG Repeat Expansions Compared With Other
Oculopharyngodistal Myopathy Subtypes. JAMA
Neurol. 2021 Jul 1; 78(7): 853-863. doi: 10.1001/
jamaneurol.2021.1509.
Sato K, Mano T, Ihara R, Suzuki K, Niimi Y,
Toda T, Iwatsubo T, Iwata A. Cohort-SpecificOptimization of Models Predicting PreclinicalAlzheimer's Disease, to Enhance Screening
Performance in the Middle of PreclinicalAlzheimer's Disease Clinical Studies. J Prev
Alzheimers Dis. 2021Aug 2;8(4):503-512. doi:
10.14283/jpad.2021.39.
Takeda N, Inuzuka R, Yagi H, Morita H, Ando M,
Yamauchi H, Taniguchi Y, Porto KJ, Kanaya T,
Ishiura H, Mitsui J, Tsuji S, Toda T, Ono M,
Komuro I,Clinical Impact of Copy Number
Variation on the Genetic Diagnosis of Syndromic
Aortopathies.Circ Genom Precis Med. 2021
Aug; 14(4): e003458. doi: 10.1161/CIRCGEN.
121.003458.
Naito T, Satake W, Ogawa K, Suzuki K, Hirata J,
Foo JN, Tan EK, Toda T, Okada Y. Trans-Ethnic
Fine-Mapping of the Major Histocompatibility
Complex Region Linked to Parkinson's Disease.
Mov Disord. 2021 Aug;36(8):1805-1814. doi:
10.1002/mds.28583.
Katsuse K, Kodama S, Okazaki K, Toda T.
Delayed Brachial Plexus Palsy after Clavicular
Fracture. Intern Med. 2021 Aug 1;60(15):25112512. doi: 10.2169/internalmedicine.6988-20.
Chen XY, Song DY, Jiang L, Tan DD, Liu YD,
Liu JY, Chang XZ, Xing GG, Toda T, Xiong H.
Phenotype and Genotype Study of Chinese
POMT2-Related α-Dystroglycanopathy. Front
Genet. 2021 Aug 3; 12:692479. doi: 10.3389/
fgene.2021.692479.

29. Sato K, Mano T, Iwata A, Toda T. Safety of
Memantine in Combination with PotentiallyInteractive Drugs in the Real World: A
Pharmacovigilance Study Using the JapaneseAdverse Drug Event Report (JADER) Database.
J Alzheimers Dis. 2021Aug 3; 82(3):1333-1344.
doi: 10.3233/JAD-210524.
30. Ishigami D, Miyawaki S, Nakatomi H,
Takayanagi S, Teranishi Y, Ohara K, Hongo H,
Dofuku S, Kin T, Abe H, Mitsui J, Komura D,
Katoh H, Ishikawa S, Saito N. Brainstem
intraparenchymal schwannoma with genetic
analysis: a case report and literature review.
BMC Med Genomics. 2021 Aug 18; 14(1): 205.
doi: 10.1186/s12920-021-01049-z.
31. Taniguchi-Ikeda M, Koyanagi-Aoi M, Maruyama
T, Takaori T, Hosoya A, Tezuka H, Nagase S,
Ishihara T, Kadoshima T, Muguruma K, Ishigaki
K, Sakurai H, Mizoguchi A, Novitch BG, Toda T,
Watanabe M, Aoi T. Restoration of the defect inradial glial fiber migration and cortical plateorganization in a brain organoid model of
Fukuyama muscular dystrophy. iScience. 2021
Sep 17; 24(10):103140. doi: 10.1016/j.isci.2021.1
03140.
32. Sato K, Mano T, Niimi Y, Iwata A, Toda T,
Iwatsubo T. The impact of COVID-19 pandemic
on the utilization of ambulatory care for patientswith chronic neurological diseases in Japan:
Evaluation of an administrative claims database.
Biosci Trends. 2021 Sep 22;15(4):219-230. doi:
10.5582/bst.2021.01194.
33. Kikuchi JK, Nagashima Y, Mano T, Ishiura H,
Hayashi T, Shimizu J, Matsukawa T, Ichikawa Y,
Takahashi Y, Karino S, Kanbayashi T, Kira J,
Goto J, Tsuji S. Cerebellar Ataxia as a Common
Clinical Presentation Associated with DNMT1
p.Y511H and a Review of the Literature. J Mol
Neurosci. 2021 Sep;71(9):1796-1801.
34. Sato K, Mano T, Niimi Y, Toda T, Iwata A,
Iwatsubo T. Facial nerve palsy following theadministration of COVID-19 mRNA vaccines:
analysis of a self-reporting database. Int J InfectDis. 2021 Oct;111:310-312. doi: 10.1016/j.ijid.
2021.08.071.
35. Mitsutake A, Nagashima Y, Mori H, Sawamura H,
Toda T. Paracentral homonymous hemianopic

109

36.

37.

38.

39.

40.

41.

scotoma caused by anterior choroidal artery
infarction. QJM. 2021 Oct 7;114(6):417-418.
doi: 10.1093/qjmed/hcab031.
Porto KJ, Hirano M, Mitsui J, Chikada A,
Matsukawa T, Ishiura H; Japan Multiple System
Atrophy Registry Consortium, Toda T, Kusunoki
S, Tsuji S. COQ2 V393A confers high risk
susceptibility for multiple system atrophy in East
Asian population. J Neurol Sci. 2021 Oct 15;
429:117623. doi: 10.1016/j.jns.2021.117623.
Neshige S, Hitomi T, Tojima M, Oi K, Kobayashi
K, Matsuhashi M, Shimotake A, Matsumoto R,
Kanda M, Maruyama H, Ishiura H, Tsuji S,
Takahashi R, Ikeda A. A Role of Aging in the
Progression of Cortical Excitability in Benign
Adult Familial Myoclonus Epilepsy type 1
Patients. Mov Disord. 2021 Oct;36(10):24462448. doi: 10.1002/mds.28718.
Teranishi Y, Miyawaki S, Hongo H, Dofuku S,
Okano A, Takayanagi S, Ota T, Yoshimura J, Qu
W, Mitsui J, Nakatomi H, Morishita S, Tsuji S,
Saito N. Targeted deep sequencing of DNA frommultiple tissue types improves the diagnostic rate
and reveals a highly diverse phenotype of mosaic
neurofibromatosis type 2. J Med Genet. 2021
Oct; 58(10):701-711. doi: 10.1136/jmedgenet2020-106973.
Kainaga M, Shirota Y, Kodama S, Toda T,
Hamada M. Effects of the Coronavirus Disease2019 Pandemic on Motor Symptoms in
Parkinson's Disease: An Observational Study.
Mov Disord. 2021 Nov;36(11):2461-2463. doi:
10.1002/mds.28766.
Kakumoto T, Kobayashi S, Yuuki H, Kainaga M,
Shirota Y, Hamada M, Hashimoto Maeda M,
Kubota A, Kawai M, Saito M, Ishiura H, Toda T.
Cranial Nerve Involvement and Dysautonomia in
Post-COVID-19
Guillain-Barré
Syndrome.
Intern Med. 2021 Nov 1;60(21): 3477-3480. doi:
10.2169/internalmedicine.7355-21.
Mitsutake A, Unuma A, Kawai M, Kubota A,
Ishiura H, Sakuishi K, Shimizu J, Maki H, Amiya
E, Hatano M, Komuro I, Tsuji S, Toda T. Severe
dilatedcardiomyopathy
andventriculararrhythmia in a Patient with Emery-Dreifuss
muscular dystrophy harboring a novel frameshift
mutation in EMD. Neurol Clin Neurosci. 2021

42.

43.

44.

45.

46.

Nov;9:490-493.doi:10.1111/ncn3.12552
Almansour A, Ishiura H, Mitsui J, Matsukawa T,
Matsukawa MK, Shimizu H, Sugiyama A, Toda
T, Tsuji S. Frequency of FMR1 Premutation
Alleles in Patients with Undiagnosed Cerebellar
Ataxia and Multiple System Atrophy in theJapanese Population.Cerebellum. 2021 Nov 29.
doi: 10. 1007/s12311-021-01329-5.
Naruse H, Ishiura H, Mitsui J, Takahashi Y,
Matsukawa T, Toda T, Tsuji S. Juvenile
amyotrophic lateral sclerosis with complex
phenotypes associated with novel SYNE1
mutations.
Amyotroph
LateralScler
Frontotemporal Degener. 2021 Nov;22(7-8):
576-578. doi: 10.1080/21678421.2020.1813312.
Mochizuki H, Aoki M, Ikenaka K, Inoue H,
Iwatsubo T, Ugawa Y, Okazawa H, Ono K,
Onodera O, Kitagawa K, Saito Y, Shimohata T,
Takahashi R, Toda T, Nakahara J, Matsumoto R,
Mizusawa H, Mitsui J, Murayama S, Katsuno M;
Future Vision Committee of Japanese Society of
Neurology, Aoki Y, Ishiura H, Izumi Y, Koike H,
Shimada H, Takahashi Y, Tokuda T, Nakajima H,
HatanoT,
MisawaS,
WatanabeH.
[Recommendations (Proposal) for promoting
research for overcoming neurological diseases
2020]. Rinsho Shinkeigaku. 2021 Nov 24;
61(11): 709-721. doi: 10.5692/clinicalneurol.cn001639.
Kuroda N, Kubota T, Horinouchi T, Ikegaya N,
Kitazawa Y, Kodama S, Matsubara T, Nagino N,
Neshige S, Soga T, Sone D, Takayama Y,
Kuramochi I; IMPACT-J EPILEPSY (In-depth
Multicenter analysis during Pandemic of Covid19
Throughout Japan for Epilepsy practice) study
group. Risk factors for psychological distress inelectroencephalography technicians during the
COVID-19 pandemic: A national-level crosssectional survey in Japan. Epilepsy Behav. 2021
Dec; 125: 108361. doi: 10.1016/j.yebeh.2021.
108361.
Watanabe N, Nakano M, Mitsuishi Y, Hara N,
Mano T, Iwata A, Murayama S, Suzuki T, Ikeuchi
T, Nishimura M. Transcriptional downregulationof FAM3C/ILEI in the Alzheimer's brain. Hum
Mol Genet. 2021 Dec 17;31(1):122-132. doi:
10.1093/hmg/ddab226.

110

Department of Neurosurgery
Professor
Nobuhito Saito, M.D., Ph.D.

Lecturer
Shota Tanaka, M.D.,Ph.D.

Naoto Kunii, M.D., Ph.D.

Satoru Miyawaki, M.D., Ph.D.

Specially Appointed Lecturer
Shota Tanaka, M.D.,Ph.D.

Naoto Kunii, M.D., Ph.D.

Asssistant Professor
Shunsaku Takayanagi, M.D., Ph.D.

Hirokazu Takami, M.D., Ph.D.

Seijiro Shimada, M.D., Ph.D.

Naoyuki Shono, M.D. , Ph.D.

Yu Teranishi, M.D.,Ph.D.

Mariko Kawashima, M.D.,Ph.D.

Satoshi Koizumi, M.D.

Hirotaka Hasegawa, M.D., Ph.D.

Satoshi Kiyofuji, M.D.,Ph.D.

Hiroki Hongo, M.D., Ph.D.

Yuki Shinya, M.D.

Motoyuki Umekawa, M.D.

Specially Appointed Associate Professor at Medical Information Engineering
Taichi Kin, M.D., Ph.D.

Homepage

http://www.m.u-tokyo.ac.jp/neurosurg/

Introduction and Organization
The Department of Neurosurgery at the Universityof Tokyo Hospital consists of 14 staff neurosurgeons,
who participate in the three major academic activities:
patient care, research, and education. The staffs
include a professor/chairman, three lecturers, ten
assistant professors and one project associate
professor at Medical Information Technology.
Clinical ward for neurosurgery in our university
hospital was founded in 1951 as the first neurosurgicalclinic in Japan. Dr. Keiji Sano, as the founding
professor, established the Department of Neurosurgery
in 1962. Dr. Kintomo Takakura and Dr. Takaaki
Kirino served as the second and the third professor,
respectively. The incumbent professor, Dr. Nobuhito

Saito, has been serving as the fourth professor since
2006.
Our department provides expertise for patients withbrain tumor, cerebrovascular disease, spinal disease,functional disorder, head trauma, etc.

Clinical activities
General outpatient clinic including new patient
clinic is open every weekday and subspecialty clinic is
open three days a week (Monday and Friday). The
latter is open for patients with brain tumor, pituitarydisease, spinal disease, cerebrovascular disease,
endovascular intervention, epilepsy, and gamma knife
treatment. From April 2020 to March 2020, 16,509
patients were treated at the outpatient clinics.

111

The neurosurgery ward has approximately 40 beds on
the seventh floor of the new hospital building opened
in September 2001. In 2020, 791 patients wereadmitted to the neurosurgery ward. 386 surgicalprocedures and 204 gamma knife procedures were
performed in 2020. Our practice covers a wide varietyof neurosurgical diseases including malignant andbenign brain tumors, hemorrhagic and thromboembolic cerebrovascular diseases, spinal disorders,
epilepsy, pain and movement disorders.
Intraoperative functional monitoring in brain tumor
surgery and pre- and intra-operative functional mapping in epilepsy surgery are frequently used topreserve brain function as much as possible.
Endoscopic endonasal surgery is also frequently
utilized as a minimally invasive therapeutic option forskull base lesions. State-of-the-art techniques
including intraoperative computer-aided navigationand intravascular procedures help our continuous
effort to increase the safety of surgical treatment.
Some endovascular procedures are performed in our
hybrid operating room with the cooperation of theoperation department and the anesthesiology doctors.
Our department is affiliated with 35 neurosurgicalinstitutions in and around the city of Tokyo including
10 university medical centers, where our residents andstudents are exposed to various clinical experiences.
Surgical case volume in all hospitals exceeds 11,500
cases.

Teaching activities
Medical students take lectures of clinicalneurosurgery in their second year. Clinical casestudies and bedside teaching are scheduled in the thirdand fourth years. The lecturers introduce general
neurosurgery as well as the state-of-art neurosurgicalpractice to the students. At the bedside teaching andclinical clerkship, they are offered opportunities tolearn clinical management of neurosurgical patients in
the hands-on style, and also are exposed to practice invarious subspecialties in neurosurgery through special
seminars given by experts in the fields.
We accepted 4 in 2016, 16 in 2017, 5 in 2018, 7 in2019, 9 in 2020 in our neurosurgical residency
program. These residents are trained in the university
hospital and affiliated hospitals to experience every

aspect of neurosurgical practice for five years on
average. Our residency training is finalized after thesixth year, when the finishing residents serve as seniorresidents at the university hospital for 6 months.
Academic training is provided through numerous
intramural clinical and research conferences, journal
clubs, seminars as well as quarterly regional meetingsof the Japan Neurosurgical Society. After or duringresidency training, our residents can choose to be
admitted into the Ph.D. course at the Graduate Schoolof Medicine, the University of Tokyo, to be involvedin advanced basic research activities for 4 years. Uponcompletion of training, our graduates stay in thedepartment to be associates in our university hospitalor become clinical staffs in our affiliated hospitals.

Research activities
Clinical research in the last few years have mainly
focused on treatments of acoustic neurinoma, techniques of skull base surgery, treatments of malignant
brain tumors, epilepsy surgery, and stereotactic
radiosurgery. The results were presented at domestic
as well as international meetings including Annual
Meetings of the Japan Neurosurgical Society andAnnual Meetings of American Association of
Neurological Surgeons.
Our department has maintained prominent basic
research activities as well. The fields of our current
research are as follows:
1) Pathogenesis of cerebral ischemia and neuronal
regeneration after ischemic brain damage
One of the major topics in recent basic science is toregenerate the brain with endogenous neuralprogenitors. Our laboratory has started basic research
to regenerate neurons in vivo following ischemic
insult. We have demonstrated that the 40% of the lost
neurons could be regenerated by administration of
growth factors. We also succeeded in regeneration of
striatal neurons. Molecular mechanisms of adultneurogenesis are currently investigated using various
models to enhance post-ischemic regeneration. By
extending the research into primate model, we are
pursuing clinical application in the future.

1122) Genetic analyses of cerebrovascular diseases andbenign brain tumors
We are conducting genetic analysis research for
cerebrovascular diseases and benign brain tumors withthe aim of identifying molecular markers with highclinical significance and elucidating the pathogenic
mechanism.
Specially, genes such as RNF213 in moyamoya
disese, NF2 in meningioma and schwannoma, CCM in
cerebral cavernous malformation were analyzed. In
addition, comprehensive genetic analyses, including
analysis of whole exome sequences, were performed
to identify novel disease-related genes..
In the field of cerebrovascular disease, analysis of
the RNF213 gene revealed that RNF213 variant isassociated with not only moyamoya disease but also
various intracranial artery stenosis. Furthermore,genome wide association study of intracranial arterystenosis was performed, and diseae related gene
polymorphisms were clarified. In addition, we haveidentified
disease-relatedgeneinvenousmalformations that occur in the head and conducting
functional analysis.
In the field of benign brain tumors, we improved
the diagnostic rate of somatic mosaics ofneurofibromatosis type 2 (NF2) by analyzing DNA
from various tissues and reveals the phenotypiccharacteristics of NF2 somatic mosaics. In the genetic
analysis of meningioma, we revealed the association
between genetic variants, pathological diagnosis, andanatomical site. We are now conducting research toclarify the characteristic of the changes in genebackground during the recurrence of meningiomas.
3) Development of new therapeutic modalities formalignant brain tumors
Genotyping is now widely accepted as an essential
component of pathological diagnosis in glioma. We
have been routinely analysisng surgically resected
tumor specimens in a semi-prospective fashion. The
genetic analyses includes sequencing of IDH1/2 andhistone 3-coding genes, as well as loss ofheterozygosity analysis of 1p, 19q, and 10q, andmethylation analysis of MGMT promotor. We optimize
therapy based upon the results of the above genetic
analyses. In addition, we have been searching for
novel biomarkers and therapeutic targets using

comprehesive genetic and epigenetic analyses withwhole exome sequencing, RNA sequencing, andmethylation analysis. The current focus of our genome
study is on spinal astrocytoma and ependymoma. Ourparticular interest also lies in heterogeneity andmalignant progression of glioma, especially from
immune-oncological perspectives.
To develop a novel strategy for the treatment ofglioma, we isolate brain tumor initiating cells, which
are supposed to be responsible for resistance toconventional therapies, from surgical specimens, andutilize them in many aspects of our studies.
Furthermore, we are at the frontier in the field of
pediatric brain tumor research, especially on CNS
germ cell tumors. We have been publishing important
articles regarding basic, translational and clinicalresearch. Multi-omics genomic investigation into thepathogenesis and clinical trials are ongoing.
We have been collaborating with a basic researchlab in our university and developing novel
fluorescence probes specifically detecting glioma witha hope that fluorescence-guided surgery may result ingreater extent of resection.
4) Development and evaluation of function-preserving
and less invasive treatment of intractable epilepsy
We have been promoting the research on development,
evaluation and standardization of the novel treatment
for intractable epilepsy. Particularly, in order toimprove the outcome of epilepsy surgery for
MRI-negative cases, we are seeking to increase theaccuracy of localizing epileptic focus using
intracranial electrodes. In addition to the state-of-art
technologies such as time-frequency analysis andcortico-cortical evoked potentials, we are developing
next-generation
intracranialelectrodes
andaccelerating research to identify epileptogenic
network. At the same time, we aim to evaluate theeffectiveness of function-preserving procedures suchas multiple hippocampal transection, which has beenoriginally developed in Japan. Also, as the first facility
to introduce vagus nerve stimulation (VNS) therapy inJapan, we are participating in an international
collaborative research on the verification of theeffectiveness of VNS in the real world.

1135) Research on brain function using non-invasive andinvasive techniques
We have been studying human brain function using
not only non-invasive techniques such as fMRI, MEG,NIRS but also electrocorticography (ECoG) obtainedby intracranial electrodes implanted in epilepsy
patients. The latter is our markedly advantageous
feature that enables us to extract brain information
with much higher spatial resolution and SN ratio. We
aim to understand brain mechanisms as complicatednetwork systems and to improve the reliability of
non-invasive techniques. Since ECoG is a strong
candidate for a decoding source of brain-computerinterface (BCI), we are planning to expand theresearch on this field to clinical implementation of
BCI for communication and motor control incooperation with other brain research laboratories andengineering laboratories.
6) Clinical applications of the functional brain
imaging and operative simulation using threedimensional computer graphics for neurosurgery
Our department intensively utilizes various kinds offunctional and metabolic imaging modalities including
magnetoencephalography, functional MRI, and diffusion tensor imaging-based tractography for presurgicalbrain mapping. Combining the results of themulti-modalities enables to visualize all cortical andsubcortical networks of the motor, language and othercognitive functions in each patient. Furthermore, we
succeeded to import the combined information into a
neuronavigation system (functional neuronavigation),
which quickly and accurately indicates the eloquent
brain areas. We could develop virtual reality operative
simulation using multi-modal fusion threedimensional computer graphics. Then, it was possible
to precisely examine surgical strategy.
7) Gamma knife radiosurgery
Gamma knife is a kind of devices for stereotactic
radiosurgery in which high doses of radiation aredelivered at one session and has been widely accepted
as one of treatment options for various intracranial
disorders such as brain tumors, vascular disorders andfunctional disorders. The first gamma knife in Japanwas introduced at our department and diverse clinicalresults have been published. Recently, less invasive

treatment has taking on an added significance in thefield of neurosurgery as well. Therefore, appropriate
combination of radical surgery and radiosurgery isnecessary to manage difficult-to-treat lesions such as
skull base tumors and deeply seated cerebral
arteriovenous malformations, and thus gamma knife
radiosurgery would play a more important role inneurosurgery. Further, technological progress has
refined treatment as an example of integration ofdiffusion tensor tractography which was firstly
attempted at our department. Such technologicalprogresses might contribute to better outcomes ofgamma knife radiosurgery in the future.

References (2021)
1.

2.

3.

4.

5.

Amemiya S., Watanabe Y., Takei N., Ueyama T.,
Miyawaki S., Koizumi S., Kato S., Takao H., Abe
O., Saito N. Reliability and Sensitivity toLongitudinal CBF Changes in Steno-Occlusive
Diseases: ASL Versus (123) I-IMP-SPECT. J
Magn Reson Imaging, 2021 doi: 10.1002/
jmri.27996
Amemiya S., Watanabe Y., Takei N., Ueyama T.,
Miyawaki S., Koizumi S., Kato S., Takao H., Abe
O., Saito N. Arterial Transit Time-BasedMultidelay Combination Strategy Improves
Arterial Spin Labeling Cerebral Blood Flow
Measurement Accuracy in Severe StenoOcclusive Diseases. J Magn Reson Imaging,2021 doi: 10.1002/jmri.27823
Aono T., Shinya Y., Miyawaki S., Sugiyama T.,
Kumagai I., Takenobu A., Shin M., Saito N.,
Teraoka A. Changes in the Risk of Stroke in
Dialysis Patients: A Retrospective Analysis over
the Last 40 Years. Toxins 13(5), 2021 doi:
10.3390/toxins13050350
Fukushima Y., Uchida S., Imai H., Nakatomi H.,
Kataoka K., Saito N., Itaka K. Treatment ofischemic neuronal death by introducing
brain-derived neurotrophic factor mRNA using
polyplex nanomicelle. Biomaterials 270:120681,
2021 doi: 10.1016/j.biomaterials.2021.120681
Hasegawa H., Kin T., Shin M., Suzuki Y.,
Kawashima M., Shinya Y., Shiode T., Nakatomi
H., Saito N. Possible Association Between
Rupture and Intranidal Microhemodynamics in114

Arteriovenous Malformations: Phase-Contrast
Magnetic Resonance Angiography-Based Flow
Quantification. World Neurosurg 150:e427e435, 2021 doi: 10.1016/j.wneu.2021.03.036
6. Hirano Y., Miyawaki S., Imai H., Hongo H.,
Teranishi Y., Dofuku S., Ishigami D., Ohara K.,
Koizumi S., Ono H., Nakatomi H., Saito N.
Differences in Clinical Features among Different
Onset Patterns in Moyamoya Disease. Journal ofclinical medicine 10(13), 2021 doi: 10.3390/
jcm10132815
7. Hirano Y., Miyawaki S., Tanaka S., Taoka K.,
Hongo H., Teranishi Y., Takami H., Takayanagi
S., Kurokawa M., Saito N. Clinical Features andPrognostic Factors for Primary Anaplastic Large
Cell Lymphoma of the Central Nervous System:
A Systematic Review. Cancers 13(17), 2021
doi: 10.3390/cancers13174358
8. Hirata T., Miyawaki S., Koizumi S., Teranishi Y.,
Ishikawa O., Saito N. Spontaneous regression ofa symptomatic developmental venous anomalywithcapillarystain.
Interventional
neuroradiology : journal of peritherapeutic
neuroradiology, surgical procedures andrelatedneurosciences:15910199211032470,
2021 doi: 10.1177/15910199211032470
9. Hong S., Hasegawa H., Shin M., Shinya Y., Saito
N. Endoscopic Transsphenoidal Resection ofSuprasellar Histiocytosis in a Patient with
Erdheim-Chester Disease: A Case Report. NMC
case report journal 8(1):117-122, 2021 doi:
10.2176/nmccrj.cr.2020-0126
10. Iihara K., Saito N., Suzuki M., Date I., Fujii Y.,
Houkin K., Inoue T., Iwama T., Kawamata T.,
Kim P., Kinouchi H., Kishima H., Kohmura E.,
Kurisu K., Maruyama K., Matsumaru Y., MikuniN., Miyamoto S., Morita A., Nakase H., Narita Y.,
Nishikawa R., Nozaki K., Ogasawara K., Ohata
K., Sakai N., Sakamoto H., Shiokawa Y.,
Takahashi J. C., Ueki K., Wakabayashi T.,
Yoshimoto K., Arai H., Tominaga T. The Japan
Neurosurgical Database: Statistics Update 2018and 2019. Neurol Med Chir (Tokyo), 2021
doi: 10.2176/nmc.st.2021-0254
11. Ishigami D., Koizumi S., Ishikawa O.,
Toshimitsu M., Iriyama T., Miyawaki S., Saito N.
Embolization of dural arteriovenous fistula

12.

13.

14.

15.

16.

17.

during twin pregnancy - A case report andliterature
review.
Interventional
neuroradiology : journal of peritherapeutic
neuroradiology, surgical procedures andrelated neurosciences 27(5):658-662, 2021
doi: 10.1177/1591019921991396
Ishigami D., Miyawaki S., Imai H., Shimizu M.,
Hongo H., Dofuku S., Ohara K., Teranishi Y.,
Shimada D., Koizumi S., Ono H., Hirano Y.,
Segawa M., Nakatomi H., Saito N. Correction to:
RNF213 p.Arg4810Lys Heterozygosity inMoyamoya Disease Indicates Early Onset and
Bilateral Cerebrovascular Events. Translational
stroke research, 2021 doi: 10.1007/s12975021-00971-9
Ishigami D., Miyawaki S., Nakatomi H.,
Takayanagi S., Teranishi Y., Ohara K., Hongo H.,
Dofuku S., Kin T., Abe H., Mitsui J., Komura D.,
Katoh H., Ishikawa S., Saito N. Brainstem
intraparenchymal schwannoma with genetic
analysis: a case report and literature review.
BMC medical genomics 14(1):205, 2021 doi:
10.1186/s12920-021-01049-z
Kawashima M., Hasegawa H., Shin M., Shinya Y.,
Katano A., Saito N. Outcomes of stereotactic
radiosurgery in young adults with vestibular
schwannomas. J Neurooncol 154(1):93-100,2021 doi: 10.1007/s11060-021-03803-w
Kawashima M., Hasegawa H., Shin M., Shinya Y.,
Saito N. Intratumoral hemorrhage in jugularforamenschwannoma
afterstereotactic
radiosurgery: A case report. Surg Neurol Int
12:479, 2021 doi: 10.25259/sni_550_2021
Kitagawa Y., Tanaka S., Kamiya M., Kuriki Y.,
Yamamoto K., Shimizu T., Nejo T., Hana T.,
Matsuura R., Koike T., Yamazawa E., KushiharaY., Takahashi S., Nomura M., Takami H.,
Takayanagi S., Mukasa A., Urano Y., Saito N. A
Novel Topical Fluorescent Probe for Detection of
Glioblastoma. Clin Cancer Res 27(14):39363947, 2021 doi: 10.1158/1078-0432.ccr-20-4518
Kiyofuji S., Kin T., Kakizawa Y., Doke T.,
Masuda T., Yamashita J., Shono N., Nakatomi H.,
Morita A., Harada K., Saito N. Development ofIntegrated 3-Dimensional Computer Graphics
Human Head Model. Operative neurosurgery(Hagerstown, Md) 20(6):565-574, 2021 doi:

115

18.

19.

20.

21.

22.

23.

24.

10.1093/ons/opab012
Koike T., Kin T., Tanaka S., Sato K., Uchida T.,
Takeda Y., Uchikawa H., Kiyofuji S., Saito T.,
Takami H., Takayanagi S., Mukasa A., Oyama H.,
Saito N. Development of a New Image-Guided
Neuronavigation
System:Mixed-Reality
Projection Mapping Is Accurate and Feasible.
Operative neurosurgery (Hagerstown, Md)
21(6):549-557, 2021 doi: 10.1093/ons/opab353
Koike T., Kin T., Tanaka S., Takeda Y., Uchikawa
H., Shiode T., Saito T., Takami H., Takayanagi S.,
Mukasa A., Oyama H., Saito N. Development of
Innovative Neurosurgical Operation Support
Method Using Mixed-Reality Computer Graphics.
World neurosurgery: X 11:100102, 2021 doi:
10.1016/j.wnsx.2021.100102
Koizumi S., Shojima M., Dofuku S., Saito A.,
Nomura S., Ono H., Ishikawa O., Saito N.
Neuroendovascular Training Using Multisource
Video-Recording System in a Hybrid OperatingRoom. World Neurosurg 154:e320-e324, 2021
doi: 10.1016/j.wneu.2021.07.029
Kunii N., Koizumi T., Kawai K., Shimada S.,
Saito N. Vagus Nerve Stimulation Amplifies
Task-Induced Cerebral Blood Flow Increase.
Frontiers in human neuroscience 15:726087,
2021 doi: 10.3389/fnhum.2021.726087
Nomura S K. T., Kunimatsu A, Shojima M,
Watanebe Y, Suzuki Y, Shono N, Imai H, Saito T,
Nakatomi H, Oyama H, Saito N. . Registration
Method Between Phase-Contrast Magnetic
Resonance Angiography and Time-of-Flight
Magnetic
Resonance
Angiography—A
Preliminary Study. Journal of Medical Imaging
and Health Informatics 11(1):33-39, 2021
doi: https://doi.org/10.1166/jmihi.2021.3505
Noyama T., Katano A., Shinya Y., Kawashima M.,
Shin M., Saito N., Yamashita H. Prognostic
Factors for Patients With Brain Metastases
Treated With Single-fraction Gamma Knife
Radiosurgery. Anticancer Res 41(6):3179-3185,
2021 doi: 10.21873/anticanres.15104
Okano A., Miyawaki S., Hongo H., Dofuku S.,
Teranishi Y., Mitsui J., Tanaka M., Shin M.,
Nakatomi H., Saito N. Associations ofpathological diagnosis and genetic abnormalities
in meningiomas with the embryological origins

25.

26.

27.

28.

29.

30.

of the meninges. Sci Rep 11(1):6987, 2021 doi:
10.1038/s41598-021-86298-9
Oya S., Takayanagi S., Takami H., Indo M.,
Yamashita T., Saito N., Matsui T. Masked
malignant phenotype with a benign appearance:beat-up copy number profile may be the key forhemangioblastoma dissemination. Brain Tumor
Pathol 38(1):71-77, 2021 doi: 10.1007/s10014020-00387-7
Saito N., Kobayashi Y., Nagaoka K., Kushihara
Y., Sato Y., Wada I., Kakimi K., Seto Y. Two
distinct phenotypes of immunologically hot
gastric cancer subtypes. Biochemistry andbiophysics reports 28:101167, 2021
doi:
10.1016/j.bbrep.2021.101167
Sato D., Hasegawa H., Shin M., Kondo K., Saito
N.
Combined
endoscopic
endonasaltranstubercular and transclival approaches forlarge neurenteric cyst in posterior cranial fossa: A
case report and literature review. Surg Neurol
Int 12:554, 2021 doi: 10.25259/sni_648_2021
Satomi K., Takami H., Fukushima S., YamashitaS., Matsushita Y., Nakazato Y., Suzuki T., Tanaka
S., Mukasa A., Saito N., Kanamori M., KumabeT., Tominaga T., Kobayashi K., Nagane M., Iuchi
T., Yoshimoto K., Tamura K., Maehara T., SakaiK., Sugiyama K., Yokogami K., Takeshima H.,
Nonaka M., Asai A., Ushijima T., Matsutani M.,
Nishikawa R., Ichimura K. 12p gain is
predominantly observed in non-germinomatous
germ cell tumors and identifies an unfavorable
subgroup of central nervous system germ celltumors. Neuro Oncol, 2021
doi: 10.1093/
neuonc/noab246
Shinya Y., Hasegawa H., Kawashima M., Shin M.,
Takahashi W., Kobayashi H., Saito N.
Stereotactic radiosurgery as a primary treatment
for metastatic skull base alveolar soft partsarcoma: a case report. Acta Neurochir (Wien)
163(2):351-355,
2021
doi:
10.1007/s00701-020-04496-2
Shinya Y., Hasegawa H., Shin M., Kawashima M.,
Sugiyama T., Ishikawa O., Koizumi S., Suzuki Y.,
Nakatomi H., Saito N. Rotational AngiographyBased Gamma Knife Radiosurgery for Brain
Arteriovenous
Malformations:
Preliminary
Therapeutic Outcomes of the Novel Method.

116

31.

32.

33.

34.

35.

36.

37.

Neurosurgery 89(1):60-69, 2021 doi: 10.1093/
neuros/nyab066
Shinya Y., Hasegawa H., Shin M., Sugiyama T.,
Kawashima M., Katano A., Kashio A., Kondo K.,
Saito N. Long-Term Outcomes of Stereotactic
Radiosurgery for Trigeminal, Facial, and Jugular
Foramen Schwannoma in Comparison with
Vestibular Schwannoma. Cancers 13(5), 2021
doi: 10.3390/cancers13051140
Sugino T., Kawase T., Onogi S., Kin T., Saito N.,
Nakajima Y. Loss Weightings for Improving
Imbalanced Brain Structure Segmentation Using
Fully Convolutional Networks. Healthcare(Basel, Switzerland) 9(8), 2021 doi: 10.3390/
healthcare9080938
Sugino T., Roth H. R., Oda M., Kin T., Saito N.,
Nakajima Y., Mori K. Performance improvementof weakly supervised fully convolutional
networks by skip connections for brain structure
segmentation. Medical physics 48(11):72157227, 2021 doi: 10.1002/mp.15192
Sugino T., Suzuki Y., Kin T., Saito N., Onogi S.,
Kawase T., Mori K., Nakajima Y. Label cleaningand propagation for improved segmentation
performance using fully convolutional networks.
Int J Comput Assist Radiol Surg 16(3):349-361,
2021 doi: 10.1007/s11548-021-02312-5
Tada M., Kirihara K., Ishishita Y., Takasago M.,
Kunii N., Uka T., Shimada S., Ibayashi K., Kawai
K., Saito N., Koshiyama D., Fujioka M., Araki T.,
Kasai K. Global and Parallel Cortical Processing
Based on Auditory Gamma Oscillatory
Responses in Humans. Cereb Cortex 31(10):4518-4532, 2021 doi: 10.1093/cercor/bhab103
Takabatake K., Kunii N., Nakatomi H., ShimadaS., Yanai K., Takasago M., Saito N. Musical
Auditory Alpha Wave Neurofeedback: Validation
andCognitive
Perspectives.
Appliedpsychophysiology and biofeedback 46(4):323334, 2021 doi: 10.1007/s10484-021-09507-1
Takahashi S., Takahashi M., Kinoshita M.,
Miyake M., Kawaguchi R., Shinojima N.,
Mukasa A., Saito K., Nagane M., Otani R.,
Higuchi F., Tanaka S., Hata N., Tamura K.,
Tateishi K., Nishikawa R., Arita H., Nonaka M.,
Uda T., Fukai J., Okita Y., Tsuyuguchi N.,
Kanemura Y., Kobayashi K., Sese J., Ichimura K.,

38.

39.

40.

41.

42.

Narita Y., Hamamoto R. Fine-Tuning Approachfor Segmentation of Gliomas in Brain Magnetic
Resonance Images with a Machine Learning
Method to Normalize Image Differences among
Facilities. Cancers 13(6), 2021 doi: 10.3390/
cancers13061415
Takami H., Graffeo C. S., Perry A., Ohno M.,
Ishida J., Giannini C., Narita Y., Nakazato Y.,
Saito N., Nishikawa R., Matsutani M., Ichimura
K., Daniels D. J. Histopathology and prognosis ofgerm cell tumors metastatic to brain: cohort study.
J Neurooncol 154(1):121-130, 2021
doi:
10.1007/s11060-021-03810-x
Takami H., Satomi K., Fukuoka K., Fukushima S.,
Matsushita Y., Yamasaki K., Nakamura T.,
Tanaka S., Mukasa A., Saito N., Suzuki T.,
Yanagisawa T., Nakamura H., Sugiyama K.,
Tamura K., Maehara T., Nakada M., Nonaka M.,
Asai A., Yokogami K., Takeshima H., Iuchi T.,
Kanemura Y., Kobayashi K., Nagane M.,
Kurozumi K., Yoshimoto K., Matsuda M.,
Matsumura A., Hirose Y., Tokuyama T., KumabeT., Narita Y., Shibui S., Nakazato Y., Nishikawa
R., Matsutani M., Ichimura K. Low tumor cell
content predicts favorable prognosis ingerminoma patients. Neuro-oncology advances
3(1):vdab110, 2021
doi: 10.1093/noajnl/
vdab110
Takami H., Tanaka S., Takayanagi S., Nakatomi
H., Saito N. Indocyanine green illuminates theway to cut the tentorium in occipitaltranstentorial approach: technical note. Br J
Neurosurg:1-3, 2021 doi: 10.1080/02688697.
2021.1927982
Takeda Y., Kin T., Sekine T., Hasegawa H.,
Suzuki Y., Uchikawa H., Koike T., Kiyofuji S.,
Shinya Y., Kawashima M., Saito N.
Hemodynamic Analysis of Cerebral AVMs with
3D Phase-Contrast MR Imaging. AJNR Am J
Neuroradiol 42(12):2138-2145, 2021
doi:
10.3174/ajnr.A7314
Tanabe R., Miyazono K., Todo T., Saito N., Iwata
C., Komuro A., Sakai S., Raja E., Koinuma D.,
Morikawa M., Westermark B., Heldin C. H.
PRRX1 induced by BMP signaling decreases
tumorigenesis by epigenetically regulating
glioma-initiating cell properties via DNA

117

43.

44.

45.

46.

47.

methyltransferase 3A. Molecular oncology, 2021
doi: 10.1002/1878-0261.13051
Tanaka H., Lee H., Morita A., Namkoong H.,
Chubachi S., Kabata H., Kamata H., Ishii M.,
Hasegawa N., Harada N., Ueda T., Ueda S.,
Ishiguro T., Arimura K., Saito F., Yoshiyama T.,
Nakano Y., Mutoh Y., Suzuki Y., Murakami K.,
Okada Y., Koike R., Kitagawa Y., Tokunaga K.,
Kimura A., Imoto S., Miyano S., Ogawa S.,
Kanai T., Fukunaga K. Clinical Characteristics ofPatients with Coronavirus Disease (COVID-19):
Preliminary Baseline Report of Japan COVID-19
Task Force, a Nationwide Consortium toInvestigate Host Genetics of COVID-19.
International journal of infectious diseases :IJID : official publication of the International
Society for Infectious Diseases 113:74-81, 2021
doi: 10.1016/j.ijid.2021.09.070
Teranishi Y., Miyawaki S., Hongo H., Dofuku S.,
Okano A., Takayanagi S., Ota T., Yoshimura J.,
Qu W., Mitsui J., Nakatomi H., Morishita S.,
Tsuji S., Saito N. Targeted deep sequencing ofDNA from multiple tissue types improves thediagnostic rate and reveals a highly diverse
phenotype of mosaic neurofibromatosis type 2.
Journal of medical genetics 58(10):701-711,
2021 doi: 10.1136/jmedgenet-2020-106973
Tsuchiya T., Koizumi S., Tomioka A., Miyawaki
S., Saito N. Acute Ischemic Stroke Due to Basilar
Artery Occlusion with Coronavirus Disease
2019: A Case Report. NMC case report journal8(1):579-585, 2021
doi: 10.2176/nmccrj.cr.
2021-0043
Tsunoda S., Inoue T., Ohwaki K., Akabane A.,
Saito N. Comparison of postoperative temporalis
muscle atrophy between the muscle-preserving
pterional approach and the mini-pterional
approach in the treatment of unruptured
intracranial aneurysms. Neurosurg Rev, 2021
doi: 10.1007/s10143-021-01558-6
Uchida T., Kin T., Koike T., Kiyofuji S.,
Uchikawa H., Takeda Y., Miyawaki S., Nakatomi
H., Saito N. Identification of the Facial
Colliculus in Two-dimensional and Threedimensional Images. Neurol Med Chir (Tokyo)
61(6):376-384, 2021
doi: 10.2176/nmc.oa.
2020-0417

48. Uchikawa H., Kin T., Takeda Y., Koike T.,
Kiyofuji S., Koizumi S., Shiode T., Suzuki Y.,
Miyawaki S., Nakatomi H., Mukasa A., Saito N.
Correlation of Inflow Velocity Ratio Detected by
Phase
Contrast
Magnetic
Resonance
Angiography with the Bleb Color of Unruptured
Intracranial Aneurysms. World neurosurgery: X
10:100098, 2021
doi: 10.1016/j.wnsx.2021.
100098

Social Medicine
1. Occupational, Environmental
and Preventive Medicine

119

Department of Preventive
Medicine
Professor
Shumpei Ishikawa, M.D., Ph.D.

Associate Professor
Hiroto Katoh, M.D., Ph.D.

Assistant Professor
Daisuke Komura, M.D., Ph.D.
Miwako Kakiuchi, M.D., Ph.D.

Homepage https://plaza.umin.ac.jp/prm/
Introduction and Organization
Department of Preventive Medicine is the oldest
laboratory in the University of Tokyo, established by
Masanori Ogata in 1885. Ever since, for more than
130 years, the laboratory has been a hub to importantresearch leading to disease prevention and developed
and produced core human resources in public healthadministration. The philosophy of the Department toPreventive Medicine has not changed throughout its
history, but its focus of research has changed fromtime to time, like infectious diseases and occupational
health to name a few, to meet the expectations of thesociety. Eventually, in response to the completion of
the Human Genome Project and the recent
advancement in molecular biology, the laboratory hadchanged its name to the Department of MolecularPreventive Medicine. Under Professor Koji
Matsushima, the 8th director of the laboratory, researchwasactively
conducted
toclarify
inflammation/immune phenomenon with focus on
cytokines in disease background, and its clinicalapplication for secondary/tertiary prevention. In
December 2018, Professor Shumpei Ishikawa became
the 9th director, and in April 2019, he changed thename of the department back to Preventive Medicine.
Currently, our lab includes (besides the professor,

the associate professor, and the assistant professors) 9
students (1 are from outside of UTokyo), 2 technicalstaffs, 7 technical assistants, 1 collaboration researcher,
3 visiting researchers, 1 academic support staff, and 1
project specialist. Also, three collaborative researchers
from private companies have joined our laboratory.

Teaching activities
We give “Preventive Medicine” lecture course tothird-year undergraduate students in the school of
medicine, practical courses to fifth-year undergraduate
students, “Introduction to Preventive Medicine” inmedical science master’s program, and "Surviving
Cancer in Asia," a doctoral program common course
in medicine. Specific emphases are on alteration of thedisease pattern associated with social change, basic
concepts of occupational and mental health, andinformation science as a key to the understanding ofgenome and abundant bio/health data, which is a basisof disease predisposition. Through our lectures andpractical courses in “Preventive Medicine”, students
learn the concept of preventive medicine.

Research activities
In Department of Preventive Medicine, we conduct
research based on genome science and information

120

science to explore the appropriate points ofintervention for various health issues, in particular,
cancer prevention and treatment. Cancer andinflammation/immune diseases are complex systems
comprised of numerous types of cells. We aim toelucidate the dynamics of such complex systems bycollecting extensive data at genome-level, as well as toexplore specific phenomena which may serve asintervenable preventive/therapeutic targets, and toevaluate their significance in the related diseases. In
addition, we are developing bioinformatics technology
to extract essential information from massive andmulti-dimensional biological data, e.g., genome
sequence and images, for human interpretation bytechniques such as dimensionality reduction andvisualization.
Our current primary focus areas of research are as
follow:
1．Immune Repertoire Analysis to Reveal
Internal/External
ImmuneEnvironment
Profiles in Individuals
Antigen receptor genes of human lymphocyte
undergo somatic hypermutation to acquire extensive
diversity. The entire set of antigen receptors inlymphocyte population is called immune repertoire,
and its profiling in individuals has now become
possible thanks to the advancement in genome
analysis technology such as next-generation
sequencing (NGS). Immune repertoires are considered
to reflect immune history affected by external factors,e.g., pathogens and foods that the individual has
encountered, and by internal factors, e.g., self-antigens
and cancer antigens. In the department of Preventive
Medicine, we are trying to develop a method to extract
not only current disease conditions but also otherrelevant health information, such as past diseasehistory and lifestyles, by analyzing immune
repertoires. In particular, in immune repertoire
analysis using gastric cancer and gastric mucosa
tissues, we combine the results with cancer genome
and microbiome analyses to decipher immune history
with regard to cancer antigens and H. pylori in its
entirety,andrevealedthatthesulfated
glycosaminoglycans are major and functional B cell
antigens in human cancers. We also use information
analysis technique such as deep learning to analyze

information related to cancer prevention and treatment.
We are also synthesizing antibodies from this immune
repertoire data to develop antibody drugs against
cancer.
2. Cancer Genome
AnalysistoExploreCarcinogenic Factors and Point of Intervention
We are combining human clinical cancer tissues
with NGS to achieve a comprehensive understandingof the cancer genome. Whole cancer genome
sequencing will provide numerous information, suchas the driver genes, which would serve direct
therapeutic targets, and the genetic background of anindividual related to carcinogenic predispositions. It
also enables mutation signature analysis to reveal
environmental factors which are also possible
carcinogenic
predispositions.
Theobtained
information is processed as a whole by the
combination of bioinformatics and experimental
validation to explore the appropriate points ofintervention for cancer prevention and treatment,
which are crucial for health in our country. We haveidentified RHOA driver mutation in diffuse-type
gastric adenocarcinoma by cancer genome sequencing.
In addition, we performed trans-ethic genome analysis
of gastric cancer and showed the existence of East
Asian-specific gastric cancer induced by alcohol
drinking and smoking. Currently, we are regarding
cancer tissues as a whole using clinical cancer tissues
and patient-derived xenografts (PDX), by applying
genomics point of view, i.e., single-cell analysis, tocancer cells, immune cells, and vascular stroma cells
that comprise cancer tissue, to elucidate carcinogenic
and progression factors and points of intervention
from higher dimensions.
3．Contribution to Elimination of Medical Care
Disparities by Histopathological Image Analysis
As the volume of available biomedical information
is growing rapidly, technology to extract essential
abstract information by compressing dimensions of anenormous amount of biological data is extremely
important in our society. In the department ofPreventive Medicine, deep neural network is applied
to extract essential information (deep texture) ofcancer from cancer histopathological images. Our goal
is to develop tools to achieve a uniform pathological121

diagnosis and to help eliminate regional medical caredisparities. We developed Luigi, a content-based
image retrieval system for cancer histopathologicalimages, and made it available to pathologists andresearchers in Web (https://luigi-pathology.com/) andsmartphone application. The database in Luigi
contains histopathologial images and their deep
texture from more than 7,000 cases of 32 cancer typesin The Cancer Genome Atlas. By uploading images,
histopathological similar cases in the database arepresented. Currently, we’re trying to expand the Luigi
database by collaborating with various hospitals. We
also focus on the development of contents which
would seamlessly connect routine lab tests performedin small clinics and cancer genome medicine given inlarge core hospitals by integrated analysis ofhistopathological information and cancer genome
information.

Publications
1.

2.

3.

4.

5.

Sueyoshi, K., Komura, D., Katoh, H., Yamamoto,A., Onoyama, T., Chijiwa, T., Isagawa, T.,
Tanaka, M., Suemizu, H., Nakamura, M., Miyagi,
Y., Aburatani, H., Ishikawa, S., 2021.
Multi-tumor
analysisofcancer-stromainteractomes of patient-derived xenografts
unveils the unique homeostatic process in renal
cell carcinomas. iScience 24, 103322.
Ishigami, D., Miyawaki, S., Nakatomi, H.,
Takayanagi, S., Teranishi, Y., Ohara, K., Hongo,
H., Dofuku, S., Kin, T., Abe, H., Mitsui, J.,
Komura, D., Katoh, H., Ishikawa, S., Saito, N.,
2021. Brainstem intraparenchymal schwannoma
with genetic analysis: a case report and literature
review. BMC Med Genomics 14, 205.
Komura, D., Ishikawa, S., 2021. Advanced deeplearning applications in diagnostic pathology.
Translational and Regulatory Sciences 3, 36–
42.
Katoh, H., Ishikawa, S., 2021. Lifestyles,
genetics, and future perspectives on gastriccancer in east Asian populations. J Hum Genet66, 887–899.
Imai, S., Ooki, T., Murata-Kamiya, N., Komura,D., Tahmina, K., Wu, W., Takahashi-Kanemitsu,
A., Knight, C.T., Kunita, A., Suzuki, N., Del

6.

Valle, A.A., Tsuboi, M., Hata, M., Hayakawa, Y.,
Ohnishi, N., Ueda, K., Fukayama, M., Ushiku, T.,
Ishikawa,
S.,
Hatakeyama,
M.,
2021.
Helicobacter pylori CagA elicits BRCAness to
induce genome instability that may underlie
bacterial gastric carcinogenesis. Cell Host
Microbe 29, 941-958.e10.
Ohkuma, R., Yada, E., Ishikawa, S., Komura, D.,
Kubota, Y., Hamada, K., Horiike, A., Ishiguro, T.,
Hirasawa, Y., Ariizumi, H., Shida, M., Watanabe,
M., Onoue, R., Ando, K., Tsurutani, J.,
Yoshimura, K., Sasada, T., Aoki, T., Murakami,M., Norose, T., Ohike, N., Takimoto, M.,
Kobayashi, S., Tsunoda, T., Wada, S., 2021.
High levels of human epididymis protein 4mRNA and protein expression are associatedwith chemoresistance and a poor prognosis inpancreatic cancer. Int J Oncol 58, 57–69.

122

Department of Public Health/
Department of Health Policy
Professor
Yasuki Kobayashi, M.D., Ph.D.

Associate Professor
Satoshi Toyokawa, M.M.S., Ph.D.

Lecturer
Jun Tomio, M.D., M.Sc., Ph.D.
(until September 30, 2021)

Research Associate
Atsushi Miyawaki, M.D., Ph.D.

Project Research Associate
Taeko Oguma, M.D., Ph.D.

Homepage

http://publichealth.m.u-tokyo.ac.jp/

Introduction and Organization
Modern concepts of public health originated in the
Industrial Revolution era in the UK, and since thendeveloped in Western countries. In Japan, theseconcepts became important and popular in the 1880s,
when the Japan Non-governmental Association for
Hygiene (a synonym of public health in that age) wasestablished to fight against repeated outbreaks ofcholera in Japan.
Public health departments in medical schools inJapan were introduced after the World War II,
following the model of the U.S. systems for publichealth and medical education. The Department of
Public Health was established in 1947, in Faculty of
Medicine, the University of Tokyo. In 1995, theDepartment became a part of Division of Social
Medicine, Graduate School of Medicine, as the resultof the shift to a graduate school system in the
University of Tokyo. In 2007, School of Public
Health was established in the University of Tokyo, andthe Department became a part of School of Public

Health (Department of Health Policy) and remained
being a part of Division of Social Medicine(Department of Public Health).
The objectives of the Department are botheducation and research of public health. The
Department trains graduate and undergraduate
students through lectures, seminars, field practice, andlaboratory work in public health and occupational
medicine, for the degrees of Medical Doctor (MD),Master of Public Health (MPH), and Doctor of
Medical Sciences (equivalent to PhD). The
Department has conducted research on a wide variety
for public health issues, including health policy andeconomics, occupational medicine, clinical epidemiology, health services research, and so on. In addition,
the staff members of the Department have offeredpublic and occupational health services to the governments, industries, and local communities.
In the academic year of 2020, the Department
consists of 5 faculty members above listed, 2 project
researchers (part-time), 2 supporting staff members, 6

123

graduate students (3 in PhD program, 3 in professional
degree course), 16 part-time lecturers, and 31 visiting
fellows.

Teaching activities
1) Undergraduate Program (Medical School)
In 2020, because of the COVID-19 pandemic, all
the lectures as well as field practice and laboratory
work were conducted online. In the Autumn term of
the fourth grade in School of Medicine (M2), students
are provided with the following lectures; current
issues of public health, preventive services,
epidemiology, clinical epidemiology, quality of care,health economics, community medicine, infectious
diseases and tuberculosis control, mental health,human ecology, global health, non-communicablediseases prevention and management, disaster publichealth, and so on. Similarly, in the sixth grade (M4),an intensive course of public health (e.g., health caresystems, current health policy, occupational andenvironmental health, nutritional epidemiology,
physical activity and health, and health services
research) is provided. All the above lectures are given
by faculty members and part-time lectures including
health practitioners.
Field practice and laboratory work in public healthis due in the summer term of the fifth grade (M3),which is jointly provided by Department of Preventive
Medicine and the other departments related to publichealth fields. Averagely four to five students (small
group) are assigned to one special topic group with atutor (faculty member or part-time lecturer; we had 18
groups this year). Each group conducts field practice,review work, or laboratory work, and writes a reportin the style of original or review paper.
The Department provides those lectures related to
public health and occupational medicine forundergraduate students in the School of Integrated
Health Sciences, Faculty of Arts and Sciences, andFaculty of Engineering. The Department also provides
part of the course for those graduate students in
Graduate School of Public Policy and the GSDM
program.
2) MPH Program
Various courses (more than 40 courses) are given by

those departments affiliated with School of Public
Health. Among them, our Department offers threecourses; “Health Policy”, “Public Health Preparedness”, and “Public Health Practice”.
3) PhD Program
The Department offers special lectures, seminars,
field practice, and laboratory work on public healthand occupational medicine to graduate students. In
these training, special emphasis has been placed on
the following points: (1) how to conduct epidemiological studies, (2) how to use epidemiological andstatistical methods, (3) how to use economic concepts
and methods in the health fields, (4) how to establish
the collaboration with health professionals in thevarious fields, and (5) how to read and write original
papers.

Research activities
1) Health policy and economics
Our research activities focus on the topics of healthcare system and economics in general. We have
performed and published those studies related tosupply and demand sides of health services in Japan;such as supply and distribution of physicians, accessto health care, cost studies of outpatient and inpatient
services, and the efficiency and equity issues of theJapan's health insurance system as well as universal
health coverage system. We also conduct research on
quality of care and social determinants of health.
These studies have been published in health policy
and health services research journals. We havecontinued a collaborative study on UHC systems bothin developed and developing countries, since such asystem involves health, behavioral, social, andeconomic factors, and would inevitably be an
important health policy issue.
2) Occupational health
We have carried on a longitudinal study on life-style,socio-economic status, occupational stress, and healthstatus of workers in various occupational settings forthe purpose of preventing occupational and life-stylediseases.
3) Others

124

Other research activities include, (1) evaluation ofdisaster preparedness in local communities and healthcare facilities, (2) study on risk communication in
public health emergencies, (3) epidemiological study
on those children with cerebral palsy, and (4) various
public health issues due to the pandemic of
COVID-19.

7.

8.

References（Original Article）
1. Tanaka H, Mackenbach JP, Kobayashi Y.
Widening socioeconomic inequalities in smoking
in Japan, 2001–2016. Journal of Epidemiology
31(6): 369-377, 2021.
2. Maeda E, Ishihara O, Tomio J, Miura H,
Kobayashi Y, Terada Y, Murata K, Nomura K.
Cesarean delivery rates for overall and multiple
pregnancies in Japan: a descriptive study using
nationwide health insurance claims data. Journalof Obstetrics and Gynaecology Research 47(6):2099–2109, 2021.
3. Jwa SC, Ishihara O, Kuwahara A, Saito K, Saito
H, Terada Y, Kobayashi Y, Maeda E. Cumulative
live birth rate according to the number ofreceiving governmental subsidies for assisted
reproductive technology in Saitama Prefecture,
Japan: A retrospective study using individual
data for governmental subsidies. Reproductive
Medicine and Biology 20: 451-459, 2021.
4. Iba A, Maeda E, Jwa SC, Yanagisawa-Sugita A,
Saito K, Kuwahara A, Saito H, Terada Y,
Ishihara O, Kobayashi Y. Household income andmedical help-seeking for fertility problems
among a representative population in Japan.
Reproductive Health 18: 165, 2021.
5. Jwa SC, Ishihara O, Kuwahara A, Saito K, Saito
H, Terada Y, Kobayashi Y, Maeda E.Social
capital and use of assisted reproductive
technology in young couples: Ecological study
using application information for government
subsidies in Japan. SSM Population Health 16:
100995, 2021.
6. Yamana H, Iba A, Tomio J, Ono S, Jo T,
Yasunaga H. Treatment of latent tuberculosis
infection in patients receiving biologic agents.
Journal of Infection and Chemotherapy 27(2):243-249, 2021.

9.

10.

11.

12.

13.

14.

Hara K, Kobayashi Y, Tomio J, Ito Y, Svensson
T, Ikesu R, Chung UI, Svensson AK.
Claims-based algorithms for common chronic
conditions were efficiently constructed using
machine learning methods. PLoS One 16(9):e0254394, 2021.
Ito Y, Hara K, Sato H, Tomio J. Knowledge,
experience, and perceptions of generic drugs
among
middle-aged
adultsandtheirwillingness-to-pay: A nationwide online survey
in Japan. Tohoku Journal of Experimental
Medicine 255(1): 9-17, 2021.
Morioka N, Moriwaki M, Tomio J, Fushimi K,
Ogata Y. Dementia and patient outcomes after
hip surgery in older patients: A retrospective
observational
study
using
nationwide
administrative data in Japan. PLoS One, 16(4):e0249364, 2021.
Abe K, Miyawaki A, Nakamura M, Ninomiya H,
Kobayashi Y. Trends in hospitalizations forasthma during the COVID-19 outbreak in Japan.
Journal of Allergy and Clinical Immunology: In
Practice 9(1): 494–496, 2021.
Miyawaki A, Tomio J, Nakamura M, Ninomiya
H, Kobayashi Y. Changes in surgeries andtherapeutic procedures during the COVID-19
outbreak: A longitudinal study of acute care
hospitals in Japan. Annals of Surgery, 273(4):e132–4, 2021.
Jin X, Abe K, Taniguchi Y, Watanabe T,
Miyawaki A, Tamiya N. Trajectories oflong-term care expenditure during the last five
years of life in Japan: a nationwide retrospective
cohort study. Journal of the American Medical
Directors Association 22(11): 2331-2336, 2021
Yamamoto A, Gelberg L, Needleman J,
Kominski G, Vangala S, Miyawaki A, Tsugawa,Y. Comparison of childbirth delivery outcomes
and costs of care between homeless andnon-homeless women. JAMA Network Open,
4(4): e217491, 2021.
Ikesu R, Miyawaki A, Svensson AK, Svensson T,
Kobayashi Y, Chung UI. Association ofmanagerial position with cardiovascular risk
factors: A fixed-effects analysis for Japaneseemployees. Scandinavian Journal of Work,
Environment & Health 47(6): 425-434, 2021

125

15. Sun Y, Iwagami M, Watanabe T, Sakata N,
Sugiyama T, Miyawaki A, Tamiya N. Factors forpsychological distress in family caregivers:
Findings from nationwide data in Japan.
Geriatrics Gerontology International 21(9):855-864, 2021.
16. Gotanda H, Miyawaki A, Tabuchi T, Tsugawa Y.
Association between trust in government andpractice of preventive measures during the
COVID-19 pandemic in Japan. Journal of
General Internal Medicine 36(11): 3471-3477,
2021.
17. Sano K, Nakamura M, Ninomiya H, Kobayashi Y,
Miyawaki A. Large decrease in paediatrichospitalisations during the COVID-19 outbreakin Japan. BMJ Pediatrics Open, 5(1): e001013,
2021.
18. Ikesu R, Miyawaki A, Sugiyama T, Nakamura M,
Ninomiya H, Kobayashi Y. Trends in diabetes
care during the COVID-19 outbreak in Japan.
Journal of General Internal Medicine, 36(5):1460-1462, 2021.
19. Miyawaki A, Evans CEL, Lucas PJ, Kobayashi Y.
Relationship between social spending andchildhood obesity in OECD Countries: an
ecological study. BMJ Open, 11(2): e044205,
2021.
20. Miyawaki A. Khullar D, Tsugawa Y. Processesof care and outcomes for homeless patients
hospitalised for cardiovascular conditions at
safety-net versus non-safety-net hospitals:
cross-sectional study. BMJ Open, 11(4): e046959,
2021.
21. Miyawaki A, Tabuchi T, Toyama Y, Tsugawa Y.
Association between participation in thegovernment subsidy program for domestic traveland symptoms indicative of COVID-19 infectionin Japan: Cross-sectional study. BMJ Open,
11(4): e049069, 2021.
22. Abe K, Kawachi I, Taniguchi Y, Tamiya N.
Municipal characteristics of in-home deathamong care-dependent older Japanese adults.
JAMA Network Open, 5(1): e2142273-e2142273,
2021.
23. Abe K, Kawachi I, Watanabe T, Tamiya N.
Association of the frequency of in-home careservices utilization and the probability of

24.

25.

26.

27.

28.

29.

30.

31.

32.

in-home death. JAMA Network Open, 4(11):e2132787-e2132787, 2021.
Abe K, Taniguchi Y, Kawachi I, Watanabe T,
Tamiya N. Municipal long-term care workforce
supply and in-home deaths at the end of life:
Panel data analysis with a fixed-effect model inJapan. Geriatrics & Gerontology International
21(8): 712-7, 2021.
Taniguchi Y, Iwagami M, Sakata N, Watanabe T,
Abe K, Tamiya N. Epidemiology of food choking
deaths in Japan: Time trends and regionalvariations. Journal of Epidemiology 31(5):356-60, 2021.
Miyawaki A, Tabuchi T, Ong MK, Tsugawa Y.
Age and social disparities in the use oftelemedicine during the COVID-19 pandemic in
Japan: Cross-sectional study. Journal of Medical
Internet Research 23(7): e27982, 2021.
Ichizuka K, Toyokawa S, Ikenoue T, Satoh S,
Hasegawa J, Ikeda T, Tamiya N, Nakai A,
Fujimori K, Maeda T, Kanayama N, Masuzaki H,
Iwashita M, Suzuki H, Takeda S. Risk factors for
cerebral palsy in neonates due to placental
abruption. Journal of Obstetrics and Gynaecology
47: 159-166, 2021.
Tanaka H, Mackenbach JP, Kobayashi Y. Trends
and socioeconomic inequalities in self-rated
health in Japan, 1986-2016. BMC Public Health
21: 1811, 2021.
Kosaka Y, Sugiyama T, Hara K, Kobayashi Y.
Adherence to daily, weekly, and monthly dosing
regimens of bisphosphonates for osteoporosis
treatment in postmenopausal women in Japan: A
retrospective study using claims data. Tohoku
Journal of Experimental Medicine 255: 147-155,
2021.
Yamagishi H, Osaka H, Toyokawa S, Kobayashi
Y, Shimoizumi H. Survey on children withcerebral palsy in Tochigi Prefecture, Japan.
Pediatrics International 63(8): 951-957, 2021.
田中宏和、小林廉毅．職業別喫煙率とその推移：国民生活基礎調査による分析 （2001-2016年）．日本公衆衛生雑誌 68 (6): 433-443, 2021.
Ihana-Sugiyama N, Sugiyama T, Imai K,
Yanagisawa-Sugita A, Tanaka H, Ohsugi M,
Ueki K, Tamiya N, Kobayashi Y. Factors
associated with the degree of glycemic

126

33.

34.

35.

36.

37.

38.

39.

deterioration among patients with type 2 diabetes
who dropped out of diabetes care: A longitudinal
analysis using medical claims and health checkup
data in Japan. Journal of Diabetes Investigation
2021 [Epub ahead of print]
Moriwaki M, Yuasa H, Kakehashi M, Suzuki H,
Kobayashi Y. Impact of social support formothers as caregivers of cerebral palsy children
in Japan. Journal of Pediatric Nursing 2021
[Epub ahead of print]
Tanaka H, Mackenbach JP, Kobayashi Y.
Estimation of socioeconomic inequalities inmortality in Japan using national census-linked
longitudinal mortality data. Journal of
Epidemiology 2021 [Epub ahead of print]
Inada H, Tomio J, Nakahara S, Ichikawa M.
Effect of annual road safety publicity andenforcement campaign on road fatalities in Japan:
a time series study from 1949 to 2019. Journal of
Epidemiology and Community Health, 2021
[Epub ahead of print]
Taniguchi Y, Kuno T, Komiyama J, Adomi M,
Suzuki T, Abe T, Ishimaru M, Miyawaki A, Saito
M, Ohbe H, Miyamoto Y, Imai S, Kamio T,
Tamiya N, Iwagami M. Comparison of patients’characteristics and in-hospital mortality between
patients admitted for COVID-19 in 2020 and
influenza in 2017-2020: a multicenter,retrospective cohort study in Japan. Lancet
Regional Health - Western Pacific, 2021 [Epubahead of print]
Taniguchi Y, Miyawaki A, Tsugawa Y,
Murayama H, Tamiya N, Tabuchi T. Family
caregiving and changes in mental health status in
Japan during the COVID-19 pandemic. Archivesof Gerontology and Geriatrics, 2021 [Epub aheadof print]
Nakahara S, Inada H, Ichikawa M, Tomio J.
Japan’s slow response to improve access to
inpatient care for COVID-19 patients. Front
Public Health, 2021 [Epub ahead of print]
Ikesu R, Taguchi A, Hara K, Kawana K, Tsuruga
T, Tomio J, Osuga Y. Prognosis of High-Risk
Human Papillomavirus-Related Cervical Lesions:
A hidden Markov Model analysis of asingle-center cohort in Japan. Cancer Medicine,2021 [Epub ahead of print]

40. Hidaka T, Ogawa K, Tomioka Y, Yoshii K,
Tomio J, Okazaki M. Change in eyelid closure in
spontaneous blinking after static eyelid
reconstruction surgery for patients with facial
paralysis. Annals of Plastic Surgery, 2021 [Epubahead of print](Others)
41. 葛西龍樹, 阿部計大, 大浦誠, 加藤大祐, 小林
直子, 佐治朝子,豊田喜弘, 原田直樹, 藤谷直樹, 森冬人(翻訳) (原著:Moira Stewart, Judith
Belle Brown, W, Wayne Weston, Ian R
McWhinney, Carol L McWilliam, Thomas R
Freeman). 患者中心の医療の方法 原著第 3
版. 羊土社, 2021. C．
42. Abe K, Kawachi I. Deaths in nursing homesduring the COVID-19 pandemic—Lessons fromJapan.
JAMA
HealthForum,
2(2):e210054-e210054, 2021.
43. Abe K, Taniguchi Y, Kawachi I, Watanabe T,
Tamiya N. Authors' reply to the letter from Dr.
Kato. Geriatrics & Gerontology International, 21:970, 2021. https://doi.org/10.1111/ggi.14270
44. 阿 部 計 大 ． COVID-19 流 行 下 の 研 究 留 学 .
DOCTORASE,37, 2021.
45. 小林廉毅．第 80 回日本公衆衛生学会総会（巻頭言）． ビルと環境 175: 3-4, 2021.
46. Miyawaki A, Tsugawa Y. Health and Public
Health Implications of COVID-19 in AsianCountries. Asian Economic Policy Review, 17,
18-36, 2021. [Epub ahead of print]
47. Miyawaki A, Tsugawa Y. Why do homeless
women in New York state experience fewer
hospital revisits after childbirth than housed
women? BMJ Quality & Safety, 2021. [Epubahead of print]
48. 宮脇敦士：「医療ビッグデータから見えてくるもの」読売新聞 (yomiDr.), 2021 年 4 月-2022
年3月
49. Kobayahsi Y (as the speaker in Session
1.1.Presentations): Session 1 Regional Focus:
AsiaandAustralia-New
Zealand.
An
International Symposium － Towards the
Post-Pandemic Era, Online, June 18-19 and 25,
2021.
50. Miyawaki A (invited speaker, with Dr. Yusuke
Tsugawa) Health and Public Health Implicationsof COVID-19 in Asian Countries. The 33rd

127

conference of Asian Economic Policy Review(AEPR) conference, Japan Center for Economic
Research, Online, April 9-10, 2021.
51. 第 80 回日本公衆衛生学会総会 (学会長: 小林廉毅), 東京, 2021 年 12 月 21-23 日.小林廉毅:
学会長講演「公衆衛生学の基盤：統計と調査」.

Social Medicine
2. Forensic Medicine, and Medical
Informatics and Economics

129

Department of Forensic Medicine
Professor
Hirotaro Iwase, M.D., Ph.D.

Associate Professor
Yohsuke Makino, M.D., Ph.D.

Assistant Professor
Suguru Torimitsu, M.D., Ph.D.,

Rutsuko Yamaguchi, M.P.H., M.D., Ph.D.

Project Assistant Professor
Go Inokuchi, M.D., Ph.D.,

Homepage

Ayumi Motomura, M.D., Ph.D.,

Fumiko Chiba, M.D., Ph.D.

http://ut-forensic.jp/

Introduction and Organization
Associate Professor Kuniyoshi Katayama lectured“judicial medicine” in the University of Tokyo since1881 before our department was founded as the firstdepartment of forensic medicine in Japan in 1889. He
renamed “judicial medicine” to “forensic medicine” in1891 since the department should cover legislation as
well as general forensic practices. Dr. Katayama
became the first professor of forensic medicine inJapan.
The 2nd Professor Sadanori Mita also founded theserological department (Department of Immunology atpresent). He studied the antigen-antibody reaction anddiscovered complement fixation reaction.
The 3rd Professor Tanemoto Furuhata was very
famous for ABO blood group genetics, and also
contributed to the development of criminology. He
autopsied several cases of historical crimes.
The 4th Professor Shokichi Ueno discovered acomplex complement. He helped foundation ofnational police academy for death investigators.
The 5th Professor Toshiyuki Miki could not perform
autopsy for four years due to the University of Tokyo
strike. However, he left many achievements in thefield of blood typing and paternity examination.
The 6th Professor Ikuo Ishiyama encouraged
forensic pathology. He also introduced DNA finger-

printing and PCR technique in the forensic practices.
The 7th Professor Takehiko Takatori studied thebiochemical changes of the lipid in cadavers. He
dissected five victims of sarin subway attacks inTokyo and identified sarin in tissue by a sophisticatedmethod.
The 8th Professor Ken-ichi Yoshida studied themolecular mechanism of ischemic heart disease andsudden cardiac death.
Hirotaro Iwase has been directing our department
since 2014 as the 9th Professor. In order to reconstruct
the field of forensic medicine as the attractive one, six
sections (forensic pathology, clinical forensic
medicine, forensic toxicology, forensic radiology,
forensic odontology, forensic genetics) have started incooperation with Chiba University. We are preparing
to teach practice and research for the future forensic
pathologists.

Postmortem examination
The determination of precise cause of death is oneof the most important practices at our department. We
perform medico-legal autopsies for around 120
criminal cases in eastern part of Tokyo every year. We
also perform post-mortem CT at the request of police.
In medico-legal autopsy, we usually examinevarious tests such as the pathological, alcohol,

130

toxicological, and blood type tests. Finally, forensic
pathologists in our department diagnose the cause ofdeath. Expert opinions express the cause of death andforensic judgment for each case.
It should be noted that this year that pandemic of
the new coronavirus (SARS-CoV-2) continued.
Infection control in dissection has become a hot topic,
but with the introduction of the laminar-flow autopsy
table following the seismic retrofitting carried out in
2019, it has become possible to accept SARS-CoV2-infected bodies. In 2020, we have newly introduced
our own real-time PCR system in our laboratory,
conducting a SARS-CoV-2 PCR test in all cases. Last
year, we had several COVID-19 cases, and autopsies
were performed with PAPRs (powered air-purifying
respirators).

Education
As for under-graduate education, our department
provides lectures for the 4th year medical students,
Free Quarter training course for the 2nd-4th year
medical students, and Elective Clerkship learning forthe 6th year medical students.
The lectures consist of forensic pathology, clinicalforensic medicine, forensic toxicology, forensic
radiology, forensic odontology and forensic genetics.
In the Free Quarter training course, students experience laboratory practices (toxicology, DNA typing,histology) or experiments. In the Elective Clerkshiplearning, each student experiences the process from
autopsy to presentation of expert opinion.
In addition, students of school of public health and(undergraduate & graduate) law school are provided
with somewhat practical lectures with exercises. We
have provided opportunity for PhD students of Schoolof Hearth Science, and master course of Medical
Science.

Research
In cooperation with other universities including
Chiba University, Tokyo Medical and Dental
University, and International University of Health andWelfare, researches in 6 sections (forensic pathology,
clinical forensic medicine, forensic toxicology,
forensic radiology, forensic odontology and forensic
genetics) have proceeded.

1. Forensic Pathology
We conduct research aimed at improving theaccuracy of cause-of-death diagnosis andepidemiological studies related to cause-of-deathinvestigation. For example, we are trying
angiographic 3D-CT and vascular endoscopy in the
search for coronary arteries and cerebral basilar
arteries. We have studied lipid oxidation in cases ofmuscle crush syndrome and methamphetamine
intoxication. We are also conducting research on
diatoms in order to improve the diagnosis ofdrowning. Additionally, we are trying to conduct a
comparative study of the cause-of-death investigation systems in Tokyo and Chiba prefectures.
2. Clinical Forensic Medicine
Clinical forensic medicine is an academic fieldthat collaborates with various clinical departments
to examine a living body that may have been
subjected to some form of invasion to determine
whether or not an invasion has occurred, and todevise measures to prevent accidents based on
information obtained from the accumulation of
cause-of-death information. Currently, in collaboration with pediatricians, we are conducting researchon the accumulation and analysis of pediatric deaths
and their application to prevention. As part of thiseffort, the Chiba Prefecture Child Death Review(CDR) Study Group has been established incooperation with Chiba University. In addition, weare also conducting research on bone strength togain knowledge that will be useful in the evaluationof abuse.
3. Forensic Toxicology
Using LC/MS/MS, LC/QTOF-MS, etc., we areconducting research on detection methods targetinga large number of drugs, including cyanide
compounds and dangerous drugs. Animal studies on
postmortem drug redistribution had also been
conducted. In collaboration with the National
Research Institute of Police Science and others, weare also conducting epidemiological studies on drug
detection in traffic accident fatalities.
4. Forensic Odontology
Studies are being conducted to examine the131

usefulness of drug analysis, DNA testing, CT
testing, etc., from teeth and palatine and mandible
bones for age estimation and other utilities.
5. Forensic Genetics
We are trying research to search for disease genes
in cases of sudden death. We are also conducting
research on the detection of novel coronavirus
genes in cadavers.
6. Forensic Radiology
Using 3D-CT, we are studying the possibility of
estimating the stature, sex, and age of the deceased
based on bone length and morphology. We are also
conducting research on the benefits and risks ofpostmortem imaging to determine the cause ofdeath. In collaboration with the University of New
Mexico Department of pathology and others, we arealso studying the characteristics of postmortem CT
in COVID-19 deaths.

Publications
1.

2.

3.

4.

5.

Nagasawa S, Saka K, Yamagishi Y, Yajima D,
Chiba F, Yamaguchi R, Torimitsu S, Iwase H.
Association between sexual activity-related deathand non-prescription use of phosphodiesterase
type 5 inhibitors. Leg Med (Tokyo). 2021; 48:
101815.
Nagasawa S, Yamaguchi R, Saka K, Torimitsu
S,Chiba F, Yajima D, Inokuchi G, Motomura A,
Kira K,Yamagishi Y, Ogra O, Iwase H.
Ropinirole involved in a fatal case; blood andurinary concentrations. Forensic Toxicology,
2021; onlone first.
Mizuno S, Ono S, Yasunaga H, Iwase H,Factors
associated with methamphetamine use inJapanese people who died of unnatural causes:
Analysis using forensic autopsy reports, Forensic
Sci. Int. 2021; 327: 110946-119453.
Kihara Y, Makino Y, Nakajima M, Tsuneya S,
Tanaka A, Yamaguchi R, Torimitsu S, Hayama SI,
Iwase H. Experimental water injection into lungs
using an animal model: Verification of the diatom
concentration test to diagnose drowning. Forensic
Sci Int. 2021 Oct; 327: 110983.
Tsuneya S, Nakajima M, Makino Y, Torimitsu S,
Yamaguchi R, Iwase H. A quantitative

comparison between using sodium hypochlorite
as a digestion method for the diatom test and theconventional method using fuming nitric acid.
Forensic Sci Int. 2021 Dec; 329: 111086.
6. Nagasawa S, Mori A, Hirata Y, Motomura A,
Ishii N, Okaba K, Horioka K, Makino Y,
Nakajima M, Torimitsu S, Yamagushi R,
Inokuchi G, Chiba F, Hoshioka Y, Saito N,
Yoshida M, Yajima D, Akitomi S, Iwase H,
Saitoh H. SmartAmp method can rapidly detect
SARS-Cov-2 in dead bodies. Foresic Sci Int
2021; 331:
7. Yoshida M, Makino Y, Hoshioka Y, Saito N,
Yamaguchi R, Chiba F, Inokuchi G, Iwase H.
Technical and interpretive pitfalls of postmortem
CT: Five examples of errors revealed by autopsy.
J Forensic Sci. 2022 Jan;67(1):395-403
8. Yamaguchi R, Sakurada K, Saitoh H, Yoshida M,
Makino Y, Torimitsu S, Mizuno S, Iwase H.
Fatal airway obstruction due to Ludwig’s angina
from severe odontogenic infection during
antipsychotic medication: A case report and aliterature review. J Forensic Sci. 2021; 66 (1):1980-1985.
9. Unuma K, Makino Y, Yamamoto K, Hattori S,
Arai N, Sakai K, Kitagawa M, Uemura K,
Kanegane H. Fatal intracranial hemorrhage due
to infantile acute lymphoblastic leukemia
mimicking abusive head trauma. J Forensic Sci.
2021; 66: 2504-2510.
10. Urabe S, Ishihara K, Chiba F, Yamaguchi R,
Shiko Y, Kawasaki Y, Iwase H. Children’s deathsurvey using death certificates in the Chiba
prefecture. Forensic Science International:
Reports. 2021; Volume 4, 100246: 1-11.
11. Torimitsu S, Abe H, Makino Y, Yamaguchi R,
Motomura A, Hoshioka Y, Iwase H.
Streptococcal toxic shock syndrome with fatal
outcome: Report on four forensic autopsy cases.
Leg Med (Tokyo). 2021; 50: 101851.
12. Tsuneya S, Makino Y, Chiba F, Kojima M,
Yoshida M, Kishimoto T, Mukai H, Hattori S,
Iwase H. Postmortem magnetic resonanceimaging revealed bilateral globi pallidi lesions ina death associated with prolonged carbon
monoxide poisoning: a case report. Int J LegalMed. 2021; 135: 921-928.

132

13. Jackson NR, Zeigler K, Torrez M, Makino Y,
Adolphi NL, Lathrop S, Decker L Dvorscak L,
Proe L, Paul ID, Zumwalt R, Jarrell H. New
Mexico's COVID-19 Experience. Am J Forensic
Med Pathol. 2021; 42: 1-8.
14. Norii T, Makino Y, Unuma K, Hatch GM,
Adolphi NL, Dallo S, Albright D, Sklar DP,
Braude D. Extraglottic Airway Device Misplacement: A Novel Classification System andFindings in Postmortem Computed Tomography.
Ann Emerg Med. 2021; 77: 285-295.
15. Norii T, Makino Y, Unuma K, Adolphi NL,
Albright D, Sklar DP, Crandall C, Braude D. CT
imaging of extraglottic airway device-pictorial
review. Emerg Radiol. 2021; 28: 665-673.
16. Kudo K, Saka K, Waters B, Hara K, Matsusue A,
Kashiwagi M, Kubo S. Effects of putrefaction on
the quantitative analyses of diphenhydramine inblood and tissues: model experiments by theroutine matrix-matched calibration method andstandard addition method with different internal
standards. Forensic Toxicol. 2021; 39: 437-450.

133

Department of Biomedical
Informatics
Professor
Kazuhiko Ohe, M.D.,Ph.D.

Associate Professor
Kayo Waki, M.D.,Ph.D.

Yoshimasa Kawazoe, M.D.,Ph.D.

Takeshi Imai, Ph.D.

Lecturer
Shinichiro Yokota, PHN,RN,Ph.D.

Homepage

http://www.m.u-tokyo.ac.jp/medinfo/

Introduction and Organization
We aim to transform medical care and contribute tosociety by applying the following methods to clinicalmedicine and medical management; development ofbasic methods that can be applied to medical
information systems in the interdisciplinary field
between medicine and informatics, development andconstruction of basic information environments related
to medical information, practical research on medical
information systems, and knowledge in these areas.
Keywords for the fields covers medical information
system, next-generation electronic medical records,
medical information network, virtual medical
information environment, computer representation andstandardization of medical concepts, medical
knowledge
engineering,
hospital
information
epidemiology, evaluation of medical quality, clinicalinformation engineering, privacy protection andencryption, Information security, medical analysis,
hospital management analysis, medical safety
management. The professor concurrently supervise as
the director of the Department of Planning andInformation Management at the University of Tokyo
Hospital, which is united with this department.
The Department of Planning and Information
Management is a place where the medical information

system is used to analyze information related to the
future plan of the University Hospital.
Our department began in 1983 when the Department
of Central Information of the University of Tokyo
Hospital, as the National University Hospitals, wasformally established, and the medical informatics
doctoral course was established in the Graduate
School of Basic Medicine I of the Graduate School of
Medicine, the University ot Tokyo at that time. The
first professor was Shigekoto Kaihara (deceased) who
established medical informatics in Japan, and thecurrent professor is the second generation. In 1997,
when the University of Tokyo became a graduate
school, it became the current Department of Social
Medicine, Medical Information Economics, and theone professor and one associate professor, who
belonged to the Department of Central Information of
the University of Tokyo Hospital, moved to full-time
staffs of the graduate school.

Teaching activities
In 2021, the faculty composition, including the
hospital staff, is 1 professor (Ohe), 1 associate
professor (Waki), 2 lecturers (Atarashi, Yokota), 1
specially appointed lecturer (Ida), 1 assistant professor(specially appointed lecturer (hospital)). (Doi), 4

134

assistant professors (Nagae, Mori, Seki, Yamada), and2 special assistant professors (Miyake, Kubota). In
addition to this, Associate Professor 1 (Disease andBiotechnology Center) (Imai) and Specially Appointed
Associate Professor 1 (Endowed Department ofMedical AI Development) (Kawazoe) are also incharge of this course. In the doctoral course of
medicine, we educate graduate students in medical
informatics, and in the public health medicine major(professional master's course), we are in charge of
medical information systems (medical information
system lecture 15 units 2 credits, practical training 30
units 1 credit), every year About 10 students are taking
elective courses.
The lecture course is 1) Overview of information
technology infrastructure and systems related to
medical computerization policies in Japan andoverseas, 2) Hospital information systems, electronic
medical record systems, and standardization of
medical information. 3) Security management of
medical personal data and information networks. 4)
Medical information database—National DB and
Sentinel DB, 5) Mobile IT medical care, lifestyledisease management and IT, 6) Knowledge andinformation handling in medical care, language
processing, 7) Open data handling and discussion. wasthe content.
Practical training consists of 1) data creation,
conversion, and Internet basic technical training, 2)
database design and database operation: learning aseries of basic operations of relational databases basedon medical sample data. Acquire the basic technologyof data interconversion.3) Learn to convert data into
standardized code.4) Create a database, extract andconvert data suitable for a given task by creating a
program, and conduct research.
It is also a health and medical informatics
cooperative course for the Department of Health
Science and Nursing, and is in charge of the healthscience and nursing doctoral course (three years). If
desired, we also accept students in the master's courseof medical science, and are mainly in charge of
Associate Professor Takeshi Imai (Center for Disease
Biotechnology), who is also in charge of thedepartment. In the master's program in medical
science, I was in charge of one lecture on medical
informatics and clinical medical ontology. In this way,

our department has an educational system that allows
students to obtain degrees such as Doctor of Medicine,
Master of Public Health Medicine, Doctor of Health
Science, and Master of Medical Science. There was 1
master of medical science and 1 master of publichealth medicine. At the Faculty of Medicine, staffs
were in charge of 5 lectures on medical informatics in
M2.
In the Ministry of Education, Culture, Sports,
Science and Technology's medical data humanresource development project " Development Projectof Medical Real World Data Utilization Human
Resource" adopted in 2019, the first batch of students
will be accepted from May 2020. Assistant professors
were in charge, and lectures and practical training
were mainly held on Saturdays as adult education
courses.
Detailsareavailableathttps://www.med-rwd.jp/.

Research activities
Main research areas: 1) Applied research on hospital
information systems and medical information
systemization represented by electronic medical
records, 2) New medical knowledge extraction andmedical economics targeting electronic medical
records and hospital information system databases 3)Standardization of descriptions of clinical medical
terminology and concepts and research on structured
knowledge representation methods 4) Basic researchon information systems for clinical research 5)
Personal information protection and security inmedical information systems 6) Research on
lifestyle-related disease management using mobile
devices. Representative research themes are as
follows.
Research and development of a standardization
platform for medical information and its utilization,
automatic information collection of hospital wards
using FHIR standard specifications, basic research on
medical text analysis for natural language processing,research on fall risk prediction model and evaluationforinpatients,
AI-based
automatic
findingclassification of renal pathological images,
development of clinical support systems based onclinical guidelines, e-Phenotyping, etc. In addition, wearecarryingoutmany
industry-university

135

collaborative researches with clinical research on
lifestyle-related diseases and self-management ofhealth using mobile devices such as smartphones as
the main research theme.
As social activities, the Ministry of Health, Laborand Welfare's study group on various medical
information
policies(MedicalInformation
Standardization Committee, ICD Special Committee),
the Japanese Association of Medical Sciences
Terminology Management Committee, the Social
Insurance Medical Fee Payment Fund Standard Injury
Name Master Review Committee, International
Several staff members play important roles in WG2 ofthe Organization for Standardization ISO/TC215(Medical Information Standardization Committee), theMinistry of Health, Labor and Welfare/PMDA medical
information database infrastructure development
project MID-NET, and research on the utilization of
the national health insurance claim database NDB.

References
1.

2.

3.

4.

5.

Aoki M, Yokota S, Kagawa R, Shinohara E, Imai
T, Ohe K. Automatic Coding Classification ofElectronic Nursing Narrative Records Based onJapanese Standard Terminology for Nursing. CIN:
Computers, Informatics, Nursing. 2021;39(11):828-834.
Ono S, Ishimaru M, Ida Y, Yamana H, Ono Y,
Hoshi K, Yasunaga H. Validity of Diagnoses andProcedures in Japanese Dental Claims Data. BMC
Health Services Research. 2021;21(1):1116.
Kodama T, Ida Y, Oshima K, Miura H. Are Public
Oral
Care
Services
EvenlyDistributed?-Nation-Wide Assessment of theProvision of Oral Care in Japan Using the
National Database of Health Insurance Claims.
International Journal of Environmental Researchand Public Health. 2021;18(20): 10850.
Oshima K, Kodama T, Ida Y, Miura H. GenderDifferences in Work Status during Early Career of
Dentists: An Analysis of National Survey Cohort
Data of 10 Years in Japan. International Journal ofEnvironmental Research and Public Health. 2021;
18(5):2335.
Kawazoe Y, Shibata D, Shinohara E, Aramaki E,
Ohe K. A clinical specific BERT developed using

a huge Japanese clinical text corpus. PLOS ONE.
2021;16(11): e0259763.
6. Kawaki Y, Sankoda A, Waki K, Miyake K,
Hayashi A, Mieno M, Wakui H, Tsurutani Y, Saito
J, Hirawa N, Yamakawa T, Komiya S, Isogawa A,
Satoh S, Minami T, Osada U, Iwamoto T, Takano
T, Terauchi Y, Tamura K, Yamauchi T, Kadowaki T,
Nangaku M, Kashihara N, Ohe K. Efficacy of the
Self-management Support System DialBetesPlus
for Diabetic Kidney Disease: Protocol for a
Randomized Controlled Trial. JMIR ResearchProtocols. 2021;10(8):e31061.
7. Nakagami G, Yokota S, Kitamura A, Takahashi T,
Morita K, Noguchi H, Ohe K, Sanada H.
Supervised machine learning-based prediction for
in-hospital pressure injury development using
electronic health records: A retrospective
observational cohort study in a university hospitalin Japan. International Journal of Nursing Studies.
2021;119: 103932.
8. Ma X, Imai T, Shinohara E, Kasai S, Kato K,
Kagawa R, Ohe K. EHR2CCAS: A framework formapping EHR to disease knowledge presenting
causal chain of disorders – chronic kidney disease
example. Journal of Biomedical Informatics. 2021;
115: 10369.
9. Yamaguchi R, Kawazoe Y, Shimamoto K,
Shinohara E, Tsukamoto T, Shintani-Domoto Y,
Nagasu H, Uozaki H, UshikuT, Nangaku M,
Kashihara N, Shimizu A, Nagata M, Ohe K.
Glomerular Classification Using Convolutional
Neural Networks Based on Defined Annotation
Criteria and Concordance Evaluation Among
Clinicians. Kidney International Reports. 2021;
6(3): 716-726.
10. Seki T, Kawazoe Y, Ohe K. Machinelearning-based prediction of in-hospital mortality
using admission laboratory data: A retrospective,
single-site study using electronic health record
data. PLoS ONE. 2021;16(2): e0246640.
11. Susumu Katsushika, Satoshi Kodera, MitsuhikoNakamoto, Kota Ninomiya, Shunsuke Inoue,
Shinnosuke Sawano, Nobutaka Kakuda, Hiroshi
Takiguchi, Hiroki Shinohara, Ryo Matsuoka,
Hirotaka Ieki, Yasutomi Higashikuni, Koki
Nakanishi, Tomoko Nakao, Tomohisa Seki,
Norifumi Takeda, Katsuhito Fujiu, Masao Daimon,

136

Hiroshi Akazawa, Hiroyuki Morita, Issei Komuro.
The Effectiveness of a Deep Learning Model to
Detect Left Ventricular Systolic Dysfunction from
Electrocardiograms. International Heart Journal62(6) 1332-1341 2021.11
12. Shinnosuke Sawano, Satoshi Kodera, Susumu
Katsushika, Mitsuhiko Nakamoto, Kota Ninomiya,
Hiroki Shinohara, Yasutomi Higashikuni, Koki
Nakanishi, Tomoko Nakao, Tomohisa Seki,
Norifumi Takeda, Katsuhito Fujiu, Masao Daimon,
Hiroshi Akazawa, Hiroyuki Morita, Issei Komuro.
Deep learning model to detect significant aortic
regurgitation using electrocardiography. Journal of
Cardiology 2021.9
13. Dai Kusumoto, Tomohisa Seki, Hiromune
Sawada, Akira Kunitomi, Toshiomi Katsuki, Mai
Kimura, Shogo Ito, Jin Komuro, Hisayuki
Hashimoto, Keiichi Fukuda, Shinsuke Yuasa.
Anti-senescent drug screening by deeplearning-based morphology senescence scoring.
Nature communications 12(1) 257-257 2021.1

Internal Medicine
1. Medicine Ⅰ

138

Department of Cardiovascular
Medicine
Professor
Issei Komuro, M.D., Ph.D.

Lecturer
Hiroyuki Morita, M.D., Ph.D.

Hiroshi Akazawa, M.D., Ph.D.

Eiki Takimoto, M.D., Ph.D.

Jiro Andoh, M.D.

Hospital Lecturer
Norifumi Takeda, M.D., Ph.D.

Homepage

Satoshi Kodera, M.D., Ph.D.

https://cardiovasc.m.u-tokyo.ac.jp/

Introduction and Organization
The Department of Cardiovascular Medicine wasestablished in 1998 by regrouping cardiologists of fiveprevious internal medical departments. After Yoshio
Yazaki, the first professor, and Ryozo Nagai, thesecond professor, the present professor Issei Komuro
was elected in August, 2012. Our department
comprises one professor, 4 lecturers, 2 hospital
lecturers, 15 research assistants, 9 staff members, and
44 graduate school students.

Clinical activities
The Department of Cardiovascular Medicine isactively involved in clinical medicine, basic researchand teaching. Not only do we have the most advanced
equipment and facilities (e.g., 24-hour cardiac careunit), but our personnel are also highly trained to beknowledgeable and experts in modern methods ofdiagnosis and treatment. Especially, we make a special
effort to treat patients with severe heart failures. As ateaching and research hospital, we also emphasize thedevelopment and integration of new treatment
methods if they may be beneficial to patients.
In 2021, a total of 1,737 patients were newly
admitted to our hospital ward of 61 beds. The average
duration of hospitalization was 11.0 days.

Because we are an authorized facility for hearttransplantation, the use of left ventricular assist device
in cases of severe heart failure has been increasing. In
2006, the first patient with heart failure from ourdepartment underwent a heart transplant procedure atthe Department of Cardiovascular Surgery. In 2021,
18 patients underwent heart transplant (total 171
cases). In March 2014, our facility was also
authorized to perform lung transplantation. Coronary
angiography was performed in 2,049 patients, ofwhich 417 patients underwent percutaneous coronary
interventions. CT coronary angiography and cardiovascular MRI were performed in 610 and 158 patients,
respectively. With regard to arrhythmias, there were
277 cases of catheter ablation, 149 cases of
implantation or replacement of pacemakers and otherspecialized pacemaker devices, including 25 cases of
implantation or replacement of implantablecardioverter-defibrillator and 20 cases of implantation
or replacement of a cardiac resynchronization device.
Out-patient clinics are available as a specialized
department and as part of the Department of Medicine.
Out-patient clinics are open in the mornings andafternoons from Monday to Friday, and approximately
178.8 patients visited each day. The disease profile
includes ischemic heart disease, heart failure,arrhythmia, hypertension and peripheral artery disease.
There are special outpatient clinics for advanced heart

139

failure,ischemicheart
disease,pulmonary
hypertension, congenital heart disease, valvular heartdisease, arrhythmia, Marfan syndrome, myocarditis,
cardiac amyloidosis, onco-cardiology, and cardiac
rehabilitation. The department is also focused on acutecases of coronary heart disease and aortic disease, as
emergent catheterization is available on a 24-hourbasis.

8. New treatments for pulmonary hypertension
9. New treatments for congenital heart disease
10. Aerobic threshold and cardiac rehabilitation
11. Imaging techniques (echocardiography, MRI, CT,
and SPECT) in cardiovascular diseases
12. Epidemiology and prevention of cardiovasculardisease13. Artificial Intelligence in Cardiology

Education

Publications (2020)

We have a particular interest in teaching not only
medical students but also residents, who are important
for the future of cardiovascular medicine. The courses
available at the medical school include clinicallectures and clinical clerkships. In clinical clerkship,
three students are placed under the guidance of one
research associate, which enables teaching in small
groups. Specialized groups provide practical lectures.
Residents are educated through specialized groupconferences, grand rounds, and clinical conferences.

1.

Research activities
From a research perspective, our interests include
all fields of cardiovascular medicine, ranging frommolecular biology to clinical research, including
genomics. Importantly, our research interests are
aimed at facilitating new diagnostic and treatment
methods for cardiovascular diseases. Our areas ofinterest include the following:
1. Cardiac hypertrophy and heart failure: multiomics
analyses of pathogenic mechanisms anddevelopment of novel therapies (e.g., genetherapy)
2. Interplay between organs, cells, and molecules inchronic inflammation
3. Genetic analysis of inherited cardiomyopathy
4. Experiments on pathophysiology ofcardiomyopathy using human iPS cells
5. Investigation of disease pathophysiology anddevelopment of novel therapies (severe heart
failure, cardiac transplantation, congenital heartdisease, etc.)
6. New treatments for structural heart disease
7. Diagnosis and treatment of Marfan syndrome andadult congenital heart disease

2.

3.

4.

Adachi Y, Kiyosue A, Ando J, Kawahara T, Kodera
S, Minatsuki S, Kikuchi H, Inaba T, Kiriyama H,
Hirose K, Shinohara H, Saito A, Fujiwara T, Hara H,
Ueda K, Sakakura K, Hatano M, Harada M,
Takimoto E, Akazawa H, Morita H, Momomura SI,
Fujita H and Komuro I. Factors associated with left
ventricular reverse remodelling after percutaneous
coronary intervention in patients with left
ventricular systolic dysfunction. Sci Rep 11:239,
2021.
Bujo C, Amiya E, Hatano M, Tsuji M, Maki H,
Ishida J, Ishii S, Narita K, Endo M, Ando M,
Shimada S, Kinoshita O, Ono M and Komuro I.
Association between infectious event and de novo
malignancy after heart transplantation. Heart
Vessels 36:499-508, 2021.
Fujiwara T, Takeda N, Hara H, Ishii S, Numata G,
Tokiwa H, Maemura S, Suzuki T, Takiguchi H,
Kubota Y, Seo K, Sakata A, Nomura S, Hatano M,
Ueda K, Harada M, Toko H, Takimoto E, Akazawa
H, Nishimura S and Komuro I. Three-Dimensional
Visualization of Hypoxia-Induced Pulmonary
Vascular Remodeling in Mice. Circulation 144:
1452-1455, 2021.
Hartiala JA, Han Y, Jia Q, Hilser JR, Huang P,
Gukasyan J, Schwartzman WS, Cai Z, Biswas S,
Tregouet DA, Smith NL, Consortium I, Group
CCHW, Consortium G-C, Seldin M, Pan C,
Mehrabian M, Lusis AJ, Bazeley P, Sun YV, Liu C,
Quyyumi AA, Scholz M, Thiery J, Delgado GE,
Kleber ME, Marz W, Howe LJ, Asselbergs FW, vanVugt M, Vlachojannis GJ, Patel RS, Lyytikainen LP,
Kahonen M, Lehtimaki T, Nieminen TVM,
Kuukasjarvi P, Laurikka JO, Chang X, Heng CK,
Jiang R, Kraus WE, Hauser ER, Ferguson JF, Reilly
MP, Ito K, Koyama S, Kamatani Y, Komuro I,

140

Biobank J, Stolze LK, Romanoski CE, Khan MD,
Turner AW, Miller CL, Aherrahrou R, Civelek M,
Ma L, Bjorkegren JLM, Kumar SR, Tang WHW,
Hazen SL and Allayee H. Genome-wide analysis
identifies novel susceptibility loci for myocardial
infarction. Eur Heart J 42:919-933, 2021.
5. Hirose K, Nakanishi K, Daimon M, Sawada N,
Yoshida Y, Ishiwata J, Hirokawa M, Koyama K,
Nakao T, Fujiu K, Morita H, Di Tullio MR, Homma
S and Komuro I. Correlation Between the Cohorts
for Heart and Aging Research in Genomic
Epidemiology-Atrial Fibrillation Risk Score andLeft Atrial Remodeling in the General Population.
Circ Arrhythm Electrophysiol 14:e009826, 2021.
6. Hirose K, Nakanishi K, Daimon M, Sawada N,
Yoshida Y, Iwama K, Yamamoto Y, Ishiwata J,
Hirokawa M, Koyama K, Nakao T, Morita H, Di
Tullio MR, Homma S and Komuro I. Impact of
insulin resistance on subclinical left ventricular
dysfunction in normal weight and overweight/obesejapanese subjects in a general community.
Cardiovasc Diabetol 20:22, 2021.
7. Ishiwata J, Daimon M, Nakanishi K, Sugimoto T,
Kawata T, Shinozaki T, Nakao T, Hirokawa M,
Sawada N, Yoshida Y, Amiya E, Hatano M, Morita
H, Yatomi Y and Komuro I. Combined evaluationofrightventricularfunctionusing
echocardiographyinnon-ischaemic
dilatedcardiomyopathy. ESC Heart Fail 8:3947-3956,
2021.
8. Ishizuka M, Harada M, Nomura S, Ko T, Ikeda Y,
Guo J, Bujo S, Yanagisawa-Murakami H, Satoh M,
Yamada S, Kumagai H, Motozawa Y, Hara H,
Fujiwara T, Sato T, Takeda N, Takeda N, Otsu K,
Morita H, Toko H and Komuro I. CXCR7
ameliorates
myocardial
infarctionasabeta-arrestin-biased receptor. Sci Rep 11:3426,
2021.
9. Itoh H, Kaneko H, Kiriyama H, Kamon T, Fujiu K,
Morita K, Yotsumoto H, Michihata N, Jo T, Takeda
N, Morita H, Yasunaga H and Komuro I. Reverse
J-shaped relationship between body mass index andin-hospital mortality of patients hospitalized forheart failure in Japan. Heart Vessels 36:383-392,
2021.
10. Itoh H, Kaneko H, Okada A, Yano Y, Morita K,
Seki H, Kiriyama H, Kamon T, Fujiu K, Matsuoka

11.

12.

13.

14.

15.

16.

S, Nakamura S, Michihata N, Jo T, Takeda N,
Morita H, Nishiyama A, Node K, Yasunaga H and
Komuro I. Fasting Plasma Glucose and Incident
Colorectal Cancer: Analysis of a Nationwide
Epidemiological Database. J Clin Endocrinol Metab,
2021.
Itoh H, Kaneko H, Okada A, Yano Y, Morita K,
Seki H, Kiriyama H, Kamon T, Fujiu K, Matsuoka
S, Nakamura S, Michihata N, Jo T, Takeda N,
Morita H, Nishiyama A, Node K, Yasunaga H and
Komuro I. Fasting Plasma Glucose and Incident
Colorectal Cancer: Analysis of a Nationwide
Epidemiological Database Fasting Plasma Glucose
and Colorectal Cancer. J Clin Endocrinol Metab,
2021.
Jimba T, Kaneko H, Yano Y, Itoh H, Yotsumoto H,
Seki H, Morita K, Kiriyama H, Kamon T, Fujiu K,
Michihata N, Jo T, Takeda N, Morita H, Nishiyama
A, Node K, Yasunaga H and Komuro I. Relation of
the Metabolic Syndrome to Incident Colorectal
Cancer in Young Adults Aged 20 to 49 Years. Am J
Cardiol 158:132-138, 2021.
Kaneko H, Itoh H, Kamiya K, Morita K, Sugimoto
T, Konishi M, Kiriyama H, Kamon T, Fujiu K,
Michihata N, Jo T, Takeda N, Morita H, Yasunaga
H and Komuro I. Acute-phase initiation of cardiac
rehabilitation and clinical outcomes in hospitalized
patients for acute heart failure. Int J Cardiol
340:36-41, 2021.
Kaneko H, Itoh H, Kiriyama H, Kamon T, Fujiu K,
Morita K, Michihata N, Jo T, Takeda N, Morita H,
Yasunaga H and Komuro I. Possible association
between eating behaviors and cardiovasculardisease in the general population: Analysis of anationwide
epidemiological
database.
Atherosclerosis 320:79-85, 2021.
Kaneko H, Itoh H, Kiriyama H, Kamon T, Fujiu K,
Morita K, Michihata N, Jo T, Takeda N, Morita H,
Yasunaga H and Komuro I. Fasting plasma glucose
and subsequent cardiovascular disease among
young adults: Analysis of a nationwide
epidemiological
database.
Atherosclerosis
319:35-41, 2021.
Kaneko H, Itoh H, Yotsumoto H, Kiriyama H,
Kamon T, Fujiu K, Morita K, Kashiwabara K,Michihata N, Jo T, Morita H, Yasunaga H and
Komuro I. Cardiovascular Health Metrics of 87,160

141

Couples: Analysis of a Nationwide Epidemiological
Database. J Atheroscler Thromb 28:535-543, 2021.
17. Kaneko H, Yano Y, Itoh H, Morita K, Kiriyama H,
Kamon T, Fujiu K, Michihata N, Jo T, Takeda N,
Morita H, Nishiyama A, Node K, Bakris G, MiuraK, Muntner P, Viera AJ, Oparil S, Lloyd-Jones DM,
Yasunaga H and Komuro I. Untreated Hypertension
and Subsequent Incidence of Colorectal Cancer:
Analysis of a Nationwide Epidemiological Database.
J Am Heart Assoc 10:e022479, 2021.
18. Kaneko H, Yano Y, Itoh H, Morita K, Kiriyama H,
Kamon T, Fujiu K, Michihata N, Jo T, Takeda N,
Morita H, Node K, Carey RM, Lima JAC, Oparil S,
Yasunaga H and Komuro I. Association of Blood
Pressure Classification Using the 2017 American
College of Cardiology/American Heart Association
Blood Pressure Guideline With Risk of Heart
Failure and Atrial Fibrillation. Circulation
143:2244-2253, 2021.
19. Kiriyama H, Kaneko H, Itoh H, Kamon T, Mizuno
Y, Fujiu K, Morita H, Yamamichi N and Komuro I.
Association between changes in body weight andlipid profile in the general population: acommunity-based cohort study. Eur Heart J Qual
Care Clin Outcomes 7:109-110, 2021.
20. Matsuoka S, Kaneko H, Kamon T, Suzuki Y, Yano Y,
Okada A, Itoh H, Morita K, Fukui A, Fujiu K,
Michihata N, Jo T, Takeda N, Morita H, Nakamura
S, Yokoo T, Nishiyama A, Node K, Yasunaga H and
KomuroI.
IncorporationofRetinalArteriolosclerosis into Risk Stratification of Blood
Pressure Category According to the 2017
ACC/AHA Blood Pressure Guideline. J Atheroscler
Thromb, 2021.
21. Matsuoka S, Kaneko H, Yano Y, Itoh H, Fukui A,
Morita K, Kiriyama H, Kamon T, Fujiu K, Seki H,
Michihata N, Jo T, Takeda N, Morita H, Nakamura
S, Yokoo T, Nishiyama A, Node K, Yasunaga H and
Komuro I. Association Between Blood Pressure
Classification Using the 2017 ACC/AHA Blood
Pressure Guideline and Retinal Atherosclerosis. Am
J Hypertens 34:1049-1056, 2021.
22. Nakanishi K, Daimon M, Yoshida Y, Sawada N,
Hirose K, Iwama K, Yamamoto Y, Ishiwata J,
Hirokawa M, Kaneko H, Nakao T, Mizuno Y,
Morita H, Di Tullio MR, Homma S and Komuro I.
Subclinical Hypothyroidism as an Independent

23.

24.

25.

26.

27.

28.

Determinant of Left Atrial Dysfunction in the
General Population. J Clin Endocrinol Metab 106:e1859-e1867, 2021.
Nakayama A, Morita H, Kawahara T, Itoh H and
Komuro I. Association between testosterone andlipid profiles under statin therapy and its clinicalimpact on the cardiovascular event risk. Heart
Vessels 36:1794-1803, 2021.
Sakaue S, Kanai M, Tanigawa Y, Karjalainen J,
Kurki M, Koshiba S, Narita A, Konuma T,
Yamamoto K, Akiyama M, Ishigaki K, Suzuki A,
Suzuki K, Obara W, Yamaji K, Takahashi K, Asai S,
Takahashi Y, Suzuki T, Shinozaki N, Yamaguchi H,
Minami S, Murayama S, Yoshimori K, Nagayama S,
Obata D, Higashiyama M, Masumoto A, Koretsune
Y, FinnGen, Ito K, Terao C, Yamauchi T, Komuro I,
Kadowaki T, Tamiya G, Yamamoto M, Nakamura Y,
Kubo M, Murakami Y, Yamamoto K, Kamatani Y,
Palotie A, Rivas MA, Daly MJ, Matsuda K and
Okada Y. A cross-population atlas of genetic
associations for 220 human phenotypes. Nat Genet
53:1415-1424, 2021.
Sawada N, Nakanishi K, Daimon M, Hirose K,
Yoshida Y, Ishiwata J, Hirokawa M, Koyama K,
Nakao T, Morita H, Di Tullio MR, Homma S and
Komuro I. Independent effect of visceral fat on left
atrial phasic function in the general population.
Nutr Metab Cardiovasc Dis 31:3426-3433, 2021.
Shinohara K, Ikeda S, Enzan N, Matsushima S,
Tohyama T, Funakoshi K, Kishimoto J, Itoh H,
Komuro I and Tsutsui H. Efficacy of intensive
lipid-lowering therapy with statins stratified byblood pressure levels in patients with type 2
diabetes mellitus and retinopathy: Insight from the
EMPATHY study. Hypertens Res 44:1606-1616,
2021.
Sugita J, Fujiu K, Nakayama Y, Matsubara T,
Matsuda J, Oshima T, Liu Y, Maru Y, Hasumi E,
Kojima T, Seno H, Asano K, Ishijima A, Tomii N,
Yamazaki M, Kudo F, Sakuma I, Nagai R, Manabe I
and Komuro I. Cardiac macrophages prevent
sudden death during heart stress. Nat Commun
12:1910, 2021.
Takeda N, Inuzuka R, Yagi H, Morita H, Ando M,
Yamauchi H, Taniguchi Y, Porto KJ, Kanaya T,
Ishiura H, Mitsui J, Tsuji S, Toda T, Ono M and
Komuro I. Clinical Impact of Copy Number

142

Variation on the Genetic Diagnosis of Syndromic
Aortopathies. Circ Genom Precis Med 14:e003458,
2021.
29. Yoshida Y, Nakanishi K, Daimon M, Ishiwata J,
Sawada N, Hirokawa M, Kaneko H, Nakao T,
Mizuno Y, Morita H, Di Tullio MR, Homma S and
Komuro I. Sex-specific difference in the association
between arterial stiffness and subclinical left
ventricular dysfunction. Eur Heart J Cardiovasc
Imaging 22:817-823, 2021.
30. Yoshida Y, Nakanishi K, Daimon M, Ishiwata J,
Sawada N, Hirokawa M, Kaneko H, Nakao T,
Mizuno Y, Morita H, Di Tullio MR, Homma S and
Komuro I. Atrioventricular and VentricularFunctional Interdependence in Individuals Without
Overt Cardiac Disease. J Am Heart Assoc 10:
e021624, 2021.

143

Department of Respiratory
Medicine
Professor
Takahide Nagase, M.D.,Ph.D.

Lecturer
Goh Tanaka, M.D.,Ph.D., Akihisa Mitani, M.D.,Ph.D.

Assistant Professor
Masanori Kawakami, M.D.,Ph.D.,

Hirokazu Urushiyama, M.D.,Ph.D.

Satoshi Noguchi, M.D.,Ph.D.,

Keita Maemura, M.D., Ph.D.

Naoya Miyashita, M.D., Ph.D.,

Keisuke Hosoki, M.D.,Ph.D.

Takahiro Ando, M.D., Ph.D.

Kensuke Fukuda, M.D., Ph.D.

Homepage

http://kokyuki.umin.jp/

Introduction and Organization

Clinical activities

The staff of the Department of Respiratory
Medicine, Graduate School of Medicine, University ofTokyo, consists of 1 professor, 2 lecturers, and 8
assistant profesors. At The University of Tokyo,
affiliatedhospitals
andotherinstitutions,approximately 70 members belong to the Department.
At the University of Tokyo Hospital, 24 physiciansbelong to the Department.
Mortality from respiratory diseases such as
primary lung cancer and COPD is expected tocontinue to increase, advancement of respiratory
medicine research is necessary. We conduct basic andclinical research for a wide variety of respiratory
disorders including primary lung cancer, COPD,
asthma and interstitial lung diseases. We have focusedon molecular mechanisms underlying the pathogenesisof lung disorders. Our research goal is to develop
novel diagnostic and therapeutic modalities for better
management of these pulmonary diseases.

The Department of Respiratory Medicine is
responsible for out-patient care as well as care of
in-patients (35 patients on average) on the 13th floor of
the hospital ward A at the University of Tokyo
Hospital. We have two teams consisting of juniorresidents, two fellows, and an experienced attending.
In-patients are mostly admitted for primary lungcancer. Other diseases include respiratory infections,interstitial pneumonia, and COPD. Many patients withprimary lung cancer also have co-existing interstitial
pneumonia or COPD. There are many emergency
visits and admissions from pneumonia, respiratory
failure due to exacerbation of COPD or interstitial
pneumonia, progression of lung cancer, etc. In casesof severe respiratory failure such as severe pneumonia
and ARDS, we provide ventilatory support incollaboration with the ICU staff.
A specialized clinical conference for respiratory
disease has been held once a week since the late 1990s,
where staff from our department, Department ofThoracic Surgery, and Department of Radiology join
and discuss together to determine the best diagnostic

144

and therapeutic approach to individual patients. Thisconference has been highly appreciated as a prototype
of Cancer Board of the University of Tokyo Hospital,
and, is now held as Respiratory Cancer Board. Thisconference is still one of the most frequently held
Cancer Board at our hospital. Our department
contributes to the pre- and post-surgical evaluation of
respiratory functions, and also provides consultation
on respiratory problems from almost every department
at our hospital.
Together with the Department of Infectious
Disease, we are responsible for taking care of COVID
patients and infection control measures. We supervise
the clinical teams that take care of inpatients withmoderate COVID-19, make decisions on PCR testingand infection prevention practices, and run the feverclinic for patients who visit our hospital on a regularbasis.
At present, primary lung cancer is the leading
cause of cancer death, and is one of the major medical
and social problem to be overcome. Recently, theremarkable effectiveness of molecular-targeted
therapies in primary lung cancer attracted muchattention in both basic science and clinical practice.
Pneumonia is the 3rd leading cause of all deaths whencombined with aspiration pneumonia, and COPD isalso a major cause of death. No effective therapeuticmodalities are currently available for many respiratory
diseases. For example, mortality of acute respiratory
distress syndrome (ARDS) is extremely high despite
intensive care using currently available tools.
Idiopathic pulmonary fibrosis is a progressive andfatal inflammatory and fibrotic disorder of the lungparenchyma, and only a few medications are currently
available to treat the disease. Our focus is to develop anovel and potential therapeutic approach to these
diseases.
Total numbers of in-patients in 2021
1.
2.
3.
4.
5.

Primary lung cancer
Abnormal lung shadowsInterstitial pneumonia
Respiratory infections
Non-tuberculous
mycobacterial infections
6. Other cancers

488
66
45
29
15
12

7. Pneumothorax
8. COPD
9. Bronchial Asthma

94
3

A weekly chart round and professor’s round arescheduled every Tuesday afternoon.
A specialized clinical conference for patients withrespiratory diseases is held as Respiratory Cancer
Board every Thursday evening, together with thoracic
surgeons and radiologists. At this conference,
radiological diagnosis, indication of CT-guided biopsy
and thoracoscopic biopsy, and treatment strategies not
only about thoracic malignancies but also otherrespiratory diseases are discussed, making it possible
to give the best care to every patient.

Teaching activities
For medical school education, our department
takes part in systematic lectures and specific learningfor diagnosis and treatment of respiratory diseases forthe 4th year medical students, clinical clerkship for 5thyear medical students, and clinical lectures for 5th and6th year medical students. During elective clerkshipfor 5th year students, students visit and learn from oneof several leading affiliated hospitals in Tokyo.
During systematic lectures, the concept,
pathogenesis, pathology, diagnosis, and treatment ofcommon respiratory diseases are comprehensively
presented. During clinical lectures, we present clinicalcases of important diseases such as primary lungcancer and pneumothorax, and discuss several
important points on the diagnostic evaluation andtreatment in collaboration with the Faculty of the
Department of Thoracic Surgery. Recent majoradvances in the relevant fields are also reviewed.
During clinical clerkship, each student, as amember of medical care team, has opportunities toexperience the daily clinical care with residents andfellows as well as with the faculty. Each student learns
how to perform a medical interview, perform physicalexams and make plans for diagnosis and treatment.
Respiratory specialists provide lecture on chest X-ray
as an essential element in clinical clerkship, which ishighly popular among the students. Elective clerkship
during the 5th year of the educational program is145

designed to facilitate the exposure to a wide range ofclinical practice both at The University of Tokyo
Hospital and at one of the affiliated hospitals for two
weeks each (although COVID-19 pandemic made thelatter unavairable in 2021). Several lectures on
respiratory diseases are also provided.
As for post-graduate education, respiratory
physicians (fellows and one attending) assemble ateam with residents, and provide medical care forpatients with various respiratory diseases. Under theseprocess, residents acquire knowledge and skills
required for diagnosis and treatment of respiratory
diseases. Seminars on important themes such as
medical treatment of lung cancer, diagnostic chest
imaging, etc. are held at regular intervals.

Research
Our department conduct basic and clinical research forvarious respiratory disorders including primary lungcancer, COPD, asthma, interstitial pneumonia, andrespiratory infection. Epidemiological, clinical,
cellular, and molecular techniques are utilized for the
elucidation of pathogenic mechanisms and for thedevelopment of novel diagnostic and therapeuticmodalities in respiratory medicine. Postgraduate
students as well as faculty members study genetic andepigenetic alterations in lung cancer, cell biology
using airway epithelial cells, fibroblast and smoothmuscle cells, both in collaboration with the Faculty of
the Department of Thoracic Surgery. Geneticallyengineered mice are also used as disease models.
These results have been presented and published inscientific meetings and peer-reviewed journals. Our
main research projects are as follows.








Search for diseases-susceptibility genes andelucidation of their pathophysiological roles in
respiratory diseases
Analysis of disease-models using geneticallyengineered mice
Analysis of DNA methylation, histone modification and miRNA in lung cancer
Search for previously unidentified oncogenic
driver mutations in lung cancer and elucidation ofresistant mechanisms to molecular-targeted dugs
Analysis of functional alterations of airwayepithelial cells and fibroblasts in relation to tissue
repair and remodeling, e.g., epithelialmesenchymal transition, and the roles of various
cytokines and chemokines, in asthma and COPD
Detection of small airway disease using impulse
oscillometry and its clinical application
Search for predictive factors for responses tochemotherapy in malignancy including lungcancerEpidemiological study of respiratory diseases,
using
Diagnosis
Procedure
Combination
database.

Takahide Nagase is a GOLD Assembly member.

References
1.

2.

3.

4.

5.

Amano Y, Kage H, Tanaka G, Sato Y, Tanaka M,
Nagase T. Multiple Brain Metastases in a Patientwith ROS1 Fusion-Positive Lung Adenocarcinoma as a Disease Flare due to Crizotinib
Cessation Caused by Disseminated Aseptic
Inflammation from Crizotinib-Associated Renal
Cysts: A Case Report. Case Rep Oncol. 2022 Mar
30;15(1):338-344.
Ando T, Kage H, Shinozaki-Ushiku A, Tatsuno K,
Tsutsumi S, Nagayama K, Nakajima J, Kohsaka
S, Miyagawa K, Aburatani H, Mano H, Nagase T.
Composite Clonal Analysis Reveals Transition of
NSCLC Subtypes Through Accumulation ofGene Mutations: A Case Report. JTO Clin Res
Rep. 2022 Jan 10;3(2):100277.
Ishii T, Murakami Y, Narita T, Nunokawa H,
Miyake K, Nagase T, Yamashita N. Myeloid
differentiation protein-2 has a protective role inhouse dust mite-mediated asthmatic characteristics with the proinflammatory regulation of
airway epithelial cells and dendritic cells. Clin
Exp Allergy. 2022 Jan;52(1):149-161.
Jo T, Michihata N, Yamana H, Morita K,
Ishimaru M, Yamauchi Y, Hasegawa W,
Urushiyama H, Uda K, Matsui H, Fushimi K,
Yasunaga H, Nagase T. Risk of drug-induced
interstitial lung disease in hospitalised patients: anested case-control study. Thorax. 2021 Dec;
76(12):1193-1199.
Miyashita N, Enokido T, Horie M, Fukuda K,

146

Urushiyama H, Strell C, Brunnström H, Micke P,
Saito A, Nagase T. TGF-β-mediated epithelialmesenchymal transition and tumor-promoting
effects in CMT64 cells are reflected in thetranscriptomic signature of human lungadenocarcinoma. Sci Rep. 2021 Nov 17;11(1):22380.
6. Sakamoto Y, Yamauchi Y, Jo T, Michihata N,
Hasegawa W, Takeshima H, Matsui H, Fushimi K,
Yasunaga H, Nagase T. In-hospital mortality
associated with community-acquired pneumonia
due to methicillin-resistant Staphylococcus
aureus: a matched-pair cohort study. BMC Pulm
Med. 2021 Nov 3;21(1):345.
7. Tamiya H, Mitani A, Isago H, Ishimori T, Saito
M, Jo T, Tanaka G, Yanagimoto S, Nagase T.
Measurement of chest wall motion using a
motion capture system with the one-pitch phaseanalysis method. Sci Rep. 2021 Nov 2;11(1):21497.
8. Ando T, Kage H, Matsumoto Y, Zokumasu K,
Nagase T. Lower dose of ethambutol may reduce
ocular toxicity without radiological deterioration
for Mycobacterium avium complex pulmonary
disease. Respir Investig. 2021 Nov;59(6):777782.
9. Ikushima H, Hiraishi Y, Toriumi K, Ando T,
Tamiya H, Ishida J, Amano Y, Kage H, Tanaka G,
Nagase T. Multiple cerebral infarctions in
ROS1-rearranged lung adenocarcinoma. Respirol
Case Rep. 2021 Aug 26;9(9):e0831.
10. Yokoyama A, Sakamoto Y, Jo T, Urushiyama H,
Tamiya H, Tanaka G, Matsui H, Fushimi K,
Yasunaga H, Nagase T. Pulmonary disease as arisk factor for transfusion-related acute lunginjury. ERJ Open Res. 2021 Aug 31;7(3):000392021.
11. Tanaka G, Jo T, Tamiya H, Sakamoto Y,
Hasegawa W, Matsui H, Fushimi K, Yasunaga H,
Nagase T. Factors affecting in-hospital mortalityof non-tuberculous mycobacterial pulmonary
disease. BMC Infect Dis. 2021 Jul 20;21(1):698.
12. Watanabe K, Suzukawa M, Arakawa S,
Kobayashi K, Igarashi S, Tashimo H, Nagai H,
Tohma S, Nagase T, Ohta K. Corrigendum to"Leptin enhances cytokine/chemokine production
by normal lung fibroblasts by binding to leptin

13.

14.

15.

16.

17.

receptor" [Allergol Int 68S (2019) S3-S8].
Allergol Int. 2021 Jul;70(3):404.
Amano Y, Kage H, Tanaka G, Gonoi W, Nakai Y,
Kurokawa R, Inui S, Okamoto K, Harada S,
Iwabu M, Morizaki Y, Abe O, Moriya K, Nagase
T. Diagnostic prediction of COVID-19 based onclinical and radiological findings in a relatively
low COVID-19 prevalence area. Respir Investig.
2021 Jul;59(4):446-453.
Urushiyama H, Jo T, Hasegawa W, Ando T,
Sakamoto Y, Uda K, Matsui H, Fushimi K,
Yasunaga H, Nagase T. Preoperative use of
pirfenidone and reduced risk of postoperative
severe respiratory complications in patients with
idiopathic pulmonary fibrosis: Propensity
score-matched analysis using a nationwide
database in Japan. Respirology. 2021 Jun;26(6):590-596.
Isago H, Mitani A, Kohno S, Nagoshi S, Ishimori
T, Saito M, Tamiya H, Miyashita N, Ishii T,
Matsuzaki H, Yatomi Y, Nagase T, Jo T. The
Japanese Herbal (Kampo) Medicine Hochuekkito
Attenuates Lung Inflammation in Lung
Emphysema. Biol Pharm Bull. 2021;44(1):39-45.
Watanabe K, Suzukawa M, Narumoto O,
Kawashima M, Suzuki J, Matsui H, Nagai H,
Kurashima A, Nagase T, Tohma S. CD64
expression on neutrophils reflects the activity of
nontuberculous mycobacterial lung disease.
Respir Investig. 2021 Jan;59(1):155-156.
Fukuda K, Matsuzaki H, Mikami Y, Makita K,
Miyakawa K, Miyashita N, Hosoki K, Ishii T,
Noguchi S, Urushiyama H, Horie M, Mitani A,
Yamauchi Y, Shimura E, Nakae S, Saito A,
Nagase T, Hiraishi Y. A mouse model ofasthma-chronic obstructive pulmonary disease
overlap induced by intratracheal papain. Allergy.
2021 Jan;76(1):390-394.

147

Department of Gastroenterology
Professor
Mitsuhiro Fujishiro, M.D., Ph.D.

Lecturer
Keisuke Tateishi, M.D., Ph.D.,

Motoyuki Otsuka, M.D., Ph.D.,

Ryosuke Tateishi, M.D., Ph.D.

Assistant Professor
Yasuo Tanaka, M.D., Ph.D.,

Hidetaka Fujinaga, M.D., Ph.D.,

Hirofumi Kogure, M.D., Ph.D.,

Kennichiro Enooku, M.D., Ph.D.,

Yoku Hayakawa, M.D., Ph.D.,

Yotaro Kudo, M.D., Ph.D.,

Yosuke Tsuji, M.D., Ph.D.,

Suguru Mizuno, M.D., Ph.D.,

Koji Miyabayashi, M.D., Ph.D.,

Keisuke Yamamoto, M.D., Ph.D.,

Tatsuya Minami, M.D., Ph.D.,

Naminatsu Takahara, M.D., Ph.D.,

Tsuyoshi Hamada, M.D., Ph.D.,

Takahiro Kishikawa, M.D., Ph.D.,

Nobumi Suzuki, M.D., Ph.D.,

Takuma Nakatsuka, M.D., Ph.D.,

Tomotaka Saito, M.D., Ph.D.,

Yoshiki Sakaguchi, M.D., Ph.D.,

Yu Takahashi, M.D., Ph.D.,

Kei Saito, M.D., Ph.D.,

Rei Ishibashi, M.D., Ph.D.

Project Assistant Professor
Tatsunori Suzuki, M.D., Ph.D.

Homepage http://gastro.m.u-tokyo.ac.jp/
Introduction and Organization
The Department of Gastroenterology was establishedthrough a reorganization of the Graduate School of
Medicine and that of the Division of Internal Medicineof The University of Tokyo Hospital in 1998. The
department is responsible for clinical services,education, and research activities in the liver,pancreato-biliary, and gastrointestinal tract. It
comprises a professor, three lecturers, 21 assistantprofessors, 14 fellows, 62 graduates, and other visiting
researchers including students from abroad as ofFebruary 2022. Some others are under a temporarytransfer inside and outside the country. The North andSouth wings on the 11th floor of Ward A haveprovided core hospital rooms for the department.
Laboratories of the department are scattered on eachfloor, mainly of Clinical Research Center. Mitsuhiro
Fujishiro succeeded Kazuhiko Koike as professor in
July 2021.

Clinical activities
The Department of Gastroenterology owns 85
inpatient beds in charge. By using these beds, we saw
total 26,779 inpatients with 2,597 new inpatients in an

148average hospital stay of 9.3 days in the fiscal year of2021. Resident, junior and senior staff members bear
the responsibility for the medical management of each
inpatient in collaboration with subspecialty groups
concerned. We saw total 61,999 outpatients with 1,710
new outpatients (2.8%) in the fiscal year of 2021.
Specialty and subspecialty clinical conferences areheld on Monday evening.
The number of treatments for hepatocellular
carcinoma, represented by percutaneous radiofrequency ablation, nearly 230 cases per year, isshowing one of the greatest achievements in the field.
The number of cases undergoing radiofrequency
ablation for metastatic liver tumors is also increasing
recent years. In addition, we are making efforts todevelop an innovation for daily clinical activities. For
example, fibrosis progression in chronic liver disease
is conventionally assessed by liver biopsy. Recently
we can evaluate the stage of liver fibrosis by
FibroScan®, newly developed equipment thatmeasures liver stiffness by ultrasound, which is usefulfor evaluating increasing non-alcoholic steatohepatitis
patients. In addition, nearly 100% cure for HCV
hepatitis can be achieved by using oral antiviral agents
instead of IFN therapy. This will be especiallybeneficial for elderly patients and advanced fibrotic
patients.
ERCP, the standard endoscopic treatment for biliary
and pancreatic diseases, is annually performed inabout 1,000 cases. Various endoscopic treatments suchas endoscopic treatment of bile duct stones in over
1,400 cases and biliary drainage with metal stents formalignant biliary strictures in over 1,000 cases havebeen performed. We have reported the development
and clinical studies of papillary balloon dilation(EPBD) and papillary large balloon dilation (EPLBD)
for the treatment of bile duct stones, and many studies
on covered metal stents for malignant as well as
benign biliary strictures. We have a lot of experiencein providing advanced endoscopic treatment forpatients who are difficult to receive standard treatment,such as ERCP using a balloon endoscope andtransluminal drainage and stone therapy using
endoscopic ultrasonography (EUS) for surgicallyaltered anatomy cases. We also perform endoscopic
treatment of chronic pancreatitis and pancreatic stonedisease. We also provide preoperative chemotherapy

for resectable pancreatic cancer and novel
chemotherapy for unresectable pancreatic and biliary
tract cancer as an advanced medical treatment. We
also perform cancer multi-gene panel testing using
tumor specimens collected by EUS-FNA. The numberof cases of primary sclerosing cholangitis and
IgG4-related diseases, which are intractable, is one of
the highest in Japan, and we provide medical care toclarify the pathogenesis of these diseases.
In the gastrointestinal field, ESD (endoscopic
submucosal dissection) is performed as a curativeendoscopic treatment for neoplasms in the esophagus,
stomach, or colon (approximately 500 patients a year).
Collaborative endoscopic surgery with other departments is actively performed: 1) ESD for superficial
pharyngeal cancer is often performed in cooperation
with the department of otorhinolaryngology; 2) ESD
for duodenal epithelial tumor with the support of the
Department of Gastrointestinal Surgery, 3) as for
Non-exposed endoscopic wall-inversion surgery(NEWS), which was developed with the Department
of Gastrointestinal Surgery, its clinical indication has
been now expanded from the resection of GIST to thetreatment of gastric cancer. In 2021, ‘Endoscopic
full-thickness resection for submucosal tumor’ hasbeen approved as a highly challenging novel medical
technology with the support of the Department of
Gastrointestinal Surgery. Our challenge to novel
endoscopic procedures continues. Double-balloon
endoscopy (DBE) and capsule endoscopy (CE)enabled the examination of whole small intestines(approximately 100 cases in 2021). Especially ininflammatory bowel disease (IBD) patients, we
perform the examination using an optimal method
including DBE, CE, and MR enterography. In severe
IBD cases, we conduct the combination therapy of
conventional immunosuppressive drugs and the latest
biologics to increase QOL and achieve mucosal
healing and prevention of relapse. About 400 metal
stent placements for malignant gastrointestinal
obstruction have been performed at our facility. All
those interventions are performed by the members ofour department, who are specially trained for eachtechnique. In addition, for the management of
inoperative malignancies, we effectively combine theinterventional treatments with various chemotherapy
regimens including immuno-checkpoint inhibiter.

149

Aiming at personalized medicine based on genetic
information, we are also actively conducting cancer
multi-gene panel testing.
On an outpatient basis, the number of performed
ultrasonography, gastroduodenal endoscopy, andcolonoscopy is 12,500 patients, 12,000 patients, and
6,000 patients per year, respectively. In the endoscopy
examinations, we diagnose approximately 350 casesof esophageal cancer, 750 cases of gastric cancer, and2000 cases of colorectal tumor annually, and half ofthem are treated endoscopically. We perform various
basic studies using these resected tissues to feed the
new finding back to actual clinical activities.

Teaching activities
The undergraduate medical students regularly take theclinical lectures of the staff in our department. Several
courses of practical teaching are also provided for the
students. Particularly, in the Clinical Clerkshipprogram during the fifth grade, each student joins in
the medical treatment of inward patients as a memberof the clinical team in our hospital. At the end of theperiod, the students make a summary presentation of
the patients and also outline the articles from theworld’s leading medical journals. In addition, recently,
we have adopted the hybrid-type clinical practice withthe online lecture.
The residents of internal medicine participate in the
training of our department for 1-4 months in the firstyear. They learn the knowledge of therapeutics anddiagnostics in gastroenterology as well as generalinternal medicine. Our department deals with thetraining curriculum as a medical specialist of internal
medicine. The residents in the course are supported toexperience some diseases in the gastrointestinal field.
The residents who major in gastroenterology as asubspecialty
taketheexperttrainingofgastroenterology in the affiliated hospitals for several
years.
The students of the Department of Gastroenterology in
the Graduate School of Medicine perform a highstandard of medical research in the basic or clinicalfield for four years. Currently, 62 students are in our
department.

Research activities
Both basic and clinical researchers are equallyencouraged on the condition that the results may
eventually contribute to the cure of gastroenterological disorders. The themes of our recent basic
researches include the study on carcinogenesis in
gastroenterological neoplasms, mechanism of viral
hepatitis infection, the pathogenesis of metabolic liverdiseases, liver regeneration, liver fibrosis, pathogenesis of Helicobacter pylori infection, molecularcharacterization of gastrointestinal morphology,
establishing new animal models, tracing celldifferentiation, and stem cell biology for various
diseases in our area. Using new concepts such astransparent organs, genomic and epigenomic profilingof clinical samples, organoids, or liquid biopsy, we
perform various experiments to translate the basic
results into clinics eventually.
Various clinical activities are recorded in data¬base
and analyzed. Studies oriented toward evidence-based
medicine are highly appreciated. Recent studies
include radiofrequency ablation for liver metastasis ofcolorectal cancer, the impact of metabolic factors inhepatocarcinogenesis. We have also designed many
clinical trials as follows; Effects of various drug
treatments on advanced hepatocellular carcinoma,
SNPs analyses for antiviral treatment for hepatitis C,
new chemotherapeutic regimens for advanced
pancreatic cancer or biliary tract cancer, balloon
endoscope-assisted ERCP for surgically alteredanatomy, the efficacy of polyglycolic acid sheets for
artificial endoscopic ulcers, development of AI for
assisted endoscopic diagnosis, and personalized
salvage therapy of Helicobacter infection.
Our department always tries to show the newest andhighest-level clinical activities, based on the various
data of many patients, especially those suffering frommalignant diseases. Furthermore, we aim to find the
new aspects of diseases and create a new strategy
against them, which is based on clinical, basic, andepidemiological studies in our area.

Selected References
1. Tsuji Y, Ushiku T, Shinozaki T, Yamashita H, Seto
Y, Fukayama M, Fujishiro M, Oda I, Katai H,
Taniguchi H, Hasatani K, Kaizaki Y, Oga A,

150

2.

3.

4.

5.

6.

Nishikawa J, Akasaka R, Endo M, Sugai T,
Matsumoto T, Koike K. Risk for lymph nodemetastasis in Epstein-Barr virus-associated gastriccarcinoma with submucosal invasion. Dig Endosc.
2021;33(4):592-7.
Kato H, Tateishi K, Fujiwara H, Nakatsuka T,
Yamamoto K, Kudo Y, Hayakawa Y, Nakagawa H,
Tanaka Y, Ijichi H, Otsuka M, Iwadate D, Oyama
H, Kanai S, Noguchi K, Suzuki T, Sato T, Hakuta
R, Ishigaki K, Saito K, Saito T, Takahara N,
Kishikawa T, Hamada T, Takahashi R,
Miyabayashi K, Mizuno S, Kogure H, Nakai Y,
Hirata Y, Toyoda A, Ichikawa K, Qu W, Morishita
S, Arita J, Tanaka M, Ushiku T, Hasegawa K,
Fujishiro M, Koike K. MNX1-HNF1B Axis Is
Indispensable for Intraductal Papillary Mucinous
Neoplasm
Lineages.
Gastro¬en¬ter-ol¬ogy.
2022;162(4):1272-87.
Aoki T, Yamada A, Kato Y, Saito H, Tsuboi A,
Nakada A, Niikura R, Fujishiro M, Oka S,
Ishihara S, Matsuda T, Nakahori M, Tanaka S,
Koike K, Tada T. Automatic detection of various
abnormalities in capsule endoscopy videos by a
deep learning-based system: a multicenter study.
Gastrointest Endosc. 2021;93(1):165-73.
Hatta W, Tsuji Y, Yoshio T, Kakushima N, Hoteya
S, Doyama H, Nagami Y, Hikichi T, Kobayashi M,
Morita Y, Sumiyoshi T, Iguchi M, Tomida H,
Inoue T, Koike T, Mikami T, Hasatani K,
Nishikawa J, Matsumura T, Nebiki H, Nakamatsu
D, Ohnita K, Suzuki H, Ueyama H, Hayashi Y,
Sugimoto M, Yamaguchi S, Michida T, Yada T,
Asahina Y, Narasaka T, Kuribasyashi S, Kiyotoki
S, Mabe K, Nakamura T, Nakaya N, Fujishiro M,
Masamune A. Prediction model of bleeding afterendoscopic sub¬mucosal dissection for earlygastric cancer: BEST-J score. Gut. 2021;70(3):476-84.
Fujishiro M, Matsumoto T. History ofendoscopes:
Contribution
of
the
Japan
Gastroenterological Endoscopy Society. Dig
Endosc. 2022;34 Suppl 2:13-4.
Hamada T, Oyama H, Nakai Y, Tada M, Koh H,
Tateishi K, Arita J, Hakuta R, Ijichi H, Ishigaki K,
Kawaguchi Y, Kogure H, Mizuno S, Morikawa T,
Saito K, Saito T, Sato T, Takagi K, Takahara N,
Takahashi R, Tanaka A, Tanaka M, Ushiku T,

Hasegawa K, Koike K. ABO Blood Group and
Risk of Pancreatic Carcinogenesis in Intraductal
Papillary
Mucinous
Neoplasms.
CancerEpidemiol Biomarkers Prev. 2021;30(5):1020-8.
7. Hayata Y, Nakagawa H, Kurosaki S, Kawamura S,
Matsushita Y, Hayakawa Y, Suzuki N, Hata M,
Tsuboi M, Kinoshita H, Miyabayashi K, Mizutani
H, Nakagomi R, Ikenoue T, Hirata Y, Arita J,
Hasegawa K, Tateishi K, Koike K. Axin2+
Peribiliary Glands in the Periampullary Region
Generate Biliary Epithelial Stem Cells That Give
Rise to Ampullary Carcinoma. Gastroenterology.
2021;160(6):2133-48.
8. Sano M, Takahashi R, Ijichi H, Ishigaki K,
Yamada T, Miyabayashi K, Kimura G, Mizuno S,
Kato H, Fujiwara H, Nakatsuka T, Tanaka Y, Kim
J, Masugi Y, Morishita Y, Tanaka M, Ushiku T,
Nakai Y, Tateishi K, Ishii Y, Isayama H, Moses
HL, Koike K. Blocking VCAM-1 inhibits
pancreatic tumour progression and cancerassociated thrombosis/thromboembolism. Gut.
2021;70(9):1713-23.
9. Kishikawa T, Higuchi H, Wang L, Panch N,
Maymi V, Best S, Lee S, Notoya G, Toker A,
Matesic LE, Wulf GM, Wei W, Otsuka M, Koike
K, Clohessy JG, Lee YR, Pandolfi PP. WWP1
inactivation enhances efficacy of PI3K inhibitors
while suppressing their toxicities in breast cancer
models. J Clin Invest. 2021;131(24):e140436.
10. Tateishi R, Matsumura T, Okanoue T, Shima T,
Uchino K, Fujiwara N, Senokuchi T, Kon K,
Sasako T, Taniai M, Kawaguchi T, Inoue H,
Watada H, Kubota N, Shimano H, Kaneko S,
Hashimoto E, Watanabe S, Shiota G, Ueki K,
Kashiwabara K, Matsuyama Y, Tanaka H, Kasuga
M, Araki E, Koike K; LUCID study investigators.
Hepatocellular carcinoma development in diabetic
patients: a nationwide survey in Japan. J
Gastroenterol. 2021;56(3):261-73.
11. Hangai S, Kawamura T, Kimura Y, Chang CY,
Hibino S, Yamamoto D, Nakai Y, Tateishi R,
Oshima M, Oshima H, Kodama T, Moriya K,
Koike K, Yanai H, Taniguchi T. Orchestration of
myeloid-derived suppres¬sor cells in the tumor
microenvironment by ubiquitous cellular protein
TCTP released by tumor cells. Nat Immunol.
2021;22(8):947-57.

Internal Medicine
2. Medicine Ⅱ152

Department of Nephrology and
Endocrinology
Professor
Masaomi Nangaku, M.D., Ph.D.

Associate Professor
Noriko Makita, M.D., Ph.D.

Hiroshi Nishi, M.D., Ph.D.Lecturer
Motonobu Nakamura, M.D., Ph.D.

Yoshifumi Hamasaki, M.D., Ph.D.

Associate
Megumi Fujita, M.D., Ph.D.,

Nobuaki Ito, M.D., Ph.D.,

Katsunori Manaka, M.D., Ph.D.,

Imari Mimura, M.D., Ph.D.,

Yosuke Hirakawa, M.D., Ph.D.,

Junichiro Satoh, M.D., Ph.D.,

Yoichiro Ikeda, M.D., Ph.D.;

Maki Takeuchi, M.D., Ph.D.,

Mai Sugahara, M.D., Ph.D.,

Ryo Matsuura, M.D., Ph.D.,

Shinji Tanaka, M.D., Ph.D.

Official website

http://www.todai-jinnai.com

Introduction and Organization

Clinical activities

The Department of Nephrology and Endocrinology
is one of the major divisions in the Department ofInternal Medicine of the University of Tokyo, which
covers nephrology, hypertension, and endocrinology,
and also renal diseases associated with diabetes
mellitus, cardiovascular diseases, collagen diseases
and so on. Usually we have up to 25 inpatients in thehospital. The Professor and each member of the staff
have an active responsibility for all clinical activities.
Each member has an office and a research laboratory.
In our department, almost all members support theclinical works of our residents. We are intimately
working together in all clinical activities under thesupervision of the professor, the associate professors,
and the lecturers.

The residents are in charge of up to 25 patients ofour department and supervised by associates andfaculty staffs. We have clinical conferences to discuss
the diagnosis and treatment of our patients with all
members of the staff. Particularly difficult cases arefurther discussed with guest specialists from outside.
Nephritis should be morphologically diagnosed byrenal biopsy and the optimal treatment should bechosen for each patient. In our department, renal
biopsy is actively performed to give the real benefitsof treatment to the patients. We also treat diabetic
patients with proteinuria and end-stage renal failure.
Each staff of our department also works at the
hemodialysis unit, thus we can manage patients inevery stage of renal diseases. In collaboration with

153

Department of Urology, we are conducting renaltransplantation and promoting peritoneal dialysis.
In the endocrine unit there is a variety of patients
having disorders in thyroid, parathyroid, pituitary,adrenal and gonadal glands. It is also our specialty todiagnose and treat secondary hypertension caused byprimary aldosteronism, Cushing’s syndrome, pheochromocytoma, renal artery stenosis and so on. We
often have consultation from other departments concerning disorders of water and mineral metabolism.

Education
We have responsibility for educating undergraduates, graduate students and residents. Our staffs
take part in several lectures for undergraduate andgraduate students. In addition, our members areactively involved in clinical clerkship for undergraduate students, and other clinical practice. Particularly, we have put emphasis on participation of thestudents in clinical practice including medical investigations, diagnosis, and treatment. In the wards, we arealso educating residents during daily clinical works
and periodical lectures concerning kidney andendocrine diseases. Our department also participatesin Metabolism Research Course for educating young
clinical researchers and fellows in collaboration with
Department of Diabetes and Metabolic Diseases,
Department of Cardiology, and Department ofGeriatric Medicine.

Research
In our department there are more than 30 studentsof the graduate school. We have research conferences
to discuss the results of the research with the Professor
and faculty members. As you see in the references
below, our research topics are various and cover every
field of nephrology, hypertension and endocrinology.
We are also actively collaborating with scientists
outside the department and outside the University
including foreign countries. Achievements of ourresearches are published in the world’s leading
journals of nephrology, hypertension and endocrinology.
1. Investigation of mechanism and development oftreatment of chronic kidney diseases: from theviewpoints of hypoxia, oxidative stress, epigen-etics, carbonyl stress and endoplasmic reticulum
stress.
2. Investigation of causes of atypical hemolyticuremic syndrome.
3. Roles of renal proximal tubule transport in theregulation of plasma volume and blood pressure.
4. Physiological and pathological significance of
Na-HCO3 cotransporter NBCe1.
5. Molecular mechanism of G protein-coupled
receptor (GPCR)-mediated signal transduction, anddevelopment of a new drug and strategy targeting
GPCR.
6. Investigation on pathogenesis of disorders andtreatments of mineral and bone metabolism

Department of Hemodialysis &Apheresis
Introduction and Organization
Hemodialysis and related blood purification therapy
had been individually performed in their respective
departments. However, all the departments’ apparatus
and human resources were centralized to form the
Department of Hemodialysis and Center for Hemodialysis in 2000 at the University Hospital. The Centerfor Hemodialysis was further renovated and started
operations in Fall of 2006.
This new Center for Hemodialysis is equipped with
one pressure control unit in addition to 12 hemodialysis machines under a state-of-the-art hemodialysis control system. Our concept of a hemodialysis
controlling system is a hub to transfer all digital andanalog data from patients and to monitor machines,
including blood purification machines, to the hostcomputer in our hospital, centralizing all data andadministering medical coding and billing robustly.
Blood purification machines in the ICU can bemonitored seamlessly under the cloud system of our
hospital. Blood purification machines are selected
uniformly to secure patients’ safety while avoiding
human error and increasing the overall educational
quality of staff members.
Clinical activities
1. Start of maintenance hemodialysis therapy forend-stage renal disease (ESRD).
2. Regular hemodialysis therapy for hospitalized
ESRD patients. Please note that our center does

154

3.
4.

5.
6.
7.
8.
9.

not accept holiday dialysis.
Emergency hemodialysis and hemodiafiltration
for ICU patients.
Plasma exchange for neurodegenerative diseases,
SLE, TTP, TMA, and pre/post-liver transplantpatients.
DFPP for collagenous diseases, MG, HCV, anddermatological disorders.
LDL apheresis for nephrotic syndrome and ASO
patients.
White blood cell elimination therapy forulcerative colitis and rheumatological arthritis.
Cell-free and concentrated ascites reinfusion
therapy (CART) for refractory ascites.
Induction and maintenance of peritoneal dialysis
for ESRD.

Education
1. A systematic review course for M2 students,
which covers clinical features, diagnosis, andevidence-based therapeutic strategies for acuteand chronic renal failure including diabetic
nephropathy.
2. Technical development course for medical
engineers and nurses.
3. Tutorial course for clinical fellows applying to thespeciality of blood purification therapy.
4. Exposure in hemodialysis & apheresis course to
second year residents on request.
5. Our state-of-the-art blood purification protocols
are summarized in Japanese handbook in 2010
[Apheresis Pocket Manual] and 2011 [CRRTPocket Manual]. “Apheresis Pocket Manual” hasbeen translated into Chinese and English, andthose translated versions have helped a number of
non-Japanese-speaking people to learn how to
perform apheresis.
6. Our department takes main part in Critical Care
Nephrology Course for educating young clinicalresearchers and fellows in collaboration with
Department of Critical Care Medicine.
Research
1. Prognostic analysis for post-liver transplantpatients who received plasma exchange therapy.
2. Development and application of a non-invasive
pulse hemoglobin meter.
3. Genome wide association study for Nephrotic

4.
5.
6.
7.
8.

syndrome and those functional analyses.
Association between factors at the initiation ofrenal replacement therapy and prognosis.
Elucidation of basic mechanisms in cardio-renal
syndrome and intervention.
Pathophysiology of acute kidney injury and its
applicability for renal regenerative study.
AKI biomarkers and their clinical significance in
ICU/CCU.
Renal biomarker to determine clinical action
ability in CKD and type-2 DN.

Publications(1) Sugawara Y, Iwagami M, Yoshida Y, Kikuchi K,
Ando R, Shinoda T, Ryuzaki M, Nakamoto H,
Sakai K, Hanafusa N, Kashihara N, Nangaku M;
COVID-19 Task Force Committee of theJapanese Association of Dialysis Physicians;
Japanese Society for Dialysis Therapy; and theJapanese Society of Nephrology. Nationwide
survey of the coronavirus disease 2019prevention and treatment systems for kidneydisease patients: a study of Japanese Society ofNephrology-certified educational facilities. Clin
Exp Nephrol. 2021 Sep;25(9):996-1002.
(2) Hasegawa S, Okada A, Aso S, Kumazawa R,
Matsui H, Fushimi K, Yasunaga H, Nangaku M.
Association Between Diabetes and Major
Bleeding Complications of Renal Biopsy. Kidney
Int Rep. 2021 Nov 25;7(2):232-240.
(3) Kurata Y, Tanaka T, Cernecka H, Eitner F,
Nangaku M. TRPM2 Plays a Minor Role in AKI
and Kidney Fibrosis. Kidney360. 2021 Oct 22;3(1):153-157.
(4) Hidaka N, Kato H, Koga M, Katsura M, Oyama
Y, Kinoshita Y, Fukumoto S, Makita N, Nangaku
M, Ito N. Induction of FGF23-related
hypophosphatemic osteomalacia by alcohol
consumption. Bone Rep. 2021 Oct 16;15:101144.
(5) Kotani A, Oda Y, Hirakawa Y, Nakamura M,
Hamasaki Y, Nangaku M. Peritoneal DialysisRelated Peritonitis Caused by Streptococcus
oralis. Intern Med. 2021 Nov 1;60(21):34473452.
(6) Kato H, Hidaka N, Koga M, Kinoshita Y,
Nangaku M, Makita N, Ito N. Altered Thyroid

155

Function Tests Observed in Hypophosphatasia
Patients Treated with Asfotase Alfa. Int J
Endocrinol. 2021 Oct 28;2021:5492267.
(7) Nangaku M, Kondo K, Takabe S, Ueta K,
Kaneko G, Otsuka M, Kawaguchi Y, Komatsu Y.
Vadadustat for anemia in chronic kidney disease
patients on peritoneal dialysis: A phase 3
open-label study in Japan. Ther Apher Dial. 2021
Oct;25(5):642-653.
(8) Fujii R, Hasegawa S, Maekawa H, Inoue T,
Yoshioka K, Uni R, Ikeda Y, Nangaku M, Inagi
R. Decreased IFT88 expression with primarycilia shortening causes mitochondrial dysfunction
in cisplatin-induced tubular injury. Am J Physiol
Renal Physiol. 2021 Sep 1;321(3):F278-F292.
(9) Kurakawa KI, Okada A, Manaka K, Konishi T,
Jo T, Ono S, Uda K, Michihata N, Matsui H,
Fushimi K, Yamaguchi S, Yamauchi T, Nangaku
M, Yasunaga H, Kadowaki T. Clinical
Characteristics and Incidences of Benign and
Malignant Insulinoma Using a National Inpatient
Database in Japan. J Clin Endocrinol Metab.
2021 Nov 19;106(12):3477-3486.
(10) Nangaku M, Kondo K, Ueta K, Kokado Y,
Kaneko G, Matsuda H, Kawaguchi Y, Komatsu
Y. Efficacy and safety of vadadustat comparedwith darbepoetin alfa in Japanese anemic patientson hemodialysis: a Phase 3, multicenter,randomized, double-blind study. Nephrol Dial
Transplant. 2021 Aug 27;36(9):1731-1741.
(11) Kato H, Koga M, Kinoshita Y, Taniguchi Y,
Kobayashi H, Fukumoto S, Nangaku M, Makita
N, Ito N. Incidence of Complications in 25 Adult
Patients With X-linked Hypophosphatemia. J
Clin Endocrinol Metab. 2021 Aug 18;106(9):e3682-e3692.
(12) Fukui K, Tanaka T, Nangaku M. Enarodustat totreat anemia in chronic kidney disease. Drugs
Today (Barc). 2021 Aug;57(8):491-497.
(13) Matsuura R, Yamashita T, Hayase N, Hamasaki
Y, Noiri E, Numata G, Takimoto E, Nangaku M,
Doi K. Preexisting heart failure with reduced
ejection fraction attenuates renal fibrosis after
ischemia reperfusion via sympathetic activation.
Sci Rep. 2021 Jul 23;11(1):15091.
(14) Akizawa T, Nangaku M, Yamaguchi T,
Koretomo R, Maeda K, Miyazawa Y, Hirakata H.

A Phase 3 Study of Enarodustat in Anemic
Patients with CKD not Requiring Dialysis: The
SYMPHONY ND Study. Kidney Int Rep. 2021
May 12;6(7):1840-1849.
(15) Manaka K, Sato J, Takeuchi M, Watanabe K,
Kage H, Kawai T, Sato Y, Miyagawa T, Yamada
D, Kume H, Sato S, Nagase T, Iiri T, Nangaku M,
Makita N. Immune checkpoint inhibitor
combination therapies very frequently induce
secondary adrenal insufficiency. Sci Rep. 2021
Jun 2;11(1):11617.
(16) Sugahara M, Pak WLW, Tanaka T, Tang SCW,
Nangaku M. Update on diagnosis, pathophysiology, and management of diabetic kidneydisease. Nephrology (Carlton). 2021 Jun;26(6):491-500.
(17) Nakai K, Tsurutani Y, Inoue K, Matsui S, Makita
K, Yamazaki Y, Sasano H, Makita N, Nangaku
M, Saito J, Omura M, Nishikawa T.
Steroidogenic Activity in Unresected Adrenals
Associated With Surgical Outcomes in Primary
Aldosteronism. Hypertension. 2021 May 5;77(5):1638-1646.
(18) Higashihara T, Nishi H, Takemura K, Watanabe
H, Maruyama T, Inagi R, Tanaka T, Nangaku M.
β2-adrenergic receptor agonist counteracts
skeletal muscle atrophy and oxidative stress inuremic mice. Sci Rep. 2021 Apr 28;11(1):9130.
(19) Nangaku M, Kondo K, Kokado Y, Ueta K,
Kaneko G, Tandai T, Kawaguchi Y, Komatsu Y.
Phase 3 Randomized Study Comparing
Vadadustat with Darbepoetin Alfa for Anemia inJapanese Patients with Nondialysis-Dependent
CKD. J Am Soc Nephrol. 2021 Apr 21;32(7):1779–90.
(20) Hasegawa S, Inoue T, Nakamura Y, Fukaya D,
Uni R, Wu CH, Fujii R, Peerapanyasut W,
Taguchi A, Kohro T, Yamada S, Katagiri M, Ko
T, Nomura S, Nakanishi Ozeki A, Susaki EA,
Ueda HR, Akimitsu N, Wada Y, Komuro I,
Nangaku M, Inagi R. Activation of Sympathetic
Signaling in Macrophages Blocks Systemic
Inflammation and Protects against Renal
Ischemia-Reperfusion Injury. J Am Soc Nephrol.
2021 Apr 19;32(7):1599–615.
(21) Tomura M, Hamasaki Y, Komaru Y, Miyamoto
Y, Matsuura R, Matsumoto A, Doi K, Kume H,

156

Nangaku M. Prognostic significance ofconcentric left ventricular hypertrophy atperitoneal dialysis initiation. BMC Nephrol. 2021
Apr 16;22(1):135.
(22) Nangaku M, Kadowaki T, Yotsuyanagi H,
Ohmagari N, Egi M, Sasaki J, Sakamoto T,
Hasegawa Y, Ogura T, Chiba S, Node K, Suzuki
R, Yamaguchi Y, Murashima A, Ikeda N,
Morishita E, Yuzawa K, Moriuchi H, Hayakawa
S, Nishi D, Irisawa A, Miyamoto T, Suzuki H,
Sone H, Fujino Y. The Japanese Medical Science
Federation COVID-19 Expert Opinion English
Version. JMA J. 2021 Apr 15;4(2):148-162.
(23) Oki R, Tsuji S, Hamasaki Y, Komaru Y,
Miyamoto Y, Matsuura R, Yamada D, Doi K,
Kume H, Nangaku M. Time until treatment
initiation is associated with catheter survival inperitoneal dialysis-related peritonitis. Sci Rep.
2021 Mar 22;11(1):6547.
(24) Nangaku M, Yoshino K, Oda Y, Kimura M,
Kimura H, Hirose Y, Shirayama Y, Iyo M.
Astroglial glutamate transporter 1 and glutaminesynthetase of the nucleus accumbens are involvedinthe
antidepressant-like
effects
ofallopregnanolone in learned helplessness rats.
Behav Brain Res. 2021 Mar 5;401:113092. doi:(25) Oki R, Hamasaki Y, Komaru Y, Miyamoto Y,
Matsuura R, Yamada D, Iwagami M, Doi K,
Kume H, Nangaku M. Catheter Diversion
Procedure With Exit-Site Renewal Promotes
Peritoneal Dialysis Catheter Survival. Kidney Int
Rep. 2020 Dec 7;6(2):325-332.
(26) Sugawara Y, Iwagami M, Kikuchi K, Yoshida Y,
Ando R, Shinoda T, Ryuzaki M, Nakamoto H,
Sakai K, Hanafusa N, Kashihara N, Nangaku M;
COVID-19 Task Force Committee of theJapanese Association of Dialysis Physicians, theJapanese Society for Dialysis Therapy, and theJapanese Society of Nephrology. Infection
prevention measures for patients undergoinghemodialysis during the COVID-19 pandemic in
Japan: a nationwide questionnaire survey. Ren
Replace Ther. 2021;7(1):27.
(27) Inoue D, Nishi H, Inoue R, Nangaku M. Regional
Distribution of Cardiologists and Prescription
Patterns of Sodium-Glucose Transporter-2

Inhibitors in Japan. Int Heart J. 2021;62(3):592-600.
(28) Nangaku M, Hamano T, Akizawa T, Tsubakihara
Y, Nagai R, Okuda N, Kurata K, Nagakubo T,
Jones NP, Endo Y, Cobitz AR. Daprodustat
Compared with Epoetin Beta Pegol for Anemia
in Japanese Patients Not on Dialysis: A 52-Week
Randomized Open-Label Phase 3 Trial. Am J
Nephrol. 2021;52(1):26-35.
(29) Yamazaki T, Mimura I, Tanaka T, Nangaku M.
Treatment of Diabetic Kidney Disease: Current
and Future. Diabetes Metab J. 2021 Jan;45(1):11-26.

157

Department of Diabetes andMetabolic Diseases
Professor
Toshimasa Yamauchi, M.D., Ph.D.

Associate Professor
Hironori Waki, M.D., Ph.D. (until May 2021)
Masato Iwabu, M.D., Ph.D. (since August 2021)

Lecturer
Masato Iwabu, M.D., Ph.D. (until July 2021)
Nobuhiro Shojima, M.D., Ph.D. (since October 2021)

Project Lecturer
Tomohisa Aoyama, M.D., Ph.D.(since May 2021)

Assistant Professor
Hiroaki Okazaki, M.D., Ph.D. (until December 2020),

Satoru Takase, M.D., Ph.D.

Tomohisa Aoyama, M.D., Ph.D. (until April 2021),

Mikio Takanashi, M.D., Ph.D.

Masaki Igarashi, M.D., Ph.D.

Yoshitaka Sakurai, M.D., Ph.D.

Takayoshi Sasako, M.D. Ph.D.

Gotaro Toda, M.D., Ph.D.,

Masakazu Aihara, M.D., Ph.D.

Yuka Kobayashi, M.D., Ph.D.

URL http://dm.umin.jp/
Introduction and Organization
In 1998 the Department of Internal Medicine at the
University of Tokyo was reorganized to the morefunctional units based on clinical specialties. The
physicians specialized in diabetes and metabolic
diseases from 3 former departments of Internal
Medicine were unified to the Department of Metabolic
Diseases. The Department of Diabetes and Metabolic
Diseases is one of the major divisions in the
Department of Internal Medicine at the University ofTokyo, and covers diabetes mellitus and metabolic
diseases including obesity disease and dyslipidemia.
Under the supervision and direction of the previous
professors Dr. Satoshi Kimura (1998-2003), Dr.

Toshiro Fujita (2003), Takashi Kadowaki (2003-2018)
and current professor Dr. Toshimasa Yamauchi(2018-present), we have been providing a wide-ranged
clinical, teaching and research activities. Currently,
we hold beds mainly on the 12th floor of the North
Wing Ward A of the University of Tokyo Hospital.
Besides the staffs listed above, our division holds
faculties in branches, for example, Department ofClinical Nutrition Therapy (Associate Professor: Dr.
Naoto Kubota), Laboratory for Advanced Research on
Pathophysiology of Metabolic Diseases (Project
Associate Professor: Dr. Miki Okada-Iwabu, ,Department of Healthcare Information Management(Associate Professor: Dr. Kayo Waki, Project
Assistant Professor: Dr. Kana Miyake), Department of158

Clinical Laboratory (Associate Professor: Dr. Makoto
Kurano), Division for Health Service Promotion, The
University of Tokyo (Assistant Professor: Dr. Sachiko
Okazaki) and Center for Epidemiology and Preventive
Medicine (Project Assistant Professor: Dr. Yukari
Masuda). With all these staffs, we actively instruct
and teach the residents and medical school students;
annual evaluation of the teaching skill by the students
always rates our department within the three places of
the top. In addition, there are 12 students of Graduate
School in our division. With all these 52 members, we
enthusiastically work on the research activities, whichlead to the outstanding contributions in the field of
metabolism.

Clinical activities
Based on the update clinical evidences and with theexperienced skills, we provide patient-centered
medical services in the highest quality. We haveoutpatient clinics from Monday through Friday, andhave been following approximately 293 new patients
this year (total 34,764 patients per year). On theinpatient ward, we not only take care of around 24
patients in our division as mentioned above, but also
provide a sophisticated management to all patients
suffering from metabolic diseases, especially diabetes
mellitus. Diabetes mellitus, metabolic syndrome, dyslipidemia and obesity disease are becoming moreprevalent in Japan, and lead to complications
including nephropathy, retinopathy, neuropathy andcardiovascular diseases. Thus, in collaboration withother departments, we optimize the treatment of eachpatient.
We provide the educational classes to the patients
every weekday in the inpatient ward, and also givelectures twice a week in the outpatient unit. In
addition, in collaboration with ancillary staffs of our
hospital, we provide patients well-reasoned
instructions regarding nutritional management, excise
therapy and medical therapy.
The weekly official activities of our department
consist of the pre-round case conference and the Ward
Round by the Professor on Monday. We also hold aweekly case conference by the consultation group
staffs.

Teaching activities
As for medical student education, our department
takes a part in systemic lectures for the 4th year
medical students, bed-side learning and clinicalclerkship for the 5th year medical students, andclinical lectures for the 6th year medical students.
In systemic lectures, comprehensive presentation for
the understanding of basic knowledge about theconcept, pathogenesis, diagnosis and treatment ofcommon metabolic diseases is performed.
In clinical lectures, we present clinical cases ofimportant diseases such as diabetes mellitus, and try
to discuss with the students several points forplanning the diagnosis and treatment in collaboration
with the faculties of the Departments of Nephrology,
Cardiology, and Ophthalmology.
During the period of clinical clerkship, the students
have opportunities to experience the daily clinical carewith junior and senior residents as well as with theFaculty members. Each student can learn how to dohistory taking, perform physical examinations andmake the actual plans for the diagnosis and treatment.
In addition, we arrange the program so that thestudents can experience the clinical practice and learn
the disease itself more profoundly. One faculty andone senior-resident always instruct one student.
Especially, Diabetes Clinical Seminar and oral
examination that lead to profound understandings ofthe metabolic diseases are regularly provided by theProfessor.
As for the post-graduate education, attending doctor(staff) and senior resident instruct the junior residents.
We provide advanced teaching through the seminars
and grand conference.

Research activities
There are several laboratories in our departments;
collaborating with each other or with other departments, we focus on the molecular mechanisms of themetabolic diseases and the establishment of the novel
therapeutics.
1) Molecular mechanisms of type 2 diabetes
We have been attempting to elucidate the mechanisms
underlying the development of type 2 diabetes at themolecular and genetic levels. To this end, in159

collaboration with RIKEN and several cohorts, we
explored the comprehensive catalog of genomic
variations to identify variations conferring susceptibility to type 2 diabetes in the Japanese population.
We are also exploring the signal transduction
pathways and physiological roles of insulin andadipokines in various tissues and the mechanisms ofinsulin secretion under the normal or pathologicalconditions, such as diabetes and obesity disease, using
a number of transgenic and knockout animal models,in parallel with information obtained by wholegenome analysis of human patients. In particular, we
are interested in the physiological and pathophysiological functions of adipokines secreted by adipocytes,
including adiponectin, and the signal transduction
pathway of adiponectin through the receptors,
AdipoR1 and AdipoR2, that we discovered andcharacterized. We have also identified “AdipoRon” asan adiponectin receptor agonist, which will contributeto the development and optimization of AdipoRtargeted therapeutics. In addition, we have beensuccessfully unraveling the molecular mechanisms of
β cell proliferation and inter-tissue communication of
glucose metabolism in obesity disease and type 2
diabetes. Recently, we are investigating brown andwhite adipocyte-specific transcriptional and epigenetic
regulations in obesity. We believe that these findings
and research activities will lead to novel therapeuticstrategies for diabetes and the metabolic syndrome.
2) Pathophysiological roles of lipid storage andatherosclerosis
Our aim is to clarify the significance of metabolic risk
factors in the onset and development of atherosclerosis. We are currently investigating thepathophysiological roles of lipid storage in obesity
disease, fatty liver, diabetes, hyperlipidemia andatherosclerosis using strategies of molecular biology
and genetic engineering techniques. Utilizing theanimal models of lipid disorders and molecularbiological technique, we are analyzing the roles oflipid transporters, nuclear receptors and the antioxidative proteins on the lipid disorders and atherosclerosis. We are currently interested in the cholesterol
and lipid absorption from the intestine and lipid
handling in the cells.

3) Clinical trials and epidemiological studies
We are conducting clinical trials and epidemiologicalstudies including “Japan Diabetes Optimal Integrated
Treatment study for 3 major risk factors ofcardiovascular diseases (J-DOIT3)” follow-up study,"Japan Diabetes compREhensive database projectbased on an Advanced electronic Medical record
System (J-DREAMS)", database project on obesity(J-ORBIT), National Database project, systematic
reviews and meta-analyses with a focus on important
issues such as metabolic syndrome. We investigatedanti-aging effect of Nicotinamide mononucleotide on
muscle function, association between tear and blood
glucose concentrations and investigator initiatedclinical trials targeting for a new class of anti-diabetic
agents.

References
1.

2.

3.

4.

Aihara M, Kubota N, Minami T, Shirakawa R,
Sakurai Y, Hayashi T, Iwamoto M, Takamoto I,
Kubota T, Suzuki R, Usami S, Jinnouchi H,
Aihara M, Yamauchi T, Sakata T, Kadowaki T.：
Association between tear and blood glucose
concentrations: Random intercept model adjustedwith confounders in tear samples negative foroccult blood. J Diabetes Investig. 12(2):266-276,
2021
Alfadda AA, Caterson ID, Coutinho W, Cuevas
A, Dicker D, Halford JCG, Hughes CA, Iwabu M,
Kang JH, Nawar R, Reynoso R, Rhee N, Rigas G,
Salvador J, Vázquez-Velázquez V, Sbraccia P.：
The 3Ds - Discussion, diagnosis and direction:
Elements for effective obesity care by healthcare
professionals. Eur.J.Intern.Med. pii:S0953-6205(21)00012-1, 2021
Amano Y, Kage H, Tanaka G, Gonoi W, Nakai Y,
Kurokawa R, Inui S, Okamoto K, Harada S,
Iwabu M, Morizaki Y, Abe O, Moriya K, Nagase
T.：Diagnostic prediction of COVID-19 based onclinical and radiological findings in a relatively
low COVID-19 prevalence area. Respir.invest.
pii: S2212-5345(21)00045-9, 2021
Dicker D, Alfadda AA, Coutinho W, Cuevas A,
Halford JCG, Hughes CA, Iwabu M, Kang JH,
Nawar R, Reynoso R, Rhee N, Rigas G, Salvador
J, Sbraccia P, Vázquez-Velázquez V, Caterson

160

ID. ： Patient motivation to lose weight:
Importance of healthcare professional support,
goals and self-efficacy. Eur.J.Intern.Med. pii:
S0953-6205(21)00019-4, 2021
5. Furuzono S, Kubota T, Taura J, Konishi M,
Naito A, Tsutsui M, Karasawa H*, Kubota N*,
KadowakiT*Axanthenederivative,
DS20060511, attenuates glucose intolerance by
inducing skeletal muscle-specific GLUT4translocation in mice. Commun. Biol. 4:994, 2021.
(*co-corresponding authors).
6. Hasegawa Y, Ijichi H*, Saito K, Ishigaki K,
Takami M, Sekine R, Usami S, Nakai Y, Koike K,
Kubota N*. Protein intake after the initiation ofchemotherapy is an independent prognostic
factor for overall survival in patients withunresectable pancreatic cancer: A prospective
cohort study. Clin. Nutr. 40:4792-4798, 2021.
(*co-corresponding authors).
7. Hayashi T, Kubota T, Inoue M, Takamoto I,
Aihara M, Sakurai Y, Wada N, Miki T, Yamauchi
T, Kubota N*, Kadowaki T*. Lack of brain
insulin receptor substrate-1 causes growth
retardation, with decreased expression of growth
hormone-releasing hormone in the hypothalamus.
Diabetes 70: 1640-1653, 2021. (*co-corresponding
authors)
8. Hamaguchi Y, Noma H, Nagashima K, Yamada
T, Furukawa TA.：Frequentist performances ofBayesian prediction intervals for random-effects
meta-analysis. Biom J. 2021 Feb;63(2):394-405.
9. Hosoe J, Kawashima-Sonoyama Y, Miya F,
Kadowaki H, Suzuki K, Kato T, Matsuzawa F,
Aikawa SI, Okada Y, Tsunoda T, Hanaki K,
Kanzaki S, Shojima N, Yamauchi T, Kadowaki T.
Kawai Y, Sankoda A, Genotype-StructurePhenotype Correlations of Disease-Associated
IGF1R Variants and Similarities to Those of
INSR Variants. Diabetes. 70:1874-1884, 2021
10. Hosoe J, Suzuki K, Miya F, Kato T, Tsunoda T,
Okada Y, Horikoshi M, Shojima N, Yamauchi T,
Kadowaki T. Structural basis of ethnic-specificvariants of PAX4 associated with type 2 diabetes.
Hum Genome Var. 8: 25, 2021
11. Imamura M, Takahashi A, Matsunami M,
Horikoshi M, Iwata M, Araki SI, Toyoda M,
Susarla G, Ahn J, Park KH, Kong J, Moon S,

12.

13.

14.

15.

16.

17.

Sobrin L, Yamauchi T, Tobe K, Maegawa H,
Kadowaki T, Maeda S. Genome-Wide
Association Studies Identify Two Novel Loci
Conferring Susceptibility to Diabetic Retinopathy
in Japanese Patients with Type 2 Diabetes. Hum
Mol Genet. 30:716-726, 2021
Ishihama S, Yoshida S, Yoshida T, Mori Y, Ouchi
N, Eguchi S, Sakaguchi T, Tsuda T, Kato K,
Shimizu Y, Ohashi K, Okumura T, Bando YK,
Yagyu H, Wettschureck N, Kubota N,
Offermanns S, Kadowaki T, Murohara T, Takefuji
M.
LPL/AQP7/GPD2
promotes
glycerolmetabolism under hypoxia and prevents cardiac
dysfunction during ischemia. FASEB J. 35:
e22048, 2021
Iso H, Cui R, Takamoto I, Kiyama M, Saito I,
Okamura T, Miyamoto Y, Higashiyama A,
Kiyohara Y, Ninomiya T, Yamada M, Nakagawa
H, Sakurai M, Shimabukuro M, Higa M,
Shimamoto K, Saito S, Daimon M, Kayama T,
Noda M, Ito S, Yokote K, Ito C, Nakao K,
Yamauchi T, Kadowaki T. Risk Classification for
Metabolic Syndrome and the incidence ofCardiovascular Disease in Japan with the Low
Prevalence of Obesity: A Pooled Analysis for 10
Prospective Cohort Studies. J Am Heart
Assoc.10:23 e 020760, 2021
Iwabu M, Okada-Iwabu M, Tanabe H, Ohuchi N,
Miyata K, Kobori T, Odawara S, Kadowaki Y,
Yokoyama S, Yamauchi T, Kadowaki T. ：AdipoR agonist increases insulin sensitivity andexercise endurance in AdipoR-humanized mice.
Commun.Biol.4(1):45, 2021
Iwabu M, Yamauchi T, Shimomura I, Eguchi K,
Ogawa Y: Perceptions, attitudes and barriers to
obesity management: Japanese data from the
ACTION-IO study. J. Diabetes Investig. 12:845858, 2021
Kato A, Fujimaki Y, Fujimori S, Isogawa A,
Onishi Y, Suzuki R, Ueki K, Yamauchi T,
Kadowaki T, Hashimoto Associations between
diabetes duration and self-stigma development inJapanese people with type 2 diabetes: asecondary analysis of cross-sectional data. BMJ
Open. 11: e055013, 2021
Kawai Y, Sankoda A, Waki K, Miyake K,
Hayashi A, Mieno M, Wakui H, Tsurutani Y,

161

Saito J, Hirawa N, Yamakawa T, Komiya S,
Isogawa A, Satoh S, Minami T, Osada U,
Iwamoto T, Takano T, Terauchi Y, Tamura K,
Yamauchi T, Kadowaki T, Nangaku M, Kashihara
N, Ohe K. Efficacy of the Self-management
Support System DialBetesPlus for Diabetic
Kidney Disease: Protocol for a Randomized
Controlled Trial. MIR Res Protoc. 10: e31061,
2021
18. Koseki M, Yamashita S, Ogura M, Ishigaki Y,
Ono K, Tsukamoto K, Hori M, Matsuki K,
Yokoyama S, Harada-Shiba M; Committee on
Primary Dyslipidemia under the Research
Program on Rare and Intractable Disease of the
Ministry of Health, Labour and Welfare of Japan.
Current Diagnosis and Management of TangierDisease. J Atheroscler Thromb. 2021 May 14.
doi: 10.5551/jat.RV17053
19. Koyama S, Sekijima Y, Ogura M, Hori M,
Matsuki K, Miida T, Harada-Shiba M;
Committee on Primary Dyslipidemia under the
Research Program on Rare and Intractable
Disease of the Ministry of Health, Labour andWelfareofJapan.
Cerebrotendinous
Xanthomatosis: Molecular Pathogenesis, Clinical
Spectrum, Diagnosis, and Disease-Modifying
Treatments. J Atheroscler Thromb. 2021 May 8.
doi: 10.5551/jat.RV17055
20. Kubota N, Kubota T, Kadowaki T. Midlobularzone 2 hepatocytes: A gatekeeper of liver
homeostasis. Cell Metabolism 33:855-856, 2021.
21. Kurakawa KI, Okada A, Manaka K, Konishi T, Jo
T, Ono S, Uda K, Michihata N, Matsui H,
Fushimi K, Yamaguchi S, Yamauchi T, Nangaku
M, Yasunaga H, Kadowaki T. Clinical
Characteristics and Incidences of Benign and
Malignant Insulinoma Using a National Inpatient
Database in Japan. J Clin Endocrinol Metab. 106:3477-3486, 2021
22. Kuroda M, Bujo H, Yokote K, Murano T,
Yamaguchi T, Ogura M, Ikewaki K, Koseki M,
Takeuchi Y, Nakatsuka A, Hori M, Matsuki K,
Miida T, Yokoyama S, Wada J, Harada-Shiba M;
Committee on Primary Dyslipidemia under the
Research Program on Rare and Intractable
Disease of the Ministry of Health, Labour andWelfare of Japan. Current Status of Familial

23.

24.

25.

26.

27.

28.

LCAT Deficiency in Japan. J Atheroscler
Thromb. 2021 Apr 18. doi: 10.5551/jat.RV17051
Local Burden of Disease Vaccine Coverage
Collaborators (incl Yamda T). Mapping routine
measles vaccination in low- and middle-income
countries. Nature. 2021 Jan;589(7842):415-419.
Momose A, Yamaguchi S, Okada A, IkedaKurakawa K, Namiki D, Nannya Y, Kato H,
Yamauchi T, Nangaku M, Kadowaki T. Factors
associated with long-term care certification inolder adults: a cross-sectional study based on anationally representative survey in Japan. BMC
Geriatr. 21:374, 2021
Nohara A, Tada H, Ogura M, Okazaki S, Ono K,
Shimano H, Daida H, Dobashi K, Hayashi T,
Hori M, Matsuki K, Minamino T, Yokoyama S,
Harada-Shiba M; Committee on Primary
Dyslipidemia under the Research Program on
Rare and Intractable Disease of the Ministry of
Health, Labour and Welfare of Japan.
Homozygous Familial Hypercholesterolemia. J
Atheroscler Thromb. 2021 Apr 18. doi: 10.5551/
jat.RV17050
Ochiai T, Sano T, Nagayama T, Kubota N,
Kadowaki T, Wakabayashi T, Iwatsubo T.
Differential involvement of insulin receptor
substrate (IRS)-1 and IRS-2 in brain insulin
signaling is associated with the effects on
amyloid pathology in a mouse model of
Alzheimer's disease. Neurobiol. Dis., in press,
2021.
Ogura M, Harada-Shiba M, Masuda D, Arai H,
Bujo H, Ishibashi S, Daida H, Koga N, Oikawa
S, Yamashita S; FAME Study Group. Factors
Associated with Carotid Atherosclerosis andAchilles Tendon Thickness in Japanese Patientswith
Familial
Hypercholesterolemia:A
Subanalysis of the Familial Hypercholesterolemia Expert Forum (FAME) Study. J Atheroscler
Thromb. 2021 Jun 10. doi: 10.5551/jat.62925
Ohn J, Been KW, Kim JY, Kim EJ, Park T, Yoon
HJ, Ji JS, Okada-Iwabu M, Iwabu M, Yamauchi
T, Kim YK, Seok C, Kwon O, Kim KH, Lee HH,
Chung JH: Discovery of a transdermallydeliverable pentapeptide for activating AdipoR1
to promote hair growth. EMBO Mol. Med.
e13790, 2021

162

29. Okada A, Ono S, Yamaguchi S, Yamana H,
Ikeda Kurakawa K, Michihata N, Matsui H,
Nangaku M, Yamauchi T, Yasunaga H,
Kadowaki T. Association between nutritional
guidance or ophthalmological examinationand discontinuation of physician visits inpatients with newly diagnosed diabetes: aretrospective cohort study using a nationwide
database. J Diabetes Investig.12:1619-1631,
2021
30. Okada A, Yamana H, Morita K, Sato Y,
Yamaguchi S, Kurakawa KI, Michihata N,
Matsui H, Fushimi K, Nangaku M, Yamauchi T,
Yasunaga
H,
KadowakiT.
Potassium
Concentration in Initial Fluid Therapy and
In-Hospital Mortality of Patients with Diabetic
Ketoacidosis. J Clin Endocrinol Metab. 106:
e2162-e2175, 2021
31. Okada A, Yamana H, Yamaguchi S, Kurakawa KI,
Michihata N, Matsui H, Fushimi K, Nangaku M,
Yamauchi T, Yasunaga H, Kadowaki T. Effect ofBranched-Chain Amino Acid Infusion on
In-Hospital Mortality of Patients With Hepatic
Encephalopathy and End-Stage Kidney Disease:
A Retrospective Cohort Study Using a National
Inpatient Database. J Ren Nutr. S1051-2276.
00160-6, 2021
32. Okazaki H, Gotoda T, Ogura M, Ishibashi S,
Inagaki K, Daida H, Hayashi T, Hori M, Masuda
D, Matsuki K, Yokoyama S and Harada-Shiba M
on behalf of the Committee on Primary
Dyslipidemia under the Research Program on
Rare and Intractable Disease of the Ministry of
Health, Labour and Welfare of Japan：Current
Diagnosis and Management of Primary Chylomicronemia. J Atheroscler Thromb, accepted for
publication on March 20, 2021.
33. Okazaki H, Gotoda T, Ogura M, Ishibashi S,
Inagaki K, Daida H, Hayashi T, Hori M, Masuda
D, Matsuki K, Yokoyama S, Harada-Shiba M;
Committee on Primary Dyslipidemia under the
Research Program on Rare and Intractable
Disease of the Ministry of Health, Labour andWelfare of Japan. Current Diagnosis andManagement of Primary Chylomicronemia. J
Atheroscler Thromb. 2021 May 13. doi: 10.5551/
jat.RV17054

34. Sakaue S, Kanai M, Tanigawa Y, Karjalainen J,
Kurki M, Koshiba S, Narita A, Konuma T,
Yamamoto K, Akiyama M, Ishigaki K, Suzuki A,
Suzuki K, Obara W, Yamaji K, Takahashi K, Asai
S, Takahashi Y, Suzuki T, Shinozaki N,
Yamaguchi H, Minami S, Murayama S,
Yoshimori K, Nagayama S, Obata D,
Higashiyama M, Masumoto A, Koretsune Y;
FinnGen, Ito K, Terao C, Yamauchi T, Komuro I,
Kadowaki T, Tamiya G, Yamamoto M, Nakamura
Y, Kubo M, Murakami Y, Yamamoto K,
Kamatani Y, Palotie A, Rivas MA, Daly MJ,
Matsuda K, Okada Y. A cross-population atlas ofgenetic associations for 220 human phenotypes.
Nat Genet. 53:1415-1424, 2021
35. Sakurai Y, Kubota N, Yamauchi T, Kadowaki T.
Role of Insulin Resistance in MAFLD. Int J Mol
Sci. 2021 Apr 16;22(8):4156.
36. Sasako T, Tanaka T, Yamauchi T. Adaptive
Response as a Potential Key Link Between
SGLT2 Inhibition and Renoprotection. Kidney
Int Rep 6(8): 2022-2024, 2021.
37. Sasako T, Ueki K. ER Stress Response Failure
and Steatohepatitis Comorbid with Diabetes.
Psychology and Patho-physiological Outcomesof Eating, IntechOpen Ltd., UK, 2021. doi:
10.5772/intechopen.100054.
38. Sasako T, Ueki K, Miyake K, Okazaki Y,
Takeuchi Y, Ohashi Y, Noda M, Kadowaki T.：
Effect of a Multifactorial Intervention on
Fracture in Patients With Type 2 Diabetes:
Subanalysis of the J-DOIT3 Study. J Clin
Endocrinol Metab 106(5): e2116-e2128, 2021.
39. Sawada M*, Kubota N*, Sekine R, Yakabe M,
Kojima T, Umeda-Kameyama Y, Usami S,
Akishita M, Ogawa S. Sex-related differences inthe effects of nutritional status and bodycomposition on functional disability in theelderly. PLoS One 16:e0246276, 2021 (*co-firstauthors).
40. Tada H, Nomura A, Ogura M, Ikewaki K,
Ishigaki Y, Inagaki K, Tsukamoto K, Dobashi K,
Nakamura K, Hori M, Matsuki K, Yamashita S,
Yokoyama S, Kawashiri MA, Harada-Shiba M;
Committee on Primary Dyslipidemia under the
Research Program on Rare and Intractable
Desease of the Ministry of Health, Labour and

163

41.

42.

43.

44.

45.

46.

Welfare of Japan. Diagnosis and Management ofSitosterolemia 2021. J Atheroscler Thromb. 2021
Apr 28. doi: 10.5551/jat.RV17052
Takahashi M, Okazaki H, Ohashi K, Ogura M,
Ishibashi S, Okazaki S, Hirayama S, Hori M,
Matsuki K, Yokoyama S, Harada-Shiba M;
Committee on Primary Dyslipidemia under the
Research Program on Rare and Intractable
Disease of the Ministry of Health, Labour andWelfare of Japan. Current Diagnosis andManagementof
Abetalipoproteinemia.
J
Atheroscler Thromb. 2021 May 16. doi: 10.5551/
jat.RV17056
Takeuchi F, Liang YQ, Isono M, Tajima M, Cui
ZH, Iizuka Y, Gotoda T, Nabika T, Kato N:
Integrative genomic analysis of blood pressure
and related phenotypes in rats. Dis Model Mech.
2021 May 1;14(5)Tanaka Y, Shimanaka Y, Caddeo A, Kubo T, Mao
Y, Kubota T, Kubota N, Yamauchi T, Mancina
RM, Baselli G, Luukkonen P, Pihlajamäki J,
Yki-Järvinen H, Valenti L, Arai H, Romeo S,
Kono N. LPIAT1/MBOAT7 depletion increases
triglyceride
synthesis
fueledbyhighphosphatidylinositol turnover. Gut 70:180-193,
2021.
Tateishi R, Matsumura T, Okanoue T, Shima T,
Uchino K, Fujiwara N, Senokuchi T, Kon K,
Sasako T, Taniai M, Kawaguchi T, Inoue H,
Watada H, Kubota N, Shimano H, Kaneko S,
Hashimoto E, Watanabe S, Shiota G, Ueki K,
Kashiwabara K, Matsuyama Y, Tanaka H,
Kasuga M, Araki E, Koike K.：LUCID study
investigators: Hepatocellular carcinoma development in diabetic patients: a nationwide survey inJapan. J Gastroenterol 56(3): 261-273, 2021.
Tian J, Chung HK, Moon JS, Nga HT, Lee HY,
Kim JT, Chang JY, Kang SG, Ryu D, Che X,
Choi JY, Tsukasaki M, Sasako T, Lee SH, Shong
M, Yi HS. Skeletal muscle mitoribosomal defects
are linked to low bone mass caused by bonemarrow inflammation in male mice. J Cachexia
Sarcopenia Muscle, Online ahead of print.
Ueki K, Sasako T, Okazaki Y, Miyake K,
Nangaku M, Ohashi Y, Noda M, Kadowaki T.：
the J-DOIT3 Study Group: Multifactorialintervention has a significant effect on diabetic

47.

48.

49.

50.

kidney disease in patients with type 2 diabetes.
Kidney Int 99(1): 256-266, 2021.
Waki H, Yamauchi T.：Body-weight-independent
glucose-lowering effect of the β3-adrenergic
receptor agonist mirabegron in humans. J
Diabetes Investig. 2021 May;12(5):689-690. doi:
10.1111/jdi.13509. Epub 2021 Feb 24.
Watanabe D, Murakami H, Ohno H, Tanisawa K,
Konishi K, Todoroki-Mori K, Tsunematsu Y, Sato
M, Ogata Y, Miyoshi N, Kubota N, Kunisawa J,
Wakabayashi K, Kubota T, Watanabe K, Miyachi
M. Stool pattern is associated with not only theprevalence of tumorigenic bacteria isolated fromfecal matter but also plasma and fecal fatty acids
in healthy Japanese adults. BMC Microbiol. 21:
196, 2021.
Yamashita S, Masuda D, Harada-Shiba M, Arai
H, Bujo H, Ishibashi S, Daida H, Koga N,
Oikawa S; FAME Study Group. Effectivenessand Safety of Lipid-Lowering Drug Treatments
in Japanese Patients with Familial Hypercholesterolemia: Familial Hypercholesterolemia
Expert Forum (FAME) Study. J Atheroscler
Thromb. 2021 May 13. doi: 10.5551/jat.62764
Yamazaki T, Inada S, Sawada M, Sekine R,
Kubota N, Fukatsu K, Yoshiuchi K. Diets withhigh carbohydrate contents were associated withrefeeding hypophosphatemia: A retrospective
study in Japanese inpatients with anorexia
nervosa. Int. J. Eat. Disord. 54:88-94, 2021.

164

Department of
Hematology and Oncology
Professor
Mineo Kurokawa, M.D., Ph.D.

Lecturer
Yosuke Masamoto, M.D., Ph.D.,

Ken Morita, M.D., Ph.D

Assistant Professor
Kumi Nakazaki, M.D., Ph.D.,

Kazuki Taoka, M.D., Ph.D.,

Hiroaki Maki, M.D., Ph.D.,

Akira Honda, M.D., Ph.D.

Megumi Yasunaga, M.D., Ph.D.,

Arika Shimura, M.D., Ph.D.

Hideaki Mizuno, M.D., Ph.D.

Kensuke Matsuda, M.D., Ph.D.

Azusa Morimoto, M.D., Ph.D.

Homepage

http://www.u-tokyo-hemat.com/

Introduction and Organization
The Department of Hematology and Oncology is
responsible for clinical activities in outpatient as wellas inpatient clinics of hematological disorders,
research activities for hematology/oncology, and education of undergraduate as well as graduate students.
We are also engaged in continuous education of
post-graduate doctors who develop into sophisticatedhematologists of eminent distinction. These activities
are performed by the united efforts of all members
who belong to the department. Dr. Mineo Kurokawa
was assigned as Professor of the Department of
Hematology and Oncology in 2005. Other staff of ourdepartment consists of 2 lecturers and 9 assistantprofessors.

Clinical activities
On the average, 60-70 patients with hematologicaldiseases are treated in the ward. Clinical facilities
include patient rooms with high-efficiency particulate
air filtration and filtrated water supply. Patients whoare eligible for the treatment with high-grade infection

prophylaxis are admitted to the facilities. Patient careis provided by team management. That is, three
doctors (a junior resident, a senior resident, and an
assistant professor) are assigned to a single patient.
Since clinical issues are highly related to hematopoietic stem cell transplantation especially for patientswith hematological diseases, a substantial portion of
our clinical conferences are shared with staff membersof the Department of Cell Therapy and Transplantation Medicine and the Department of Pediatrics(Hematology/Oncology). Many problems arising indaily clinical practice are discussed in the morning
clinical conference held thrice a week. Diagnostic andtherapeutic issues as well as pathological aspects ofindicative and/or educational cases are discussed inclinical conferences held twice a month.
Outpatient clinical services are provided from
Monday to Friday in the morning and afternoon using
three booths. Approximately 60-65 patients visit our
outpatient clinic every weekday. One of our ultimate
goals in the clinical activities is to cure patients withhematological malignancies.
We perform various kinds of genetic or molecular

165

tests to detect, characterize, and monitor neoplastic
cells and their results are used in the diagnosis andtreatment.
Here we introduce technical aspects on the treatment strategy:
1. High dose chemotherapy with autologous stem
cell transplant: High-dose chemotherapy isadministered for the treatment of hematologicalneoplasms and solid tumors. For the autologous
stem cell support, peripheral blood stem cell isusually selected as a source of stem cells. Recently,
weareactively
performing
autologoustransplantation as a treatment for CNS malignant
lymphoma, which is considered intractable, toimprove the prognosis.
2. Allogeneic hematopoietic stem cell transplant:
Bone marrow cells are harvested from healthy
donors by operation under general anesthesia andimmediately infused to a recipient. Peripheral
blood stem cells (PBSCs) are harvested fromhealthy donors by leukapheresis using an
automated continuous flow blood cell separator.
PBSCs are immediately infused to a recipient orpreserved in liquid nitrogen in cooperation with
the Department of Transfusion Medicine.
Allogeneic transplant with non-myeloablative
conditioning (also referred to as reduced-intensity
stem cell transplant (RIST)) is commonly
performed for elderly patients and patients with
impaired organ function. HLA-haploidentical
hematopoietic stem cell transplantation is also
ready to be performed to patients if necessary.
Allogeneic hematopoietic stem cell transplant for
the elderly are performed under the admission ofPatient Relations and Clinical Ethics Center. Cord
blood cells are also used as a source ofhematopoietic stem cells.

Teaching activities
A lecture course on etiology, pathogenesis, clinicaland laboratory features, differential diagnosis, therapy
and prognosis for all hematological diseases isprovided for the second grade medical students. The
course contents include:
1. Mechanisms of hematopoiesis, transplantation
medicine and cell therapy

2. Acute leukemia and myeloproliferative disorders
3. Bone marrow failure syndrome (aplastic anemia
and myelodysplastic syndrome)
4. Lymphoma and myeloma
5. Hemostasis and thrombosis
6. Hemolytic anemia and anemia of various causes
Clinical clerkships on diagnostic and therapeutic
issues and arts are given for the third grade medical
students on a man-to-man basis with a senior faculty
member who is erudite both in general internal
medicine and in hematology and oncology. During thecourse, students are required to learn the basic techniques of medical interview and physical examination,interpretation of laboratory tests, and practical
medical procedures.
Undergraduate students are educated to become
independent researchers both in basic and clinicalresearch.
Education of clinical fellows to train hematologists
is also provided. They are trained to achieve knowledge and techniques necessary for hematologists in
our hospital and encouraged to present clinical studies
at academic meetings.

Research activities
The major research projects are as follow: (1)molecular mechanisms of hematopoietic neoplasms,(2) hematopoietic transcription factors, (3) signaltransduction in hematopoietic cells, (4) chromosomal
and genomic approaches to leukemogenesis, (5)generation of murine models for leukemias, (6)reprogramming of leukemic cells into iPS cells, andfunctional analysis using iPS cells, (7) regulation ofhematopoiesis. (8) genetic and pathologicalmechanism of Erdheim-Chester disease. Translational
research to develop novel methods for diagnosis andtreatment based on basic research is also performed.
Every effort has been made to achieve the highest
quality in both clinical and basic medical research.
The ultimate aims of our research are the applicationof epoch-making discoveries in research fields to theclinical hematology and oncology. Representative
publications from our departments published in thepast year are listed in the reference.

166

References
1.

2.

3.

4.

5.

6.

7.

Ebisawa K, Shimura A, Honda A, Masamoto Y,
Nakahara F, and Kurokawa M. Hemoglobin
and C-reactive protein levels as predictive factors
for long-term successful glucocorticoid treatment
for multicentric Castleman’s disease. Leukemia
and Lymphoma 62(3): 614-619, 2021.
Kurihara Y, Taoka K, Takagi E, Toyama K,
Nakazaki K, and Kurokawa M. Treatment of
secondary immune thrombocytopenia with nonHodgkin lymphoma: A case report and literature
review. Internal Medicine 60(10): 1583-1588,
2021.
Kato H, Koga M, Kobayashi H, Maki H, Ikemura
M, Kurokawa M, Nangaku M, Makita N, and Ito
N. Primary bone adult T-cell lymphoma withmultiple skeletal lesions and debilitating painful
osteolysis: A case report.
Osteoporosis
International 32(5): 1013-1017, 2021.
Kawai M, Mano Tatsuo, Naito T, Honda A,
Nakai Y, Toyama K, Fujioka Y, Makise N,
Hasegawa H, Sakuishi K, Kurokawa M, andToda T.
Disseminated necrotizing leukoencephalopathy after allogeneic peripheral blood
stem cell transplantation and methotrexate
administration. Neurology and Clinical Neuroscience 9:155–156, 2021.
Maki H, Yoshimi A, Shimada T, Arai S,
Nakahara F, Morita K, Kamikubo Y, Ikegawa M,
and Kurokawa
M.
Physical interaction
between
BAALC
and
DBN1
induceschemoresistance in leukemia.
Experimental
Hematology 94:31-36, 2021.
Sasaki K, Matsuda K, Miyauchi M, Honda A,
Shimura A, Masamoto Y, and Kurokawa M.
A retrospective analysis on arteritis afteradministration of granulocyte colony-stimulating
factor. Annals of Hematology 100(5): 13411343, 2021.
Matsuda K, Jo T, Miyauchi M, Toyama K,
Nakazaki K, Matsui H, Fushimi K, Yasunaga H,
and Kurokawa M. Difference of preventing
effects of G-CSF according to age in patientswith malignant lymphoma: a nation-wide
analysis in Japan. Journal of Infection andChemotherapy, S1341-321X(21): 00078-7, 2021.

8.

9.

10.

11.

12.

13.

14.

Takezaki T, Nakazaki K, Toyama K, Matsuda K,
Honda A, and Kurokawa M. Reduction ofcycles of bendamustine plus rituximab therapy inthe cases with good response for indolent B-cell
lymphomas.
Hematological Oncology, 2021
May 2. doi: 10.1002/hon.2871.
Ito K, Ito J, Yamamoto Y, Nakajima R, Fujii M,
Katakura Y, Muramatsu A, Takayashiki N,
Toyama K, Kurokawa M, and Hiroaki Yagyu.
Serial assessments of anterior pituitary hormonesin a case of mixed histiocytosis representing
Langerhans cell histiocytosis overlapping with
Erdheim–Chester disease. Endocrinol Diabetes
Metab Case Rep. 2021 May 1;2021:EDM210030.
doi: 10.1530/EDM-21-0030.
Masamoto Y, Shimura A, and Kurokawa M.
Reduced bendamustine for elderly patients withfollicular lymphoma. Annals of Haematology,
101(3): 713–715, 2022.
Ito Y, Honda A, and Kurokawa M. Impact ofvitamin D level at diagnosis and transplantationon the prognosis of hematological malignancy: asystematic review and meta-analysis. Blood
Advances, 6(5):1499-1511, 2022.
Homan CC, King-Smith SL, Lawrence DM, Arts
P, Feng J, Andrews J, Armstrong M, Ha T,
Dobbins J, Drazer MW, Yu K, Bödör C, Cantor
A, Cazzola M, Degelman E, DiNardo CD,
Duployez N, Favier R, Fröhling S, Fitzgibbon J,
Klco JM, Krämer A, Kurokawa M, Lee J ,Malcovati L, Morgan NV, Natsoulis G, Owen C,
Patel KP, Preudhomme C, Raslova H, Rienhoff H,
Ripperger T, Schulte R, Tawana K, Velloso E,
Yan B, Liu P, Godley LA, Schreiber AW, Hahn
CN, Scott HS, and Brown AL. On behalf of the
RUNX1 international data-sharing consortium.
The RUNX1 database (RUNX1db): establishment of an expert curated RUNX1 registry andgenomics database as a publicc resource forfamilial platelet disorder with myeloid malignancy. Haematologica, 106(11):3004-3007, 2021.
Miyauchi M, Sasaki K, Kagoya Y, Taoka K,
Masamoto Y, Yamazaki S, Arai S, Mizuno H,
and Kurokawa M. CAMK2G is identified as anovel therapeutic target for myelofibrosis.
Blood Advances, 6(5):1585-1597, 2022.
Hanata N, Shoda H, Kono M, Komai T,

167

15.

16.

17.

18.

19.

20.

21.

Natsumoto B, Tsuchida Y, Tsuchiya H,
Nagafuchi Y, Taoka K, Kurokawa M, and Fujio
K.
Immature platelet levels correlate withdisease activity and predict treatment response ofthrombocytopenia in lupus patients.
Lupus,
30(11):1764-1772, 2021.
Yoshioka K, Kurokawa R, Amemiya S, Matsuda
K, Honda A, Kurokawa M, Shinozaki-Ushiku A,
and Abe O.
Rapidly progressed blastic
plasmacytoid dendritic cell neoplasm causing
diffuse skin thickening: a case report withsequential CT examinations. Radiology Case
Reports, 16(10):2929-2933, 2021.
Matsuda K, Ise M, Shimura A, Honda A,
Masamoto Y, Jo T, Yasunaga H, and Kurokawa
M. Use of wide-spectrum antimicrobials withblood culture tests during chemotherapy as an
accurate marker of febrile neutropenia in the
DPC database: A validation study. Journal of
Infection and Chemotherapy, (10):1541-1542,
2021.
Matsuda K, Jo T, Toyama K, Nakazaki K, Matsui
H, Fushimi K, Yasunaga H, and Kurokawa M.
Risk factors for early in-hospital death in patients
who developed coagulopathy during induction
therapy for acute promyelocytic leukemia: anation-wide analysis in Japan.
Annals of
Hematology, 100(10):2613-2619, 2021.
Honda A, Koya J, Yoshimi A, Miyauchi M,
Taoka K, Kataoka K, Arai S, and Kurokawa M.
Loss-of-function mutations in BCOR contributeto chemotherapy resistance in acute myeloid
leukemia. Experimental Hematology, 101-102:
42-48.e11, 2021.
Mizuno H, Koya J, Masamoto Y, Kagoya Yuki,
and Kurokawa M. Evi1 upregulates Fbp1 andsupports progression of acute myeloid leukemia
through pentose phosphate pathway activation.
Cancer Science, 112(10):4112-4126, 2021.
Kato K, Yabe H, Shimozawa N, Adachi S,
Kurokawa M, Hashii Y, Sato A, Yoshida N,
Kaga M, Onodera O, Kato S, Atsuta Y, andMorio T. Stem cell transplantation for pediatricpatients with adrenoleukodystrophy: a nationwide retrospective analysis in Japan. PediatricTransplantation, 26(1):e14125, 2022.
Hirano Y, Miyawaki S, Tanaka S, Taoka K,

22.

23.

24.

25.

Hongo H, Teranishi Y, Takami H, Takayanagi S,
Kurokawa M, and Saito N. Clinical featuresand prognostic factors for primary anaplastic
large cell lymphoma of the central nervous
system: a systematic review. Cancers, 13(17):4358, 2021.
Murakami D, Maki H, Matsuda K, Masamoto Y,
Suzuki F, Amemiya S, Osawa K, Hinata M,
Ikemura M, Ushiku T, and Kurokawa M.
Cerebral Toxoplasmosis complicating lymphoplasmacytic lymphoma in partial remission.
Journal of Infection and Chemotherapy, 28(2):279-282, 2022.
Miyauchi M, Ito Y, Nakahara F, Hino T,
Nakamura F, Iwasaki Y, Kawagoshi T, Koya J,
Yoshimi A, Arai S, Kagoya Y, and Kurokawa M.
Efficient production of human neutrophils from
iPSCs that prevent murine lethal infection withimmune cell recruitment. Blood, 138(24):25552569, 2021.
Takano H, Yasunaga M, Yamazaki I, Nishikawa
M, Masamoto Y, Kawakami M, Yatomi Y, andKurokawa M. Degenerated mitochondria inleukemic blast appeared as granules on
May-Grunwald-Giemsa staining.
Annals of
Hematology，101(5):1135-1136, 2022.
Ito Y, Nakahara F, Kagoya Y, and Kurokawa M.
CD62L expression level determines the cell fateof myeloid progenitors. Stem Cell Reports,
16(12):2871-2886, 2021.

168

Department of Allergy andRheumatology
Professor
Keishi Fujio, M.D., Ph.D. (Rheumatology)

Associate Professor
Hirofumi Shoda, M.D., Ph.D. (Rheumatology)

Lecturer
Hiroaki Harada, M.D., Ph.D. (Allergology)

Hospital Lecturer
Haruka Tsuchiya, M.D., Ph.D. (Rheumatology)

Research Associate
Yumi Tsuchida，M.D., Ph.D. (Rheumatology)
Toshihiko Komai, M.D., Ph.D. (Rheumatology)
Toshiaki Shimizu, M.D., Ph.D. (Rheumatology)
Bunki Natsumoto, M.D., Ph.D. (Rheumatology)
Masanori Kono, M.D., Ph.D. (Rheumatology)

Project Associate professor
Tomohisa Okamura, M.D., Ph.D. (Rheumatology)

Project Research Associate
Yasuo Nagafuchi，M.D., Ph.D. (Rheumatology)
Mineto Ohta, M.D., Ph.D. (Rheumatology)

Homepage

http://www.m.u-tokyo.ac.jp/mcm/

Introduction and Organization

Central Ward and the Clinical Research Center A.

The Department of Allergy and Rheumatology
presently consists of 13 staffs mentioned above, who
preside over 3 medical staff, 14 graduate students for"Doctor of Medical Science". The outpatient facilities
are situated on the 2nd floor of the Outpatient Clinic.
The inpatient facility is mainly located on the 14th
floor of the Hospital Ward A. The physician's office issituated in the East Hospital Ward and the researchrooms are located in the East Hospital Ward, theEducation
In regard to undergraduate education, the Department is in charge of internal medicine diagnosis andsystemic lectures for M2 students and clinical lecturesand bedside education for M3 and M4 students incooperation with other departments of internal
medicine. The systemic lectures and clinical lectures
cover clinical immunology, connective tissue diseases

169

and allergy. Bedside education provides students witha good opportunity to learn patient care as well aspractical knowledge through numerous seminars.
For postgraduate education, internal medicine
trainees are accepted on rotation basis and trained asinternist. Our department accepts students for "Doctorof Medical Science". Our 4-year education covers
clinical immunology, molecular immunology,
rheumatology and allergology.

7. Exploration of the roles of protein prenylation in
the animal models of lung disease.
8. Analysis of bone strength in glucocorticoidinduced osteoporosis.
9. Investigation of biomarkers in autoimmune
disease.

Publications
1.

Medical Care
General and special outpatient clinics are opened from
Monday to Friday. Special outpatients clinics include
clinics for rheumatoid arthritis, connective tissue
diseases, bronchial asthma, allergy, and kidney
disorders. For inpatients, there are presently 25 to 30
beds. Every week on Monday afternoon the charts arerounded and on Tuesday afternoon the professor
makes his rounds. To achieve the highest quality of
medical care, clinical conferences are held. Majorityof patients in the ward are suffered from connective
tissue diseases and usually exhibit multiple organ
involvements. Therefore, a careful, well-rounded
approach to each patient as a whole is required rather
than a limited special approach to a single organsystem.

2.

3.

Research
The Department consists of some laboratories inwhich clinical and basic studies are carried out
concerning mainly rheumatology and allergology.
Recently the mainstream of research has employedvarious techniques of molecular biology and cellularimmunology. The principal research topics are listed
below.
1. Functional genomics in autoimmune diseases
2. Analysis of newly-identified regulatory T cellsubset and inhibitory cytokines, and its roles in
autoimmune diseases.
3. Analysis of T cell and B cell repertoires in
autoimmune diseases.
4. Analysis of autoimmune associated gene functions in mice and human models.
5. Analysis of signal transduction mechanisms in
autoimmune diseases.
6. Analysis of autoimmune disease-specific iPS cells

4.

5.

6.

Clinical remission of rheumatoid arthritis in a
multicenter real-world study in Asia-Pacificregion. Sun X, Li R, Cai Y, Al-Herz A, Lahiri M,
Choudhury MR, Hidayat R, Suryana BPP,
Kaneko Y, Fujio K, Van Hung N, Pandya S, Pang
LK, Katchamart W, Sigdel KR, Paudyal B,
Narongroeknawin P, Chevaisrakul P, Sun F, Lu Y,
Ho C, Yeap SS, Li Z; APLAR RA SIG group.
Lancet Reg Health West Pac. 2021;15:100240.
Serum Amphiregulin and Heparin-Binding
Epidermal Growth Factor as Biomarkers inPatients with Idiopathic Inflammatory Myopathy.
Hanata N, Nagafuchi Y, Sugimori Y, Kobayashi S,
Tsuchida Y, Iwasaki Y, Shoda H, Fujio K. J Clin
Med. 2021;10(16):3730.
Immature platelet levels correlate with diseaseactivity and predict treatment response ofthrombocytopenia in lupus patients. Hanata N,
Shoda H, Kono M, Komai T, Natsumoto B,
Tsuchida Y, Tsuchiya H, Nagafuchi Y, Taoka K,
Kurokawa M, Fujio K. Lupus. 2021;30(11):1764-1772.
ANCA-associated vasculitis with protein-losing
enteropathy is characterized by hypocomplementemia. Goto M, Tsuchida Y, Terada K,
Takahashi H, Sugimori Y, Komai T, Iwasaki Y,
Shoda H, Fujio K. Rheumatol Int. 2021 Jun 22.
doi: 10.1007/s00296-021-04923-2
Nailfold capillaroscopic abnormalities inangioedema with eosinophilia. Tsuzuki S, Komai
T, Terada K, Tsuchida Y, Tanaka M, Tateishi Y,
Shinozaki-Ushiku A, Shoda H, Fujio K. Allergol
Int. 2021;70(4):501-503.
Dynamic landscape of immune cell-specific gene
regulation in immune-mediated diseases. Ota M,
Nagafuchi Y, Hatano H, Ishigaki K, Terao C,
Takeshima Y, Yanaoka H, Kobayashi S, Okubo
M, Shirai H, Sugimori Y, Maeda J, Nakano M,

170

Yamada S, Yoshida R, Tsuchiya H, Tsuchida Y,
Akizuki S, Yoshifuji H, Ohmura K, Mimori T,
Yoshida K, Kurosaka D, Okada M, Setoguchi K,
Kaneko H, Ban N, Yabuki N, Matsuki K, Mutoh
H, Oyama S, Okazaki M, Tsunoda H, Iwasaki Y,
Sumitomo S, Shoda H, Kochi Y, Okada Y,
Yamamoto K, Okamura T, Fujio K. Cell. 2021;
184(11):3006-3021.e17
7. Multiomics landscape of synovial fibroblasts inrheumatoid arthritis. Tsuchiya H, Ota M, Fujio K.
Inflamm Regen. 2021;41(1):7.
8. Identifying the most influential gene expression
profile in distinguishing ANCA-associatedvasculitis from healthy controls. Yanaoka H,
Nagafuchi Y, Hanata N, Takeshima Y, Ota M,
Suwa Y, Shirai H, Sugimori Y, Okubo M,
Kobayashi S, Hatano H, Yamada S, Tsuchida Y,
Iwasaki Y, Sumitomo S, Shoda H, Okada M,
Okamura T, Yamamoto K, Fujio K. J
Autoimmun. 2021 May;119:102617.
9. Parsing multiomics landscape of activatedsynovial fibroblasts highlights drug targets
linked to genetic risk of rheumatoid arthritis.
Tsuchiya H, Ota M, Sumitomo S, Ishigaki K,
Suzuki A, Sakata T, Tsuchida Y, Inui H, Hirose J,
Kochi Y, Kadono Y, Shirahige K, Tanaka S,
Yamamoto K, Fujio K. Ann Rheum Dis. 2021;
80(4):440-450.
10. Contribution of a European-Prevalent Variant
near CD83 and an East Asian-Prevalent Variant
near IL17RB to Herpes Zoster Risk in Tofacitinib
Treatment: Results of Genome-Wide Association
Study Meta-Analyses. Bing N, Zhou H, Chen X,
Hirose T, Kochi Y, Tsuchida Y, Ishigaki K,
Sumitomo S, Fujio K, Zhang B, Valdez H,
Vincent MS, Martin D, Clark JD. Arthritis
Rheumatol. 2021 Jul;73(7):1155-1166.

171

Department of Infectious
Diseases (Internal Medicine)
Professor
Kyoji Moriya, M.D., Ph.D.

Associate Professor
Shu Okugawa, M.D., Ph.D.

Assistant Professor
Koh Okamoto, M.D.

Homepage

Daisuke Jubishi, M.D, Ph.D. Hideki Hashimoto, M.D., Ph.D.

https://plaza.umin.ac.jp/utid/index.html

Introduction and Organization
The Department of Infectious Diseases has been
one of the leading academic organizations specialized
for internal medicine, in particular, infectious disease
medicine in Japan since 1998, when the Departmentsof Internal Medicine, established in 1890, wererearranged into new ones according to subspecialty ofinternal medicine. Our department has been chiefly
engaged in clinical, educational and research activities
for infectious diseases including bacterial, fungal andviral infections of all organs including HIV infection,
tuberculosis and viral hepatitis. Our department islocated on 13th floor of the University of Tokyo
Hospital Building and has well-furnished researchlaboratories including P-2 class laboratory, andcomputer rooms as own properties. In clinical andresearch activities, we are collaborating with the
Department of Infection Control and Prevention. One
professor, one associate professor, three assistantprofessors, some residents and full-time staff members
are all performing their own duties in clinical,
educational and research activities.

Clinical activities
We have hospital beds on the 13th floor of the Ward
A of University of Tokyo Hospital. Diseases include
HIV infection, viral hepatitis, pneumonia, drug-

resistant bacteria infections or tuberculosis, EBV
infection, CMV infection, parasite infection, sexualtransmitted infection, etc. Every effort is made to givepatients the best care and best quality of life. Assistantassociates and residents take care of inpatients. The
case presentation by residents is held every day.
Weekly clinical conference is held to discuss all cases,in particular, those with clinical problems difficult tobe solved. Consultations are very frequent from otherdepartments on the management of infectious diseases.
The general diagnostic, therapeutic plans anddecisions for each patient are given at the Professor’s
round.
Our department offers out-patient care everyday on
infectious diseases and general medicine. We are also
engaged in infection control and prevention of
emerging infectious diseases with the department of
infection control and prevention.

Teaching activities
Our department takes a part in clinical lectures andbed-side learning of the internal medicine for undergraduate medical students according to the educational programs of the University of Tokyo. For the fourthyear medical students, six lectures of infectious
diseases are given. In addition, principles of medical
diagnosis are taught at the bedside. During the
bed-side teaching for fifth and sixth year students, our172

associates teach them on man-to man basis the basic
way of thinking for correct diagnosis and therapy, thetechniques of interrogation and physical examination,
the way for interpretations of laboratory tests andother medical examinations, and the basic medical
procedures on each case. The education of juniorresidents and fellows is performed as described in“Clinical Activities”.

Research activities
Both clinical and basic research are necessary to
improve the diagnosis and treatment to infectious
diseases. The members of our department are doing
best to obtain new findings using highly sophisticatedmethodologies. A intramural research conference isheld, in which some members present their annual
research progresses to be discussed by all the
department staff. In addition, each laboratory holds its
own conference and/or journal club on a weekly or
bi-weekly basis.
The research field covers wide areas of infectious
diseases including HIV infection, viral hepatitis andhepatocarcinogenesis, and bacterial infection. Also,
various emerging and re-emerging infectious diseases
are covered. Following themes are currently being
investigated in the department.
(1) Establishment of effective therapy for HIV
infection: we have made a great contribution in
the establishment of the guideline for treatment of
HIV infection in Japan.
(2) Elucidation of the mechanism of hepatocarcinogenesis in hepatitis viral infection: the direct
involvement of both HBV and HCV in hepatocarcinogenesis has been demonstrated using ourtransgenic mouse systems.
(3) Establishment of effective therapy for HCV and
HBV infection: we have made a great contribution
in the establishment of the guideline for treatmentof hepatitis viral infection in Japan.
(4) Establishment of effective therapy for HCV/HIV
co-infection: we have made a great contribution in
the establishment of the guideline for treatment of
HCV/HIV co-infection in Japan.
(5) Innovation of new methods to control viral
hepatitis or prevent the development of hepatocellular carcinoma in chronic viral hepatitis.

(6) Establishment of the effective infection control
method and therapy of MRSA and other MDRO
infection.
(7) Elucidating the mechanism and signal transduction of bacterial infection through toll-likereceptors.
(8) Establishment of effective diagnosis methods andtherapy for C. difficile infection(9) Clinical research on COVID-19.

References(1-26)
1.

2.

3.

4.

5.

6.

7.

Hangai S, Kawamura T, Kimura Y, Chang CY,
Hibino S, Yamamoto D, et al. Orchestration of
myeloid-derived suppressor cells in the tumor
microenvironment by ubiquitous cellular protein
TCTP released by tumor cells. Nat Immunol.
2021;22(8):947-57.
Harada S, Aoki K, Ohkushi D, Okamoto K,
Takehana K, Akatsuchi T, et al. Institutional
outbreakinvolving
multiplecladesofIMP-producing Enterobacter cloacae complex
sequence type 78 at a cancer center in Tokyo,
Japan. BMC Infect Dis. 2021;21(1):289.
Hirano J, Yoshio S, Sakai Y, Songling L, Suzuki
T, Itoh Y, et al. Hepatitis C virus modulates signal
peptide peptidase to alter host protein processing.
Proc Natl Acad Sci U S A. 2021;118(22).
Ikeda M, Kobayashi T, Fujimoto F, Okada Y,
Higurashi Y, Tatsuno K, et al. The prevalence of
the iutA and ibeA genes in Escherichia coli
isolates from severe and non-severe patients withbacteremic acute biliary tract infection issignificantly different. Gut Pathog. 2021;13(1):32.
Ikeda M, Wakabayashi Y, Okamoto K,
Yanagimoto S, Okugawa S, Moriya K. Changing
trends in lipid profile and biomarkers of renal
function and bone metabolism before and afterswitching from tenofovir disoproxil fumarate to
tenofovir alafenamide: a prospective observational study. AIDS Res Ther. 2021;18(1):30.
Ikeuchi K, Okamoto K, Inoue N, Okugawa S,
Moriya K. Chronic Disseminated Gonococcal
Infection in a Japanese Man with Novel C5 Gene
Mutation. J Clin Immunol. 2021;41(3):691-3.
Ishihara Y, Okamoto K, Shimosaka H, Ono Y,

173

8.

9.

10.

11.

12.

13.

14.

Kanno Y, Ikeda M, et al. Prevalence and clinicalcharacteristics of patients with biologicallyfalse-positive reactions with serological syphilis
testing in contemporary practice: 10-year
experience at a tertiary academic hospital. Sex
Transm Infect. 2021;97(6):397-401.
Ito H, Okamoto K, Yamamoto S, Yamashita M,
Kanno Y, Jubishi D, et al. Incidence and Risk
Factors for Inappropriate Use of Non-CultureBased Fungal Assays: Implication for Diagnostic
Stewardship. Open Forum Infect Dis. 2022;9(1):ofab601.
Jubishi D, Okamoto K, Hamada K, Ishii T,
Hashimoto H, Shinohara T, et al. The association
between adverse reactions and immune response
against SARS-CoV-2 spike protein after
vaccination with BNT162b2 among healthcare
workers in a single healthcare system: aprospective observational cohort study. Hum
Vaccin Immunother. 2022;18(5):2048559.
Kitaura S, Okamoto K, Wakabayashi Y, Okada Y,
Okazaki A, Ikeda M, et al. A Cold-Blooded
Tiptoer: Nonresolving Cellulitis in an Immunocompromised Patient. Open Forum Infect Dis.
2022;9(4):ofac074.
Kobayashi T, Ikeda M, Okada Y, Higurashi Y,
Okugawa S, Moriya K. Clinical andMicrobiological Characteristics of Recurrent
Escherichia coli Bacteremia. Microbiol Spectr.
2021;9(3):e0139921.
Kurano M, Ohmiya H, Kishi Y, Okada J, Nakano
Y, Yokoyama R, et al. Measurement of
SARS-CoV-2 Antibody Titers Improves thePrediction Accuracy of COVID-19 Maximum
Severity by Machine Learning in Non-VaccinatedPatients. Front Immunol. 2022;13:811952.
Minami T, Tateishi R, Fujiwara N, Nakagomi R,
Nakatsuka T, Sato M, et al. Impact of Obesityand Heavy Alcohol Consumption on Hepatocellular Carcinoma Development after HCVEradication with Antivirals. Liver Cancer. 2021;
10(4):309-19.
Mizoguchi M, Harada S, Okamoto K, Higurashi
Y, Ikeda M, Moriya K. Comparative performanceand cycle threshold values of 10 nucleic acidamplification tests for SARS-CoV-2 on clinicalsamples. PLoS One. 2021;16(6):e0252757.

15. Nakano Y, Kurano M, Morita Y, Shimura T,
Yokoyama R, Qian C, et al. Time course of thesensitivity and specificity of anti-SARS-CoV-2
IgM and IgG antibodies for symptomatic
COVID-19 in Japan. Sci Rep. 2021;11(1):2776.
16. Nishikawa H, Shiraki M, Hiramatsu A, Hara N,
Moriya K, Hino K, et al. Reduced handgrip
strength predicts poorer survival in chronic liverdiseases: A large multicenter study in Japan.
Hepatol Res. 2021;51(9):957-67.
17. Nomura Y, Okamoto K, Ohama Y, Higurashi Y,
Harada S, Moriya K. Tenosynovitis caused by
Mycobacterium marseillense, initially identified
as Mycobacterium avium complex using
AccuProbe and COBAS TaqMan. BMC InfectDis. 2021;21(1):1092.
18. Ohama Y, Aoki K, Harada S, Nagasawa T,
Sawabe T, Nonaka L, et al. Genetic Environment
Surrounding blaOXA-55-like in Clinical Isolatesof Shewanella algae Clade and Enhanced
Expression of blaOXA-55-like in a CarbapenemResistant Isolate. mSphere. 2021;6(5):e0059321.
19. Okushin K, Suzuki R, Tsutsumi T, Okamoto K,
Ikeuchi K, Kado A, et al. Change in hepatitis C
virus positivity among needle-stick injury source
patients: a 10-year experience in a Japanesetertiary hospital. BMC Infect Dis. 2021;21(1):399.
20. Osawa I, Okamoto K, Ikeda M, Otani A,
Wakimoto Y, Yamashita M, et al. Dynamicchanges in fibrinogen and D-dimer levels in
COVID-19 patients on nafamostat mesylate. J
Thromb Thrombolysis. 2021;51(3):649-56.
21. Oyama Y, Yasunaga M, Honda A, Maki H,
Masamoto Y, Kobayashi T, et al. Severe cellulitis
caused by Achromobacter xylosoxidans after
allogeneic hematopoietic stem cell transplantation. J Infect Chemother. 2021;27(5):770-2.
22. Sato Y, Atarashi K, Plichta DR, Arai Y, Sasajima
S, Kearney SM, et al. Novel bile acidbiosynthetic pathways are enriched in the
microbiome of centenarians. Nature. 2021;
599(7885):458-64.
23. Shimura T, Kurano M, Kanno Y, Ikeda M,
Okamoto K, Jubishi D, et al. Clot waveform of
APTT has abnormal patterns in subjects with
COVID-19. Sci Rep. 2021;11(1):5190.

174

24. Shimura T, Kurano M, Okamoto K, Jubishi D,
Kano K, Igarashi K, et al. Increase in serum
levels of phosphatidylserine-specific phospholipase A1 in COVID-19 patients. Cell Mol
Immunol. 2021;18(9):2275-7.
25. Yamashita M, Ikeda M, Kato I, Ohama Y, Ando
M, Ikemura M, et al. Protothecosis in the mucosaof the pharynx mimicking pharyngeal cancer in
an immunocompetent individual: a case report.
Ann Clin Microbiol Antimicrob. 2022;21(1):5.
26. Yokoyama R, Kurano M, Morita Y, Shimura T,
Nakano Y, Qian C, et al. Validation of a newautomated chemiluminescent anti-SARS-CoV-2
IgM and IgG antibody assay system detecting
both N and S proteins in Japan. PLoS One. 2021;
16(3):e0247711.

175

Department of Stress Science andPsychosomatic Medicine
Associate Professor
Kazuhiro Yoshiuchi, M.D., Ph.D.

Associate
Makoto Otani, M.D., Ph.D.

Research Associate
Ryo Yoneda, M.D.

Homepagehttps://plaza.umin.ac.jp/~psmut/

Introduction and Organization
The Department of Stress Science andPsychosomatic Medicine is one of 11 divisions of the
Department of Internal Medicine, the University ofTokyo. It covers eating disorder, panic disorder, andvarious psychosomatic diseases such as chronicheadache, irritable bowel syndrome, functional
dyspepsia, hypertension, diabetes mellitus, andhyperthyroidism. Our teaching staff consists of one
associate professor, one associate, one research
associate, and 5 adjunct professors, and othermembers are 4 senior residents, 15 graduate students,
and 4 researchers.

Clinical activities
Our department is responsible for both outpatient
clinic and inpatient ward. The ward is managed as apart of the Division of General Internal Medicine, andsenior residents, an associate, and the associate
professor attend it every day and provide close sideby-side instruction to junior residents. The weekly
professor’s round is scheduled on Thursday morning.
During 2021 April to 2022 March, overall 2,453
patients (99 individuals) were admitted to the ward,
most of whom were eating disorder patients.
Outpatient clinic is attended on every morning andafternoon in three consultation rooms by approximate-ly fifteen physicians. During 2021 April to 2022
March, the numbers of the new outpatients and of theoverall outpatients in our department were 172 and
4,847, respectively.

Teaching activities
We are giving 6 methodical lectures on
psychosomatic medicine for fourth grade medical
students, ‘clinical clerkship’ for fifth grade students
lasting two weeks, ‘advanced clinical clerkship’ for 3
to 4 fifth grade students lasting 4 weeks each, andclinical lectures on psychosomatic diseases in
cardiology for fifth grade students and on eating
disorders for sixth grade students. We are trying toteach them not only basic knowledge of specificdiseases, ways of physical examination, or interpretation of laboratory data, but also relevant ways ofclinical interview, doctor-patient relationship building,and behavior modification.
As for education for junior residents, our seniorresidents and an associate provide man-to-man
instruction. In addition, they can learn how to present
the history of newly-admitted patients at the weekly
professor’s round from our teaching staff.

Research activities
Targeting stress-related diseases such as not only

176

those covered by our department but also otherlifestyle-related disease, and cancers, we areinvestigating their pathophysiology and psychopathology through assessing bio-psycho-behavioral
time-series data, various questionnaire data, andautonomic nervous function. We are also actively
conducting basic as well as clinical research on
eating-related substances.
Some representative research methods are as
follows:
1) Ecological momentary assessment (EMA):
Investigation on neurobehavioral basis of stressrelated diseases such as tension-type headache,eating disorders, insomnia, and panic disorderusing portable computers for real-time assessmentof subjective symptoms in combination withambulatory monitors such as electrocardiogramand actigraphy.
2) Neuroendocrinological and neuroimmunologicalstudies in anorexia nervosa patients: multidisciplinary investigation on energy metabolism
during a refeeding phase; changes in various
substances such as neuropeptides before and after
treatment; relationship between bone metabolism
and various makers; and exploration of biomarkers
for evaluating treatment efficacy.
3) Psycho-oncology: Development of a new questionnaire for evaluating depressive mood in cancer
patients.
Fifteen graduate students and 4 researchers actively
conducted their researches along with our teaching
staff. We have been also collaborating with many
scientists belonging to other departments either inJapan or abroad. Research conferences are held once amonth, where one of the graduate students presents
his/her research for open discussion by all themembers of our department.

2.

3.

4.

5.

6.

7.

References1.

Miyamoto S, Harashima S, Yoshiuchi K.
Validating the family coping questionnaire foreating disorders for caregivers of Japanesepatients with eating disorders: association
between coping strategies and psychological8.

characteristics. J Eat Disord. 2021 Dec 18;9(1):163.
Shirane S, Michihata N, Yoshiuchi K, Ariyoshi K,
Iwase S, Morita K, Matsui H, Fushimi K,
Yasunaga H. Evaluation of quality indicatorsnear death in older adult cancer decedents inJapan: A nationwide retrospective cohort study.
Jpn J Clin Oncol. 2021 Nov 1;51(11):1643-1648.
Kurisu K, Yamanaka Y, Yamazaki T, Yoneda R,
Otani M, Takimoto Y, Yoshiuchi K. A clinicalcourse of a patient with anorexia nervosa
receiving surgery for superior mesenteric artery
syndrome. J Eat Disord. 2021 Jun 30;9(1):79.
Kurisu K, Yoshiuchi K. Comparison of
Antipsychotics for the Treatment of Patients
With Delirium and QTc Interval Prolongation: A
Clinical Decision Analysis. Front Psychiatry.
2021 Jun 25;12:609678.
Inada S, Yoshiuchi K, Park S, Aoyagi Y.
Trajectories of objectively measured physicalactivity and mood states in older Japanese adults:
longitudinal data from the Nakanojo Study.
Biopsychosoc Med. 2021 Feb 23;15(1):5.
Maeda I, Inoue S, Uemura K, Tanimukai H,
Hatano Y, Yokomichi N, Amano K, Tagami K,
Yoshiuchi K, Ogawa A, Iwase S; Phase-R
Delirium Study Group. Low-Dose Trazodone for
Delirium in Patients with Cancer Who Received
Specialist Palliative Care: A Multicenter
Prospective Study. J Palliat Med. 2021 Jun;24(6):914-918.
Hamatani S, Hirano Y, Sugawara A, Isobe M,
Kodama N, Yoshihara K, Moriguchi Y, Ando T,
Endo Y, Takahashi J, Nohara N, Takamura T,
Hori H, Noda T, Tose K, Watanabe K, Adachi H,
Gondo M, Takakura S, Fukudo S, Shimizu E,
Yoshiuchi K, Sato Y, Sekiguchi A. Eating
Disorder Neuroimaging Initiative (EDNI): a
multicentre prospective cohort study protocol for
elucidating the neural effects of cognitivebehavioural therapy for eating disorders. BMJ
Open. 2021 Jan 25;11(1):e042685.
Harashima S, Fujimori M, Akechi T, Matsuda T,
Saika K, Hasegawa T, Inoue K, Yoshiuchi K,
Miyashiro I, Uchitomi Y, J Matsuoka Y. Deathby suicide, other externally caused injuries andcardiovascular diseases within 6 months of177cancer diagnosis (J-SUPPORT 1902). Jpn J Clin
Oncol. 2021 Apr 30;51(5):744-752.
9. Yamazaki T, Inada S, Sawada M, Sekine R,
Kubota N, Fukatsu K, Yoshiuchi K. Diets withhigh carbohydrate contents were associated withrefeeding hypophosphatemia: A retrospective
study in Japanese inpatients with anorexia
nervosa. Int J Eat Disord. 2021 Jan;54(1):88-94.
10. Qian K, Koike T, Yoshiuchi K, Schuller BW,
Yamamoto Y. Can Appliances Understand the
Behavior of Elderly Via Machine Learning? A
Feasibility Study. IEEE Internet of Things
Journal. 2021;8(10):8343-55.
11. Otani M, Hiraide M, Horie T, Mitsui T, Yoshida
T, Takamiya S, Sakuta R, Usami M, Komaki G,
Yoshiuchi K. Psychometric properties of theEating Disorder Examination-Questionnaire andpsychopathology in Japanese patients with eating
disorders. Int J Eat Disord. 2021 Feb;54(2):203211.

Internal Medicine
3. Clinical Laboratory Medicine
and Pathology

179

Department of Transfusion
Medicine
Professor
Hitoshi Okazaki, M.D.,Ph.D.

Research Associate
Toshiyuki Ikeda, M.D., Kazutoshi Ebisawa, M.D., Ph.D., Kazuhiko Ishii, M.D.

Homepage

http://square.umin.ac.jp/traf-tky/

Introduction and Organization
The Transfusion Medicine service was established in1949, as an internal provisional measure, andofficially established in 1966. In 1984, Professor
Hiroshi Toyama assumed as the first Professor of thedepartment. Professor Toyama greatly contributed to
the field of transfusion medicine, especially by
publishing “Transfusion Medicine” (actually in its 3rd.
edition), which is the bible of transfusion medicine inJapan. Other great contributions from the department
are as follows. Dr. Kazuo Okochi, ex-lecturer of thedepartment, is the pioneer in the field of transfusionassociated hepatitis research, ex-Professor Takeo Jujiclarified the mechanisms of transfusion-associatedgraft-versus-host disease (TA-GVHD), a serious posttransfusion complication, and ex-Professor Yoichi
Shibata contributed enormously to the field of platelet
immunology. In 1997, the Department of Transfusion
Medicine was established as a chair of the Division ofInternal Medicine of the Graduate School of Medical
Sciences, the University of Tokyo.
Actually, the department is composed of 6 medical
doctors (4 full-time, and 2 partial-time), 10 laboratory
technicians, 2-3 nurses and 1 office assistant.

Clinical activities
The main activity of the department of Transfusion
Medicine is the control, preservation, and provision ofsafe blood products and their derivatives (including
albumin). The control of all blood products in thehospital is centralized to the department, which, in
addition, provides information and orientation related
to blood transfusion. Transfusion-related laboratory
tests and tests for transfusion-transmitted infectious
diseases are routine practices of the department, which
also actively takes part in the diagnosis, prevention
and treatment of adverse reactions and posttransfusion complications. Collection, preservationand provision of autologous blood are also importantfunctions of the department, where the outpatient
clinic for autologous blood was established by
ex-Professor Koki Takahashi in January 2006. At theoutpatient clinic, the first established in Japan, thetransfusionist gives consultation to the patients,
prepares the adequate blood collection schedule, takes
the informed consent, and performs the bloodcollection, according to the surgeons’ needs.
Additionally, collection and preservation of peripheral
blood stem cells are also performed.
The main activities are as follows:
I Control and preservation of blood products and its
derivatives;
II. Laboratory tests
1) Blood typing and histocompatibility testing;2) Detection of anti-erythrocyte, anti-leukocyte
and anti-platelet antibodies;3) Detection of HBV antigens and antibodies, HCV,
HAV, HTLV and HIV antibodies;
4) HLA typing for hematopoietic stem cell transplantation and organ transplantation;
III. Clinical work

1801) Pre-operative autologous blood collection andpreservation;2) Collection and preservation of peripheral blood
stem cells for transplantation;

Teaching activities
Sixth-grade medical students are provided withpractical courses focusing on clinical practice of bloodtransfusion and laboratory tests. Courses are given insmall groups of 6 students each, in a total of 18 groups
per year. The course lasts 5 days/week, including thefollowing subjects;
1) Visit to the laboratories of the department tounderstand the routine of a laboratory;
2) Introduction to the blood group types (red cells,
platelets, leukocytes) and their importance intransfusion medicine and in transplantation (bonemarrow and organ);3) Methodology of blood typing and compatibility
testing for transfusion;4) Methodology for screening of irregular antibodies,and their importance in transfusion practice;5) Introduction to the post-transfusional complications, their etiology, prevention and treatment.
6) Introduction to the preventive measures of bloodborne viral transmission, especially focusing on
the NAT test and the look-back survey.
7) Acquisition of informed consents related to bloodtransfusion, using the role playing method.
8) The indications and techniques of autologous
blood collection and preservation;9) The techniques for peripheral blood stem cells(PBSCs) collection and preservation, as well as
their clinical application;10) The recent advances in the field of bloodtransfusion, including the “Blood Law”, and therecently revised “Indications of blood products”
and “The principles of transfusion practice”.
11) One-day visit to the Japanese Red Cross Blood
Center, to learn the general process of blood
donation and transfusion, including the types ofblood products, and their indications.

Research activities
Research on red cells, leukocytes, and platelets, thepost-tranfusional complications, transplantation im-

munology, immunotherapy, and stem cell biology are
the main themes of the department. Typing of blood
cells is performed by serological and DNA-based
methods. The HLA typing, which was introduced by
ex-Professor Takeo Juji, one of the pioneers of thisfield, is an essential test for hematopoietic stem celland organ transplantations, and still continues as oneof the most important research fields of the department. The mixed-passive hemagglutination (MPHA)
method, the most popular methodology for platelet
serology in Japan, was developed by ex-Professor
Yoichi Shibata and its applicability is now extended
for granulocyte as well as endothelial cell serology.
Transplantation immunology, including stem cellbiology is also an important subject. Also, development of new materials for medical use is also being
researched. Recently, the risk factors of the
detrimental effects of autologous blood donation,
especially focusing on the noninvasive measurementof circulating blood volume, are being investigated.
Following are the main themes.
1. Detection of platelet alloantigens and antibodies
and their role in the transfusion practice.
2. Diagnosis and prevention of post-transfusional
complications and thrombocytopenic purpura of
the newborn.
3. Clinical application of refrigerated and frozenstored blood for autologous transfusion in surgicalpatients, and the improvement of the preservation
methods.
4. Study on the effect of pre-storage leukoreductionof autologous blood for the prevention of possible
adverse effects.
5. Development of a new methodology for plateletcross-match.
6. HLA and HPA genotyping.
7. Development of a new methodology for evaluationof platelet function.
8. Ex-vivo expansion of hematopoietic stem cells andtheir clinical application.
9. Pathophysiology of TRALI and TACO.
10. Study on the risk factors of autologous blood
donation.
11. Study on the correlation between the results
obtained by conventional coagulation tests and themeasurement results of thromboelastograms.

181

References
1.

2.

3.

Yoshiko Tamai, Hitoshi Ohto, Hideto Takahashi,
Junnichi Kitazawa1)5), for the Pediatric RBC
Alloimmunization Consortium. Toshiyuki Ikeda,
Yutaka Nagura, Hitoshi Okazaki, et al. Transfusionrelated alloimmunization to red blood cell antigens
in pediatric recipients Transfusion Medicine
Reviews 2021 Jan;35(1):29-36.
Yuki Nakano, Makoto Kurano, Yoshifumi Morita,
Takuya Shimura, Rin Yokoyama, Chungen Qian,
Fuzhen Xia, Fan He, Yoshiro Kishi, Jun Okada,
Naoyuki Yoshikawa, Yutaka Nagura, Hitoshi
Okazaki, Kyoji Moriya, Yasuyuki Seto, Tatsuhiko
Kodama, Yutaka Yatomi. Time course of thesensitivity and specificity of anti-SARS-CoV-2
IgM and IgG antibodies for symptomatic
COVID-19 in Japan. Scientific Reports 2021
Feb 2;11(1):2776
Yokoyama R, Kurano M, Morita Y, Shimura T,
Nakano Y, Qian C, Xia F, He F, Kishi Y, Okada J,
Yoshikawa N, Nagura Y, Okazaki H, Moriya K,
Seto Y, Kodama T, Yatomi Y. Validation of a newautomated chemiluminescent anti-SARS-CoV-2
IgM and IgG antibody assay system detecting
both N and S proteins in Japan. PLOS ONE
2021 Mar 4;16(3):e0247711

Reproductive, Developmental andAging Sciences
1. Obstetrics and Gynecology

183

Department of
Reproductive Endocrinology
Associate Professors
Takeshi Nagamatsu

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/a_joseika02/index.html#reproduction
https://www.gynecology-htu.jp/

Organization
The Department of Reproductive Endocrinology isorganized by Assistant Professors Takeshi Nagamatsu.
All the staff members are taking part in both clinicaland research activities. For the clinical aspect, we areengaged with in-patient and out-patient care including
the activities in the delivery units.

Activities
In clinical section, we have an out-patient clinic for
infertility, gynecological endocrine diseases, genetic
counseling and assisted reproductive technologies(ART).
We have a highly organized infertility clinic, where
every patient is systemically examined and after diagnosis of underlying infertility factor (s) appropriate
treatment is performed following our protocol. Once itturns out that higher level of treatment is necessary,
ART is applied to such cases. We have been engaged
in in vitro fertilization and embryo transfer (IVF-ET)
as a main axis of ART for twenty years. Conventional
IVF-ET is mainly indicated to cases with tubal factor,
mild male factor, immunological factor or of
unexplained infertility factor. In case of severe male
factor or other fertilization disorder intracytoplasmic
sperm injection (ICSI) is performed. Now we haveabout 220 OPU cycles of IVF-ET every year, whichconventional IVF-ET and ICSI share almost equally.
The clinical pregnancy rate of conventional IVF-ET isaround 30% per embryo transfer cycle, which iscomparable with that of ICSI. Other ART techniquessuch as embryo cryopreservation and assisted hatching
are also performed.
In basic research section, a couple of projects asfollows are under way, some of which have alreadyyielded interesting findings; 1) the mechanism offolliculogenesis and follicular apoptosis in the ovary,2) the functions of gynecologic hormones such as
gonadotropins and ovarian steroids, 3) the analysis /etiology of endometriosis, adenomyosis and fibroma
and so on.

References published in 2021
1. Katagiri Y, Jwa SC, Kuwahara A, Iwasa T, Ono
M, Kato K, et al. Assisted reproductive
technology in Japan: A summary report for 2019by the Ethics Committee of the Japan Society of
Obstetrics and Gynecology. Reprod Med Biol.
2021 Dec 14;21(1):e12434.
2. Kanda R, Miyagawa Y, Wada-Hiraike O, Hiraike
H, Nagasaka K, Ryo E, et al. Ulipristal acetate
simultaneously provokes antiproliferative andproinflammatory responses in endometrial cancer
cells. Heliyon. 2021 Dec 29;8(1).
3. Kuji S, Harada M, Yoshioka N, Kajiyama H,
Satoh T, Mikami M, et al. Survival andreproductive outcomes after fertility-sparing
surgery performed for borderline epithelial
ovarian tumor in Japanese adolescents and young
adults: Results of a retrospective nationwide

184

study. J Obstet Gynaecol Res. 2022 Mar;48(3):806-816.
4. Harada T, Osuga Y, Suzuki Y, Fujisawa M, Fukui
M, Kitawaki J. Relugolix, an oral gonadotropinreleasing hormone receptor antagonist, reduces
endometriosis-associated pain compared withleuprorelin in Japanese women: a phase 3,
randomized, double-blind, noninferiority study.
Fertil Steril. 2022 Mar;117(3):583-592.
5. Fukui Y, Hirota Y, Aikawa S, Ishizawa C, Iida R,
Kaku T, et al. Uterine Receptivity is Reflected by
LIF Expression in the Cervix. Reprod Sci. 2022
May;29(5):1457-1462.
6. Ono Y, Kawakita T, Yoshino O, Sato E, Kano K,
Ohba M, et al. Sphingosine 1-Phosphate (S1P) in
the Peritoneal Fluid Skews M2 Macrophage andContributes to the Development of Endometriosis.
Biomedicines. 2021 Oct 22;9(11):1519.
7. Ono M, Matsumoto K, Boku N, Fujii N, TsuchidaY, Furui T, et al. Indications for fertility
preservation not included in the 2017 Japan
Society of Clinical Oncology Guideline for
Fertility Preservation in Pediatric, Adolescent,and Young Adult Patients treated with gonadal
toxicity, including benign diseases. Int J Clin
Oncol. 2022 Feb;27(2):301-309.
8. Kusamoto A, Harada M, Azhary JMK, Kunitomi
C, Nose E, Koike H, et al. Temporal relationshipbetween alterations in the gut microbiome andthe development of polycystic ovary syndromelike phenotypes in prenatally androgenized
female mice. FASEB J. 2021 Nov;35(11)9. Satake E, Koga K, Takamura M, Izumi G,
Elsherbini M, Taguchi A, et al. The roles ofpolymorphonuclear myeloid-derived suppressor
cells in endometriosis. J Reprod Immunol. 2021
Nov;148:103371.
10. Shimamoto K, Hirano M, Wada-Hiraike O, Goto
R, Osuga Y. Examining the association between
menstrual symptoms and health-related quality oflife among working women in Japan using theEQ-5D. BMC Womens Health. 2021 Sep 7;21(1):325.
11. Fukui Y, Hirota Y, Saito-Fujita T, Aikawa S,
Hiraoka T, Kaku T, et al. Uterine Epithelial LIF
Receptors Contribute to Implantation Chamber

Formationin
Blastocyst
Attachment.
Endocrinology. 2021 Nov 1;162(11)12. Harada M, Osuga Y. Does polycystic ovary
syndrome independently affect oncologic andreproductive outcomes in patients withendometrial cancer receiving fertility-sparing
treatment? J Gynecol Oncol. 2021 Sep;32(5):e80.
13. Osuga Y, Seki Y, Tanimoto M, Kusumoto T,
Kudou K, Terakawa N. Relugolix, an oral
gonadotropin-releasing hormone (GnRH) receptor antagonist, in women with endometriosisassociated pain: phase 2 safety and efficacy
24-week results. BMC Womens Health. 2021 Jun
21;21(1):250.
14. Osuga Y, Nakano Y, Yamauchi Y, Murakawa H.
Phase III long-term study to evaluate the efficacy
and safety of ulipristal acetate in Japanesepatients with uterine fibroids. J Obstet Gynaecol
Res. 2021 Sep;47(9):3269-3278.
15. Fukuoka K, Hirata T, Koga K, Morimoto C,
Osuga Y. An Unusual Imaging Appearance of
Peritoneal Endometriosis Presenting a Pelvic
Multilocular Tumor. J Minim Invasive Gynecol.
2021 Sep;28(9):1561-1563.
16. Ota K, Tsutsumi O, Mitani T, Morimoto Y,
Tanaka A, Osuga Y, et al. Reproductive medical
providers' behaviors, considerations, and plans
for fertility treatments during the COVID-19
pandemic in Japan: A nationwide web-based
survey. Reprod Med Biol. 2021 Mar 22;20(2):123-132.
17. Osuga Y, Nakano Y, Yamauchi Y, Takanashi M.
Ulipristal acetate compared with leuprorelin
acetate for Japanese women with symptomatic
uterine fibroids: a phase III randomized
controlled trial.Fertil Steril. 2021 Jul;116(1):189197.
18. Harada M, Takahashi N, Azhary JM, Kunitomi C,
Fujii T, Osuga Y. Endoplasmic reticulum stress: a
key regulator of the follicular microenvironment
in the ovary. Mol Hum Reprod. 2021 Jan 22;27(1):
19. Makabe T, Koga K, Nagabukuro H, Asada M,
Satake E, Taguchi A, et al.Use of selective PGE2
receptor antagonists on human endometriotic
stromal cells and peritoneal macrophages. Mol
Hum Reprod. 2021 Jan 22;27(1)185

20. Kunitomi C, Harada M, Kusamoto A, Azhary JM,
Nose E, Koike H, et al. Induction of arylhydrocarbon receptor in granulosa cells byendoplasmic reticulum stress contributes topathology of polycystic ovary syndrome. Mol
Hum Reprod. 2021 Feb 27;27(3)21. Ishihara O, Jwa SC, Kuwahara A, Katagiri Y,
Kuwabara Y, Hamatani T, et al. Assisted
reproductive technology in Japan: A summary
report for 2018 by the Ethics Committee of theJapan Society of Obstetrics and Gynecology.
Reprod Med Biol. 2020 Nov 20;20(1):3-12.
22. Ono Y, Yoshino O, Hiraoka T, Sato E, Furue A,
Nawaz A, et al. CD206+ macrophage is anaccelerator of endometriotic-like lesion via
promoting angiogenesis in the endometriosis
mouse model. Sci Rep. 2021 Jan 13;11(1):853
23. Akaeda S, Hirota Y, Fukui Y, Aikawa S,
Shimizu-Hirota R, Kaku T, et al. Retinoblastoma
protein promotes uterine epithelial cell cycle
arrest and necroptosis for embryo invasion.
EMBO Rep. 2021 Feb 3;22(2):24. Hirata T, Koga K, Taniguchi F, Takazawa N,
Honda R, Tanaka T, et al. National survey of
bladder endometriosis cases in Japan. J Obstet
Gynaecol Res. 2021 Apr;47(4):1451-1461.
25. Haraguchi H, Harada M, Kashimada K,
Horikawa R, Sakakibara H, Shozu M, et al.
National survey of primary amenorrhea andrelevant conditions in Japan. J Obstet Gynaecol
Res. 2021 Feb;47(2):774-777.
26. Halimi SA, Maeda D, Ushiku-Shinozaki A, Goto
A, Oda K, Osuga Y, et al. Comprehensive
immunohistochemical
analysisofthegastrointestinal and Müllerian phenotypes of 139
ovarian mucinous cystadenomas. Hum Pathol.
2021 Mar;109:21-30.
27. Tsuchida Y, Harada M, Shoda H, Goto A, Suzuki
N, Murashima A, et al. Fertility preservation inpatients receiving gonadotoxic therapies for
systemic autoimmune diseases in Japan. Mod
Rheumatol. 2021 Sep;31(5):1004-1009
28. Okamoto S, Fujii N, Yoshioka N, Harada M,
Tanimoto M, Maeda Y, et al. Nationwide surveyof fertility preservation in patients withhematological malignancies in Japan. Int J Clin
Oncol. 2021 Feb;26(2):438-442.

29. Osuga Y, Seki Y, Tanimoto M, Kusumoto T,
Kudou K, Terakawa N. Relugolix, an oral
gonadotropin-releasing
hormonereceptor
antagonist, reduces endometriosis-associated pain
in a dose-response manner: a randomized,
double-blind, placebo-controlled study. Fertil
Steril. 2021 Feb;115(2):397-405.
30. Sanada Y, Harada M, Kunitomi C, Kanatani M,
Izumi G, Hirata T, et al. A Japanese nationwide
survey on the cryopreservation of embryos,
oocytes and ovarian tissue for cancer patients. J
Obstet Gynaecol Res. 2019 Oct;45(10):20212028.

186

Department of
Gynecologic Oncology
Associate Professor
Yutaka Osuga, Yasushi Hirota

Homepagehttps://www.gynecology-htu.jp/

Organization
The Department of Gynecologic Oncology isorganized by one professor and one associate
professors, being directed practically by Professor
Yutaka Osuga, the Department of Obstetrics andGynecology. The staff members are taking part inclinical and research activities as well as teachingactivities.

Activities
In the clinical activities, more than 150 patientswith gynecological cancer and more than one
thousand patients with benign gynecological diseases
are treated in our department every year. Appropriate
combinations of surgical treatment, chemotherapy andradiotherapy have been chosen according to thepatients’ conditions, and favorable clinical outcomes
have been achieved. Minimally-invasive surgery isfrequently employed in the treatment of benign andgynecological tumors and genital organ malformation.
We take charge of more than 400 cases of endoscopic
gynecological surgery including robotically-assisted
laparoscopic surgery annually. We also employ theclinical trials of JCOG (Japan Clinical Oncology
Group) and JGOG (Japanese Gynecologic Oncology
Group) as well as the single-institution clinical trials.
Advanced treatment performed in our department is asfollows:(1) Cancer genomic medicine (Genetic tests of thehereditary gynecologic cancers)(2) Radical trachelectomy for women of childbearing
age with early cervical cancer(3) Laparoscopic sacralcolpopexy for pelvic organ
prolapse(4) Adenomyomectomy
Based on our knowledge and experience in thisfield, we also perform clinical, translational and basic
research energetically. Our department focuses on thepathogenesis and the pathophysiology of malignant
gynecological diseases such as cervical, endometrial
and ovarian cancers, and benign diseases such as
endometriosis and adenomyosis. Our ongoing projects
are as follows:(1) Establishment of new therapeutic approachtargeting histone modification enzymes ingynecological malignancies(2) Search for epigenomic biomarkers using deeplearning in gynecological malignancies(3) Development of an automated hysteroscopic
diagnosis system for gynecological diseases using
deep learning(4) Control mechanism of genome stability ingynecological malignancies(5) Search for novel biomarkers using germline andsomatic variants in gynecological cancers(6) Genomic approach to elucidate the pathogenesis
and pathophysiology of endometriosis andadenomyosis(7) Immunological aspects in the pathophysiology ofendometriosis

References published in 2021
(1) Kaneko S, Mitsuyama T, Shiraishi K, Ikawa N,
Shozu K, Dozen A, Machino H, Asada K,

187

(2)

(3)

(4)

(5)

(6)

Komatsu M, Kukita A, Sone K, Yoshida H,
Motoi N, Hayami S, Yoneoka Y, Kato T, Kohno
T, Natsume T, Keudell GV, Saloura V, Yamaue
H, Hamamoto R. Genome-Wide Chromatin
Analysis of FFPE Tissues Using a Dual-Arm
Robot with Clinical Potential. Cancers (Basel).
2021 Apr 28;13(9):2126. doi: 10.3390/cancers
13092126.
Furusawa A, Takekuma M, Mori K, Usami T,
Kondo E, Nishio S, Nishino K, Miyamoto Y,
Yoshimura R, Watanabe M, Mikami M, Enomoto
T. A randomized phase III trial of adjuvant
chemotherapy
versusconcurrent
chemoradiotherapy for postoperative cervical cancer:
Japanese Gynecologic Oncology Group study(JGOG1082). Int J Gynecol Cancer. 2021 Apr;
31(4):623-626. doi: 10.1136/ijgc-2020-002344.
Ishikawa M, Shibata T, Iwata T, Nishio S,
Takada T, Suzuki S, Horie K, Kudaka W,
Kagabu M, Tanikawa M, Kitagawa R, Takekuma
M, Kobayashi H, Yaegashi N; Japan ClinicalOncology Group. A randomized phase II/III
trial of conventional paclitaxel and carboplatinwith or without bevacizumab versus dose-dense
paclitaxel and carboplatin with or without
bevacizumab, in stage IVB, recurrent, or
persistent cervical carcinoma (JCOG1311):
Primary analysis.
Gynecol Oncol. 2021
Aug;162(2):292-298.
doi:
10.1016/j.ygyno.2021.05.007.
Tanikawa M, Oda K. [ . Current Status andIssues of Genome Medicine in Gynecological
Oncology].
Gan To Kagaku Ryoho. 2021
Feb;48(2):195-199.
Konno Y, Asano H, Shikama A, Aoki D,
Tanikawa M, Oki A, Horie K, Mitsuhashi A,
Kikuchi A, Tokunaga H, Terao Y, Satoh T,
Ushijima K, Ishikawa M, Yaegashi N, Watari H.
Lymphadenectomy issues in endometrial cancer.
J Gynecol Oncol. 2021 Mar;32(2):e25. doi: 10.
3802/jgo.2021.32.e25.
Yamaguchi K, Matsumoto Y, Suzuki R, Nishida
H, Omata D, Inaba H, Kukita A, Tanikawa M,
Sone K, Oda K, Osuga Y, Maruyama K, Fujii T.
Enhanced antitumor activity of combined lipid
bubble ultrasound and anticancer drugs in
gynecological cervical cancers. Cancer Sci.

2021 Jun;112(6):2493-2503. doi: 10.1111/cas.
14907.
(7) Sone K, Inoue F, Taguchi A, Hinata M, Ikemura
M, Miyamoto Y, Michihiro T, Ohno T, Iriyama T,
Mori-Uchino M, Tsuruga T, Mishima M, Osuga
Y. A case of difficult-to-diagnose non-invasive
papillary squamous cell carcinoma of the uterine
cervix infected with human papilloma virus 6: A
diagnostic pitfall. Clin Case Rep. 2021 Oct 4;9(10):e04905. doi: 10.1002/ccr3.4905.
(8) Nara K, Taguchi A, Tojima Y, Miyamoto Y,
Tanikawa M, Sone K, Mori M, Tsuruga T,
Yamamoto T, Takenaka R, Takada T, Osuga Y,
Suzuki H.
History of whole pelvis plus
para-aortic radiation is a risk factor associatedwith febrile neutropenia during chemotherapy forrecurrent cervical cancer. Int J Clin Oncol.
2021
Sep;26(9):1759-1766.
doi:
10.1007/s10147-021-01950-8.
(9) Sone K, Toyohara Y, Taguchi A, Miyamoto Y,
Tanikawa M, Uchino-Mori M, Iriyama T,
Tsuruga T, Osuga Y. Application of artificial
intelligence in gynecologic malignancies: A
review.
J Obstet Gynaecol Res. 2021
Aug;47(8):2577-2585. doi: 10.1111/jog.14818.
(10) Ikeda Y, Adachi K, Tomio K, Eguchi-Kojima S,
Tsuruga T, Uchino-Mori M, Taguchi A, Komatsu
A, Nagamatsu T, Oda K, Kawana-Tachikawa A,
Uemura Y, Igimi S, Osuga Y, Fujii T, Kawana K.
A
Placebo-Controlled,
Double-Blind
Randomized (Phase IIB) Trial of Oral
Administration with HPV16 E7-Expressing
Lactobacillus, GLBL101c, for the Treatment ofCervical Intraepithelial Neoplasia Grade 2(CIN2). Vaccines (Basel). 2021 Apr 1; 9(4):329.
doi: 10.3390/vaccines9040329(11) Takahashi Y, Sone K, Noda K, Yoshida K,
Toyohara Y, Kato K, Inoue F, Kukita A, Taguchi
A, Nishida H, Miyamoto Y, Tanikawa M,
Tsuruga T, Iriyama T, Nagasaka K, Matsumoto Y,
Hirota Y, Hiraike-Wada O, Oda K, Maruyama M,
Osuga Y, Fujii T.
Automated system fordiagnosing endometrial cancer by adopting
deep-learning technology in hysteroscopy.
PLoS One. 2021 Mar 31;16(3):e0248526. doi:
10.1371/journal.pone.0248526.

188(12) Inoue F, Sone K, Toyohara Y, Takahashi Y,
Kukita A, Hara A, Taguchi A, Tanikawa M,
Tsuruga T, Osuga Y. Targeting Epigenetic
Regulators for Endometrial Cancer Therapy: Its
Molecular Biology and Potential ClinicalApplications. Int J Mol Sci. 2021 Feb 25;22(5):2305. doi: 10.3390/ijms22052305.
(13) Taguchi A, Nakajima Y, Furusawa A, Yoshino Y,
Takao M, Kashiyama T, Kino N, Yasugi T.
High neutrophil-to-lymphocyte ratio is apredictor of short-term survival for patients withrecurrent cervical cancer after radiation-based
therapy.
J Obstet Gynaecol Res. 2021
May;47(5):1862-1870. doi: 10.1111/jog.14712.
(14) Kawata A, Taguchi A, Baba S, Miyamoto Y,
Tanikawa M, Sone K, Tsuruga T, Mori M, Oda K,
Kawana K, Osuga Y, Fujii T.
A low
preoperative albumin-to-globulin ratio is anegative prognostic factor in patients withsurgically treated cervical cancer. Int J Clin
Oncol. 2021 May;26(5):980-985. doi: 10.1007/
s10147-021-01861-8.

189

Department of Perinatal Medicine
Associate Professor
Kaori Koga

Homepagehttps://www.obstetrics-htu.jp/english/

Organization
The Department of Perinatal Medicine is organized
by one professor and one associate professor, being
directed practically by Professor Tomoyuki Fujii, thechairman of the Department of Obstetrics andGynecology. All the staff members take part in bothclinical and research activities, as well as teachingactivities, with about 20 associates of the Universityof Tokyo Hospital. From the clinical aspect, they are
engaged with in-patient and out-patient care including
the activities in the delivery units.

Activities
Clinical service for perinatology in the Universityof Tokyo Hospital consists of out-patient clinic andthe delivery unit. [See Delivery Unit of the Universityof Tokyo Hospital]
With the advance of the techniques for prenatal
diagnosis of pathological pregnancies and congenital
malformations, the area of fetal medicine is spreading.
Intensive scrutiny using ultrasonography makes it
possible to clarify background causes of fetal growth
restriction. New techniques for genetic analysis havebeen introduced into prenatal diagnosis. The
perinatologists and medical engineering team in our
department are working on clinical research to clarify
the pathoetiology of preterm birth and preeclampsia.
Perineal ultrasound is a new approach for assessing
labor progress. Using this technique, our challenge isto establish novel clinical approach for precise andobjective evaluation of labor progression which cancontribute to safer labor management. Pregnancy
complicated with adenomyosis is associated withvariety of adverse perinatal events, such as second
trimester miscarriage, preeclampsia, and placental
malposition. Our mission is to establish optimal

clinical management which improves perinatal
outcomes for both the mother and the neonate.
Recurrent pregnancy loss (RPL) is a condition inwhich a woman has two or more clinical pregnancy
losses. Our department has been providing a “special
clinic for RPL”. About 150 new couples with RPLvisit us every year. Underlying causes of RPL are
identifiedbyscreening
tests.
Anatomical,
chromosomal, hormonal, biological, and autoimmune
factors can trigger RPL. For RPL women with
autoimmune factors, especially with antiphospholipid
antibodies, anti-coagulation therapy using heparin andlow dose aspirin is performed. For low risk group, lowdose aspirin is administered. Causative factor is notdetectable in half of the women with RPL. Supportive
care rather than pharmacological intervention isimportant for those women. In our clinic, mental
stress in RPL women is evaluated using K6 scale. We
are investigating the relationship between their mental
status and the outcome in the subsequent pregnancy.
After a renewal of the inpatient’s wards forobstetrics and NICU/GCU/PICU in 2019, the newperinatal medical center restarted as one of the largest
facility in Japan and is accommodated with full
capacity to treat with all maternal and fetal diseases.
We are proud to provide advanced medical care forevery patient.

References published in 2021
1.

Matsui H, Iriyama T, Sayama S, Inaoka N,
Suzuki K, Yoshikawa M, Ichinose M, Sone K,
Kumasawa K, Nagamatsu T, Fujisawa T, Naguro
I, Ichijo H, Fujii T, Osuga Y. Elevated placental

190

histone H3K4 methylation via upregulated
histone methyltransferases SETD1A and SMYD3
in preeclampsia and its possible involvement in
hypoxia-induced pathophysiological process.
Placenta. 2021 Nov; 115:60-69.
2. Oda H, Nagamatsu T, Cabral H, Miyazaki T,
Iriyama T, Kawana K, Fujii T, Osuga Y.
Thrombomodulin promotes placental function by
up-regulating placental growth factor via
inhibition of high-mobility-group box 1 andhypoxia-inducible factor 1α. Placenta. 2021 Aug;
111:1-9.
3. Toshimitsu M, Iriyama T, Sayama S, Suzuki K,
Kakiuchi S, Ichinose M, Seyama T, Sone K,
Kumasawa K, Nagamatsu T, Fujii T, Osuga Y. A
Fetus with Imperforate Anus Developing
Pulmonary Hypoplasia Triggered by Transient
Urethral Obstruction. Case Rep Obstet Gynecol.
2021 May: 9950578.
4. Oda H, Nagamatsu T, Schust DJ, Cabral H,
Miyazaki T, Iriyama T, Kawana K, Osuga Y,
Fujii
T.
Recombinant
Thrombomodulin
Attenuates Preeclamptic Symptoms by Inhibiting
High-Mobility Group Box 1 in Mice.
Endocrinology. 2021 Apr 1;162(4)5. Akiba N, Iriyama T, Nakayama T, Seyama T,
Sayama S, Kumasawa K, Komatsu A, Yabe S,
Nagamatsu
T,
Osuga
Y,
Fujii
T.
Ultrasonographic vascularity assessment forpredicting future severe hemorrhage in retained
products of conception after second-trimester
abortion.J Matern Fetal Neonatal Med. 2021 Feb;
34(4):562-568.
6. Shitara R, Iriyama T, Sayama S, Takeda N,
Nagamatsu T, Osuga Y, Fujii T. Postpartum
Stanford type B aortic dissection in a woman
with Loeys-Dietz syndrome who underwent aprophylactic aortic root replacement before
conception: A case report. Taiwan J Obstet
Gynecol. 2021 Jan;60(1):145-147.
7. Ohkuchi A, Saito S, Yamamoto T, Minakami H,
Masuyama H, Kumasawa K, Yoshimatsu J,
Nagamatsu T, Dietl A, Grill S, Hund M.
Short-term prediction of preeclampsia using thesFlt-1/PlGF ratio: a subanalysis of pregnant
Japanese women from the PROGNOSIS Asia
study. Hypertens Res. 2021 Jul;44(7):813-821.

8.

Azuma K, Okubo A, Suzuki T, Igarashi N,
Nomura Y, Soga H, Murata H, Fujino R, Ogawa
A, Matsui H, Nagamatsu T, Iriyama T, Asaoka R,
Inoue T, Maruyama-Inoue M, Kadonosono K,
Obata R. Assessment of the choroidal structure inpregnant women in the first trimester. Sci Rep.
2021 Feb 25;11(1):4629.
9. Shibuya M, Matsui H, Sasagawa T, Nagamatsu T.
A simple detection method for the serum sFLT1
protein in preeclampsia. Sci Rep. 2021 Oct 18;
11(1):20613.
10. Shindo R, Aoki S, Misumi T, Nakanishi S,
Umazume T, Nagamatsu T, Masuyama H, Itakura
A, Ikeda T; Japan Society of Obstetrics andGynecology Perinatal Committee. Spontaneous
labor curve based on a retrospective multi-center
study in Japan. J Obstet Gynaecol Res. 2021 Dec;
47(12):4263-4269.
11. Nomoto M, Kotani T, Miki R, Ushida T, Imai K,
Iitani Y, Tano S, Wang J, Moriyama Y,
Kobayashi T, Mimura N, Iriyama T, Kikkawa F,
Kajiyama H. Upregulation of ENDOU in
cytotrophoblasts from placenta complicated withpreeclampsia and fetal growth restriction. J Clin
Biochem Nutr. 2021 Nov;69(3):280-285.
12. Ishigami D, Koizumi S, Ishikawa O, Toshimitsu
M, Iriyama T, Miyawaki S, Saito N.
Embolization of dural arteriovenous fistuladuring twin pregnancy - A case report andliterature review. Interv Neuroradiol. 2021 Oct;27(5):658-662.
13. Suzuki T, Inoue T, Igarashi N, Agata C, Okubo A,
Nagamatsu T, Iriyama T, Maruyama-Inoue M,
Yanagi Y, Kadonosono K, Asaoka R, Azuma K,
Obata R. Association between serum soluble
fms-like tyrosine kinase-1 and the central
choroidal thickness during pregnancy: aprospective study. BMJ Open Ophthalmol. 2021
Nov 5;6(1):e000888.
14. Sasagawa T, Nagamatsu T, Yanagisawa M, Fujii
T, Shibuya M. Hypoxia-inducible factor-1β isessential for upregulation of the hypoxia-induced
FLT1 gene in placental trophoblasts. Mol Hum
Reprod. 2021 Nov 27;27(12)15. Suzuki T, Inoue T, Igarashi N, Agata C, Okubo A,
Nagamatsu T, Iriyama T, Maruyama-Inoue M,
Yanagi Y, Kadonosono K, Asaoka R, Azuma K,

191

16.

17.

18.

19.

20.

Obata R. Association between serum soluble
fms-like tyrosine kinase-1 and the central
choroidal thickness during pregnancy: aprospective study. BMJ Open Ophthalmol. 2021
Nov 5;6(1):e000888.
Samejima T, Yamashita T, Takeda Y, Adachi T.
Identifying the associated factors with onset ofpreterm PROM compared with term PROM - A
retrospective cross-sectional study. Taiwan J
Obstet Gynecol. 2021 Jul;60(4):653-657.
Samejima T, Yamashita T, Takeda Y, Adachi T.
Low antithrombin levels accompanied by highurine protein/creatinine ratios are predictive ofacute kidney injury among CS patients withpreeclampsia. J Matern Fetal Neonatal Med. 2021
May;34(10):1550-1556.
Ichinose M, Suzuki N, Wang T, Kobayashi H,
Vrbanac L, Ng JQ, Wright JA, Lannagan TRM,
Gieniec KA, Lewis M, Ando R, Enomoto A,
Koblar S, Thomas P, Worthley DL, Woods SL:
The BMP antagonist gremlin1 contributes to thedevelopment of cortical excitatory neurons,
motor balance and fear responses. Development.
2021 Jul 15;148(14)Ichinose M, Suzuki N, Wang T, Wright JA,
Lannagan TRM, Vrbanac L, Kobayashi H,
Gieniec KA, Ng JQ, Hayakawa Y, GarcíaGallastegui P, Monsalve EM, Bauer SR, Laborda
J, García-Ramírez JJ, Ibarretxe G, Worthley DL,
Woods SL. Stromal DLK1 promotes proliferationand inhibits differentiation of the intestinal
epithelium during development. Am J Physiol
Gastrointest Liver Physiol. 2021 Apr 1;320(4):G506-G520.
Ichinose M, Suzuki N, Wang T, Wright JA,
Lannagan TRM, Vrbanac L, Kobayashi H,
Gieniec K, Ng JQ, Ihara S, Mavrangelos C,
Hayakawa Y, Hughes P, Worthley DL, Woods
SL.
Delineating
proinflammatory
microenvironmental signals by ex vivo modeling of theimmature intestinal stroma. Sci Rep Mar 30;
11(1):7200.

192

Department of Molecular andCellular Reproductive Medicine
Professor
Yutaka Osuga

Associate Professor
Osamu Hiraike

Homepage https://www.gynecology-htu.jp/
Organization
The Department of Molecular and Cellular
Reproductive Medicine is organized by one professor
and one associate professor.

Activities
Our department mainly aims to investigate thereproductive endocrinology, and molecular biologicalmethods are utilized to accomplish this purpose. Basic
researches are currently performed and we reportmany interesting findings annualy. We specificallyfocus on the role of inflammation and transcription
machinery in these issues. Senescence and aging
process are also extensively investigated.
1) The mechanism of folliculogenesis, follicularatresia and intrafollicular microenvironment in theovary.
2) The physiological functions of sex steroid
hormones and gonadotoropins.
3) The molecular mechanisms of endometriosis.
4) The molecular mechanisms of uterine fibroid andadenomyosis.
5) The effects of aging and cellular senescence on the
reproductive system.
In clinical section, we have an out-patient clinic for
infertility, gynecological endocrine disorders andgenetic counseling. We also perform minimallyinvasive surgery for benign gynecological diseases
including endometriosis, uterine fibroid, adenomyosis,

infertility, and pelvic organ prolapse. More than 90%of surgery cases for benign gynecological disorders
are operated using endoscope, and we deal with morethan 400 cases annually.
In accordance with the notion of life stage specificapproches, we also manage patients complaining
primary/secondary amenorrhea, infertility, dysmenorrhea, heavy menstrual bleeding, and climactirium.
Osteoporosis in their 10’s to 20’s and perimenopausal
age could be a heavy burden for patinets and we havealready established the primary care system for these
women. Numerous number of female athletes refer toour clinic as well.

References published in 2021
1.

2.

3.

Katagiri Y, Jwa SC, Kuwahara A, Iwasa T, Ono
M, Kato K, et al. Assisted reproductive
technology in Japan: A summary report for 2019by the Ethics Committee of the Japan Society of
Obstetrics and Gynecology. Reprod Med Biol.
2021 Dec 14;21(1):e12434.
Kanda R, Miyagawa Y, Wada-Hiraike O, Hiraike
H, Nagasaka K, Ryo E, et al. Ulipristal acetate
simultaneously provokes antiproliferative andproinflammatory responses in endometrial cancer
cells. Heliyon. 2021 Dec 29;8(1).
Kuji S, Harada M, Yoshioka N, Kajiyama H,
Satoh T, Mikami M, et al. Survival andreproductive outcomes after fertility-sparing
surgery performed for borderline epithelial

193

ovarian tumor in Japanese adolescents and young
adults: Results of a retrospective nationwide
study. J Obstet Gynaecol Res. 2022 Mar;48(3):806-816.
4. Harada T, Osuga Y, Suzuki Y, Fujisawa M, Fukui
M, Kitawaki J. Relugolix, an oral gonadotropinreleasing hormone receptor antagonist, reduces
endometriosis-associated pain compared withleuprorelin in Japanese women: a phase 3,
randomized, double-blind, noninferiority study.
Fertil Steril. 2022 Mar;117(3):583-592.
5. Fukui Y, Hirota Y, Aikawa S, Ishizawa C, Iida R,
Kaku T, et al. Uterine Receptivity is Reflected by
LIF Expression in the Cervix. Reprod Sci. 2022
May;29(5):1457-1462.
6. Ono Y, Kawakita T, Yoshino O, Sato E, Kano K,
Ohba M, et al. Sphingosine 1-Phosphate (S1P) in
the Peritoneal Fluid Skews M2 Macrophage andContributes to the Development of Endometriosis.
Biomedicines. 2021 Oct 22;9(11):1519.
7. Ono M, Matsumoto K, Boku N, Fujii N, TsuchidaY, Furui T, et al. Indications for fertility
preservation not included in the 2017 Japan
Society of Clinical Oncology Guideline for
Fertility Preservation in Pediatric, Adolescent,and Young Adult Patients treated with gonadal
toxicity, including benign diseases. Int J Clin
Oncol. 2022 Feb;27(2):301-309.
8. Kusamoto A, Harada M, Azhary JMK, Kunitomi
C, Nose E, Koike H, et al. Temporal relationshipbetween alterations in the gut microbiome andthe development of polycystic ovary syndromelike phenotypes in prenatally androgenized
female mice. FASEB J. 2021 Nov;35(11)9. Satake E, Koga K, Takamura M, Izumi G,
Elsherbini M, Taguchi A, et al. The roles ofpolymorphonuclear myeloid-derived suppressor
cells in endometriosis. J Reprod Immunol. 2021
Nov;148:103371.
10. Shimamoto K, Hirano M, Wada-Hiraike O, Goto
R, Osuga Y. Examining the association between
menstrual symptoms and health-related quality oflife among working women in Japan using theEQ-5D. BMC Womens Health. 2021 Sep 7;21(1):325.
11. Fukui Y, Hirota Y, Saito-Fujita T, Aikawa S,
Hiraoka T, Kaku T, et al. Uterine Epithelial LIF

12.

13.

14.

15.

16.

17.

18.

19.

Receptors Contribute to Implantation Chamber
Formationin
Blastocyst
Attachment.
Endocrinology. 2021 Nov 1;162(11)Harada M, Osuga Y. Does polycystic ovary
syndrome independently affect oncologic andreproductive outcomes in patients withendometrial cancer receiving fertility-sparing
treatment? J Gynecol Oncol. 2021 Sep;32(5):e80.
Osuga Y, Seki Y, Tanimoto M, Kusumoto T,
Kudou K, Terakawa N. Relugolix, an oral
gonadotropin-releasing
hormone(GnRH)
receptor
antagonist,
in
women
with
endometriosis-associated pain: phase 2 safety andefficacy 24-week results. BMC Womens Health.
2021 Jun 21;21(1):250.
Osuga Y, Nakano Y, Yamauchi Y, Murakawa H.
Phase III long-term study to evaluate the efficacy
and safety of ulipristal acetate in Japanesepatients with uterine fibroids. J Obstet Gynaecol
Res. 2021 Sep;47(9):3269-3278.
Fukuoka K, Hirata T, Koga K, Morimoto C,
Osuga Y. An Unusual Imaging Appearance of
Peritoneal Endometriosis Presenting a Pelvic
Multilocular Tumor. J Minim Invasive Gynecol.
2021 Sep;28(9):1561-1563.
Ota K, Tsutsumi O, Mitani T, Morimoto Y,
Tanaka A, Osuga Y, et al. Reproductive medical
providers' behaviors, considerations, and plans
for fertility treatments during the COVID-19
pandemic in Japan: A nationwide web-based
survey. Reprod Med Biol. 2021 Mar 22;20(2):123-132.
Osuga Y, Nakano Y, Yamauchi Y, Takanashi M.
Ulipristal acetate compared with leuprorelin
acetate for Japanese women with symptomatic
uterine fibroids: a phase III randomized
controlled trial.Fertil Steril. 2021 Jul;116(1):189197.
Harada M, Takahashi N, Azhary JM, Kunitomi C,
Fujii T, Osuga Y. Endoplasmic reticulum stress: a
key regulator of the follicular microenvironment
in the ovary. Mol Hum Reprod. 2021 Jan 22;27(1):
Makabe T, Koga K, Nagabukuro H, Asada M,
Satake E, Taguchi A, et al.Use of selective PGE2
receptor antagonists on human endometriotic

194

20.

21.

22.

23.

24.

25.

26.

27.

28.

stromal cells and peritoneal macrophages. Mol
Hum Reprod. 2021 Jan 22;27(1)Kunitomi C, Harada M, Kusamoto A, Azhary JM,
Nose E, Koike H, et al. Induction of arylhydrocarbon receptor in granulosa cells byendoplasmic reticulum stress contributes topathology of polycystic ovary syndrome. Mol
Hum Reprod. 2021 Feb 27;27(3)Ishihara O, Jwa SC, Kuwahara A, Katagiri Y,
Kuwabara Y, Hamatani T, et al. Assisted
reproductive technology in Japan: A summary
report for 2018 by the Ethics Committee of theJapan Society of Obstetrics and Gynecology.
Reprod Med Biol. 2020 Nov 20;20(1):3-12.
Ono Y, Yoshino O, Hiraoka T, Sato E, Furue A,
Nawaz A, et al. CD206+ macrophage is anaccelerator of endometriotic-like lesion via
promoting angiogenesis in the endometriosis
mouse model. Sci Rep. 2021 Jan 13;11(1):853
Akaeda S, Hirota Y, Fukui Y, Aikawa S, ShimizuHirota R, Kaku T, et al. Retinoblastoma protein
promotes uterine epithelial cell cycle arrest andnecroptosis for embryo invasion. EMBO Rep.
2021 Feb 3;22(2):Hirata T, Koga K, Taniguchi F, Takazawa N,
Honda R, Tanaka T, et al. National survey of
bladder endometriosis cases in Japan. J Obstet
Gynaecol Res. 2021 Apr;47(4):1451-1461.
Haraguchi H, Harada M, Kashimada K,
Horikawa R, Sakakibara H, Shozu M, et al.
National survey of primary amenorrhea andrelevant conditions in Japan. J Obstet Gynaecol
Res. 2021 Feb;47(2):774-777.
Halimi SA, Maeda D, Ushiku-Shinozaki A, Goto
A, Oda K, Osuga Y, et al. Comprehensive
immunohistochemical analysis of the gastrointestinal and Müllerian phenotypes of 139
ovarian mucinous cystadenomas. Hum Pathol.
2021 Mar;109:21-30.
Tsuchida Y, Harada M, Shoda H, Goto A, Suzuki
N, Murashima A, et al. Fertility preservation inpatients receiving gonadotoxic therapies for
systemic autoimmune diseases in Japan. Mod
Rheumatol. 2021 Sep;31(5):1004-1009
Okamoto S, Fujii N, Yoshioka N, Harada M,
Tanimoto M, Maeda Y, et al. Nationwide surveyof fertility preservation in patients withhematological malignancies in Japan. Int J Clin
Oncol. 2021 Feb;26(2):438-442.
29. Osuga Y, Seki Y, Tanimoto M, Kusumoto T,
Kudou K, Terakawa N. Relugolix, an oral
gonadotropin-releasing
hormonereceptor
antagonist, reduces endometriosis-associated pain
in a dose-response manner: a randomized,
double-blind, placebo-controlled study. Fertil
Steril. 2021 Feb;115(2):397-405.
30. Sanada Y, Harada M, Kunitomi C, Kanatani M,
Izumi G, Hirata T, et al. A Japanese nationwide
survey on the cryopreservation of embryos,
oocytes and ovarian tissue for cancer patients. J
Obstet Gynaecol Res. 2019 Oct;45(10):20212028.

Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

196

Department of Pediatrics,
Department of Developmental
Pediatrics
Professor
Motohiro Kato, M.D., Ph.D.
Naoto Takahashi, M.D., Ph.D. (Department of Pediatric and Neonatal Intensive Care Unit)

Associate Professor
Yutaka Harita, M.D., Ph.D., Hikoro Matsui M.D., Ph.D.

Lecturer
Ryo Inuzuka, M.D., PhD., Shoichiro Kanda, M.D.,Ph.D., Kohei Kashima, M.D.,Ph.D.
(Department of Maternal, Fetal and Neonatal Medicine)

Project Lecturer
Atsushi Sato, M.D.,Ph.D., Yuko Kajiho, M.D.,Ph.D., Akiko Kinumaki, M.D.,Ph.D.

Research Associate
Takako Matsuoka, M.D.,Ph.D., Konomi Shimoda, M.D., Shunpei Uchino, M.D.,Ph.D.,
Takanobu Inoue, M.D.,Ph.D., Yoshihiko Shitara, , M.D., Takeo Mukai, M.D.,Ph.D., Atsushi
Ito, M.D.,Ph.D., Kentaro Watanabe, M.D.,Ph.D., Yu Tanaka, M.D.,Ph.D., Mieko Maezawa,
M.D., Yoshiko Nakano, M.D., Kenichiro Hayashi, M.D., Miki Sugimoto, M.D., Masahiro
Sekiguchi, M.D.,Ph.D., Hiroyuki Tanaka, M.D.,Ph.D., Yu Kakimoto, M.D., Hidetoshi Ohta,
M.D., Chie Takahashi, M.D., Kaname Uchida, M.D., Go Kimoto, M.D., Moe Hidaka, M.D.,
Koji Hirohata, M.D., Akiharu Omori, M.D., Yosuke Ogawa, M.D., Kazuhiro Shiraga, M.D.,
Shota Kato, M.D., Yuriko Katayama, M.D., Yui Ozawa, M.D., Takashi Kuze, M.D., Hitomi
Masuda M.D., Mami Kobayashi, M.D., Kaname Sato, M.D.
(As of March 31, 2022)

Homepage

http://square.umin.ac.jp/ped/

Introduction and Organization
The former Department of Pediatrics developed
into the Department of Pediatrics and Department ofDevelopmental Pediatrics, which comprise subgroupsof the Group of Reproductive, Developmental andAging Medicines, Graduate School of Medicine, The
University of Tokyo.
Our staff consists of 2 professors, 2 associate
professors, 3 lecturers, 3 project lecturers, 34 research
associates on March 31, 2022.

197

The outpatient clinic of our department is on thesecond floor of the outpatient clinic building. We treat
patients at the Pediatric Medical Center in theinpatient building. The offices are on the second andthird floors of the East Research Building.
Our laboratories are also located on the seventh
floor of the Clinical Research Building Center and on
the second and third floors of the East Research
Building.

Clinical activities
The outpatient pediatric clinics cover a large part ofpediatric disorders; hematology / oncology,
cardiology, neurology, nephrology, endocrinology,
and neonatology. Additionally, patients with genetics,
pulmonology, and allergology / immunology arefollowed by part-time physicians who cover eachfield.
In cooperation with Department of Family Nursing,
we have been managing two clinics for supporting thepatients by nurses and other health care professionals,“Post-transplantation
follow-up
clinic”
and“Transitional care clinic”. Both clinics offer thepatients opportunities to discuss their diseases without
their parents, aiming for attaining self-management
regarding their disease and health care.
We also follows up with patients after discharge
from the hospital in an outpatient clinic and provides
medical care that meets the needs of patients and theirfamilies based on collaboration with local medical
institutions.
We have specialized clinics that cover all fields ofpediatric disorders. Children or neonates stay in thePediatric Medical Center and receive appropriate
treatments. Since June, 2019, we have increased
activity of intensive care and developed the section of
Pediatric and Perinatal Intensive Care including
neonatal intensive care unit (NICU) and the pediatricintensive care unit (PICU). PICU is one of the tertiary
centers of pediatric emergency covering the easternpart of Tokyo. There are 12 beds in the PICU and ourinstitution is going to fulfill the designation as achildren's hospital affiliated with the university
hospital. The PICU provides advanced monitoring
and comprehensive care for children with critical
illness or injury, as well as those with complex

medical needs. Our highly skilled team has
specialized training and equipment to quickly assess
and treat children with serious or life-threatening
medical issues. Our PICUs provide critical care to any
child who needs it. We care for children who face awide range of severe and complex medical conditions,
including severe infections, single or multi-organsystem failure, traumatic injuries, such as burns andinjuries to the head, chest and abdomen, respiratory
failure and severe asthma attacks, recovery fromcomplex orthopedic, neurologic and general surgeries,
as well as organ transplants.
There are 21 beds in the NICU and 36 beds in thegrowing care unit (GCU). In the NICU/GCU, we aretaking care of many high-risk infants which comprisesmall premature babies weighing less than 500g andnewborns with congenital disorders requiring invasive
interventions (e.g. congenital heart disease,gastrointestinal malformation). Our team have manywell-trained staffs, and we provide high-quality
specialized medical care as one of the representative
perinatal centers of Tokyo, by collaborating withobstetricians, pediatric cardiologists, cardiac surgeons,pediatric surgeons, ophthalmologists, neurosurgeons,etc. Moreover, we facilitate family-centered care bycollaborating with co-medical staffs.
In the general ward of the Pediatric Medical Center,
we treat a variety of patients with diseases, such ashematological/oncological disorders, cardiac disorders,
neuromuscular disorders, immunological/allergic
disorders, renal and urinary tract diseases,
endocrinological disorders, metabolic disorders, andpsychosomatic diseases are admitted to the wards. In
addition, we provide comprehensive medical care forpatients with systemic diseases or biopsychosocial
problems in cooperation with related departments. The
hospital was also accredited as a provider of chimericantigen receptor T-cell therapy.
At the Department of Pediatrics, we pay for all
treatment; McDonald House housing for families with
options for larger accommodations with low-pricestaying. Our on-site school allows patients to keep
up with their school program back home. We offer
numerous other services for our families, including
psychosocial help for caregivers and siblings copingwith a child’s diseases diagnosis; child life specialists,
translation help for those who do not speak Japanese

198

as a first language, Niko-niko Volunteer and much
more.
Many patients need to stay longer in the hospital.
We provide an official in-hospital school 'Kodama
Gakkyu' where patients receive education and havethe opportunity to communicate with other patientsand their family members. Members of the 'Niko-nikoVolunteer', an official volunteer group in the hospital,
visit the pediatric ward every weekday to play withpatients and help their mothers, providing enormous
comfort to both patients and their mothers. Various
activities are scheduled for patients in the hospital. All
the residents, fellows and nurses participate in these
activities. We have two child care specialists in thepediatric ward.

Teaching activities
Systematic lectures about general and highly
specialized pediatrics are provided for the secondgrade students with staff members and visiting
lecturers. The third-grade students receive two weeks
of practical training in hospital wards (M3 clinicalclerkship). During the bedside training period,
students are as-signed to each clinical team and arein charge of in-patients, taking their medical history,
examining them, recording their hospital records,
and observing various examinations. During theperiod, specific pediatric lectures are provided
including about pediatric neurology, nephrology,transfusion,
endocrinology,
neonatology,
hematology/oncology, emergency resuscitation, andso on. The practice will be interactive, combining
face-to-face and online under current social situation.
We also offer an elective clinical clerkship course forthose who are especially interested in pediatrics intheir fourth grade. Students are assigned to a ward ona month-to-month basis, allowing them to experiencehighly specialized training tailored to their individual
needs. Observing the outpatient clinic and learning
the normal development of children are another goal
for the fourth-grade students (M4 clinical clerkship).
On the last day of each clerkship, the professor
evaluates the students’ achievements. We also
provide a variety of online learning contents throughthe educational website of department of pe-diatrics(https://sites.google.com/d/1EXrB_7WZBlLzw9Soo

Y3a4bm2MnNe_PbJ/p/1h3YBWtv_FcpVQy98dkUB
fN1-4bdlkIRg/edit).

Research activities
Our departments have the following research groups:
nephrology,
hematology/oncology,
neurology,
cardiology, endocrinology/metabolism, immunology/
allergy, and neonatology. We also have multidisciplinary research groups and laboratories such ascell biology, genetic molecular biology, andepidemiology. The main research topics during thelast year are listed below.
Hematology/Oncology group:
Our division has performed whole-genome
sequencing (WGS), whole-exome sequencing (WES)
and RNA-Sequencing with more than 500 pediatriccancer patients to investigate the underlying
mechanism of pediatric hematologic diseases andcancer such as leukemia, rhabdomyosarcoma andneuroblastoma.
Nephrology group:
Our aim is to reveal the molecular mechanism ofpediatric kidney diseases. We identified novel
causative mutations on several proteinuric diseases
including pediatric nephrotic syndrome and congenital
anomalies of the kidney and urinary tract. We also
analyze the pathogenic mechanism of nail-patella
syndrome.
Endocrinology and Metabolism group:
We are analyzing genes and mechanisms involved in
endocrinology and metabolic diseases. We analyze themolecular biological mechanisms using model
animals and iPS cells. We are also studying pathways
in growth plate cartilage in relation to pediatricgrowth and development, including single-cell RNA
analysis using mouse and human specimens.
Cardiology group:To
revealthemolecular
mechanismofcardiomyopathy,
weperformed
genome-wide
association studies and generated an animal model for
cardiomyopathy.
Additionally,
we
perform
hemodynamic analysis for patients with congenital
heart disease using clinical imaging modalities.
Neurology Group:
Using mouse models of genetic disorders (e.g.,tuberous sclerosis) and environmental burdens (e.g.,

199

in utero exposure to valproic acid), the pathogenetic
mechanism of neuro-developmental disorders isinvestigated. A clinical trial of valganciclovir, anantiviral drug for cytomegalovirus infection has been
conducted for infants with congenital cytomegalovirus
infection, which showed therapeutic efficacy ofvalganciclovir for recovering hearing difficulty.
Neonatology group:
Epigenetic changes in cord blood and postnatal
peripheral blood of preterm and SGA infants areinvestigated using epigenome-wide methylation
analysis. The influence of gut microbiome on neonatal
immune function and nutritional status is also
investigated. Cytokine profiles have been investigatedin order to elucidate pathophysiology of several
diseases in perinatal period. Molecular mechanism of
neonatal immune tolerance is also an importantresearch topic in the group.
PICU group:
The Pediatric Intensive Care Unit (PICU) groupconducts biological response research using
physiological data of critical illnesses, such as heart
rate variability analysis, quantification of neuralreflexes, evaluation of cerebral blood flow regulation,and pulse wave analysis, as well as medical safety
research using DWH, development of digitalfundoscopes, and echo imaging research of
postoperative hemodynamics.

3.

4.

5.

Selected References
1.

2.

Kotajima-Murakami H, Hagihara H, Sato A,
Hagino Y, Tanaka M, Katoh Y, Nishito Y,
Takamatsu Y, Uchino S, Miyakawa T, Ikeda K.
Exposure to GABAA Receptor Antagonist
Picrotoxin in Pregnant Mice Causes Autism-Like
Behaviors and Aberrant Gene Expression in
Offspring. Front Psychiatry. 2022 Feb 3;13:821354. doi: 10.3389/fpsyt.2022.821354.
Morioka I, Kakei Y, Omori T, Nozu K, Fujioka
K, Takahashi N, Yoshikawa T, Moriuchi H, Ito Y,
Oka A; Japanese Congenital Cytomegalovirus
Study Group. Oral Valganciclovir Therapy in
Infants Aged ≤2 Months with Congenital
Cytomegalovirus Disease: A Multicenter, SingleArm, Open-Label Clinical Trial in Japan. J Clin
Med. 2022 Jun 21;11(13):3582.

6.

7.

Yoshida M, Nakabayashi K, Yang W, SatoOtsubo A, Tsujimoto SI, Ogata-Kawata H, Kawai
T, Ishiwata K, Sakamoto M, Okamura K,
Yoshida K, Shirai R, Osumi T, Moriyama T,
Nishii R, Takahashi H, Kiyotani C, Shioda Y,
Terashima K, Ishimaru S, Yuza Y, Takagi M,
Arakawa Y, Kinoshita A, Hino M, Imamura T,
Hasegawa D, Nakazawa Y, Okuya M, Kakuda H,
Takasugi N, Inoue A, Ohki K, Yoshioka T, Ito S,
Tomizawa D, Koh K, Matsumoto K, Sanada M,
Kiyokawa N, Ohara A, Ogawa S, Manabe A,
Niwa A, Hata K, Yang JJ, Kato M. NUDT15
variants confer high incidence of second
malignancies
inchildrenwith
acutelymphoblastic leukemia. Blood Adv 2021 Dec
14;5(23):5420-5428.
Nishii R, Mizuno T, Rehling D, Smith C, Clark
BL, Zhao X, Brown SA, Smart B, Moriyama T,
Yamada Y, Ichinohe T, Onizuka M, Atsuta Y,
Yang L, Yang W, Thomas PG, Stenmark P, Kato
M, Yang JJ. NUDT15 polymorphism influences
the metabolism and therapeutic effects ofacyclovir and ganciclovir. Nat Commun. 2021
Jul 7;12(1):4181.
Takeda N, Inuzuka R, Yagi H, Morita H, Ando
M, Yamauchi H, Taniguchi Y, Porto KJ, Kanaya
T, Ishiura H, Mitsui J, Tsuji S, Toda T, Ono M,
Komuro I. Clinical Impact of Copy Number
Variation on the Genetic Diagnosis of Syndromic
Aortopathies. Circ Genom Precis Med. 2021
Aug;14(4)Nii M, Inuzuka R, Inai K, Shimada E, Shinohara
T, Kogiso T, Ono H, Ootsuki S, Kurita Y,
Takeda A, Hirono K, Takei K, Yasukochi S,
Yoshikawa T, Furutani Y, Shinozaki T,
Matsuyama Y, Senzaki H, Tokushige K,
Nakanishi T. Incidence and Expected Probabilityof Liver Cirrhosis and Hepatocellular Carcinoma
After Fontan Operation. Circulation. 2021 Dec
21;144(25):2043-2045.
Tomita H, Kim SH, Inuzuka R, Matsui H,
Tachimori H, Kobayashi T, Kato A, Fujii T,
Haishima Y, Okamoto Y, Sakoda H. Stent
Implantation for Congenital Heart Diseases inJapan - Comprehensive Analysis From theJapanese Society of Congenital Interventional
Cardiology Registry. Circ J. 2021 Aug 25;85(9):

200

8.

9.

1517-1524.
Shitara Y, Kakiuchi S, Mukai T, Kashima K,
Kato M, Takahashi N. Case Report: Treatment ofExtremely Preterm Infants With Birthweight
Below 300 g: Case Series. Front Pediatr. 2021
Dec 6;9:758683.
Shitara Y, Watanabe E, Takahashi N. A term
infant with fetal giant meconium hydrocele
caused by meconium peritonitis. Pediatr
Neonatol. 2021 Jul;62(4):445-446.

201

Department of Pediatric Surgery
Professor
Jun Fujishiro, M.D., Ph.D.

Lecturer
Mariko Yoshida, M.D., Ph.D.

Shinya Takazawa, M.D., Ph.D.

Research Associate
Toshiko Takezoe, M.D., Ph.D.

Keisuke Suzuki, M.D., Ph.D.

Akinori Ichinose, M.D.

Takashi Tsutsuno, M.D.

Homepagepedsurg.umin.jp/

History and organization
In 1951, a pediatric surgical team was established in
the Department of Second Surgery. Subsequently, in
1961, a pediatric surgical research team, which would
eventually research diaphragmatic hernia, was established, with a chief, Dr. Ishida, appointed by Professor
Kimoto.
In 1971, the department was authorized to be the firstclinical Department of Pediatric Surgery at a national
university.
A pediatric intensive care unit was founded by Prof.
Ishida in 1973, and the construction of a ward capableof accommodating mainly pediatric surgical patientswas completed.
Assistant Prof. Saito assumed office as the first
director of this clinical department.
Dr. Sumio Saito became a professor of pediatricsurgery in 1983. Professor Saito has enthusiastically
performed clinical studies on operation techniques andthe use of biliary atresia.
Dr. Toshio Nakajo took office as a professor in 1985.
Prof. Nakajo has developed original operative
procedures, such as a radical operation for umbilicalhernia, and an anti-reflex valve for biliary atresia.
These original operative procedures have since been
inherited by other pediatric surgeons as Nakajo
methods.
Our department was authorized as the Department ofPediatric Surgery of Kyusyu University by the
Ministry of Education in 1989.
Dr. Yoshiaki Tsuchida assumed the role of Professor in1990 and published many highly regarded articles,
mainly concerning neuroblastoma and Wilm’s tumor,
based on his research and clinical work.
In 1995, the department was reorganized as the
Department of Reproductive, Developmental andAging Science, Pediatric Science and PediatricSurgery, due to a university policy for the graduate
school.
In 1997, Dr. Kohei Hashizume became a professor in
the Department of Pediatric Surgery. He started
performing living-related partial liver transplantation(LRPLT) for children with Professor Makuuchi in the
Department of Second Surgery.
Dr. Tadashi Iwanaka became the sixth professor in
August 2006. He engaged in clinical and research
activity on pediatric minimally invasive surgery, andretired in 2015. In 2016, Associate Prof. Jun Fujishiro
became a chief of the department of pediatric surgeryof Tokyo University. In 2019, Dr. Fujishiro promoted
to a professor from an associate professor.
The present staff includes one professor and chief, two
lecturers, four research associates and nine graduate
students. More than 20 members of our department
shoulder the clinical work as pediatric surgeons.

202

Clinical activities
Staff members higher than the level of research
associate take charge of the outpatient clinic from
Monday through Friday. The pediatric surgicaloutpatient clinic takes place in the same location as
the pediatric outpatient clinic, and we closelycooperate with pediatricians to diagnose and treat
patients. We also have specialized outpatient clinics,
liver and biliary tract clinics, a tumor clinic, and aspina bifida clinic. Recently, a second-opinion clinic
opened to provide careful detailed explanations, andthis has received a favorable reception.
Our ward was transferred to the hospital's second floorof B wing from the second floor of south of the A
wing on January 2018. Other pediatric surgicalpatients also are admitted to this ward. We have sevenbeds in the ward, and about 300 patients a year are
hospitalized within it. Most operation cases are
inguinal hernia, but we manage other cases such as
respiratory surgery disease, neonatal digestive organ
obstructions, infant malignant tumors such as Wilms'
tumor and neuroblastoma, biliary tract diseases suchas biliary tract dilatation and biliary atresia,
respiratory anomalies such as tracheal stenosis andlung cysts, gastrointestinal anomalies, and urologicaldisorders including hydronephrosis and vesicoureteral
reflux.
We work with other pediatric surgery teams at otherinstitutions who perform endoscopic surgery (laparoscopic surgery/thoracoscopic surgery). We havedeveloped an endoscopic surgery technique forpediatric diseases not covered by insurance, for cases
requiring advanced medical care. Furthermore, we
surgically manage seriously ill, mentally andphysically handicapped infants, as well as patientswith intractable nervous system diseases, to improvetheir quality of life, and we cooperate withpediatricians (neonatologists) to treat patients withprenatal diagnoses.

Education
We expose first and second year students to our dailyclinical work, as well as to our research work, during
the “Free Quarter” and “Research Lab Visit” courses.
These students are guided to be concerned withclinical areas, and are in charge of parts of various

research projects. The students hold a results
announcement party at the end of training. For M2
students, general pediatric surgery and neonatal
surgery instruction is provided by the associate
professor and the lecturer.
An education program is also provided for M3 and M4
students for five days.
The bedside education of pediatric surgery consists ofparticipation in clinical conferences, attendance at
operations, and small group lectures concerning
neonatal surgery; pediatric surgical oncology;
pediatric hepatobiliary surgery; and pediatricemergency medicine, which includes the practice ofperforming cardiac massage and intra-tracheal
intubation using mannequins for practice.
Additionally, we take charge of the core surgicalcurriculum during the “super-rotation” postgraduate
training. We offer a program in which each resident
can learn basic knowledge about pediatric surgicaldisease and surgery and hemodynamic and respiratory
evaluation, as well as basic surgical techniques andpatient management strategies.

Research activities
There are two pillers of the research projects in ourgroup recently. One is the elucidation of the course
and the development of new therapy of pediatric
surgical disease using proteome analysis. The other isthe clinical research using NCD (National Clinical
Database). The results of these studies has been
already announced in some articles.
We concentrate power on the study for thepathophysiology of biliary atresia and approach itfrom many aspects including an animal model,
disease-specific iPS cells, and the search of thebiomarkers.
In addition, We now goes a research of the organ
regeneration using in-body tissue architecture andstart diaphragm and the trachea and gastrointestinal
reproduction from bio-sheet or bio-tube technology.

References(1) Fujishiro J, Fujiogi M, Hirahara N, Terui K,
Okamoto T, Watanabe E, Ishimaru T, Miyata H:
Abdominal Drainage at Appendectomy forComplicatedAppendicitis
inChildren:

203

(2)

(3)

(4)

(5)

(6)

(7)

(8)

A Propensity-matched Comparative Study. Ann
Surg 274: e599-e604, 2021. doi: 10.1097/SLA.
0000000000003804.
Sunouchi T, Watanabe Y, Tomonaga K, Watanabe
E, Ichijo C, Hoshino N, Suzuki K, Fujishiro J:
Optimal treatment of pneumothorax inadolescents with Marfan syndrome. J Pediatr
Surg 56: 1103-1106, 2021. doi: 10.1016/j.
jpedsurg.2021.03.021.
Suzuki K, Komura M, Obana K, Komura H,
Inaki R, Fujishiro J, Suzuki K, Nakayama Y: A
new method of primary engineering of esophagus
using orthotopic in-body tissue architecture. J
Pediatr Surg 56: 1186-1191, 2021. doi: 10.1016/j.
jpedsurg.2021.03.025.
Fujishiro J, Watanabe E, Hirahara N, Terui K,
Tomita H, Ishimaru T, Miyata H: Laparoscopic
Versus Open Appendectomy for AcuteAppendicitis in Children: a Nationwide
Retrospective Study on Postoperative Outcomes.
J Gastrointest Surg 25: 1036-1044, 2021. doi:
10.1007/s11605-020-04544-3.
Konishi KI, Mizuochi T, Takei H, Yasuda R,
Sakaguchi H, Ishihara J, Takaki Y, Kinoshita M,
Hashizume N, Fukahori S, Shoji H, Miyano G,
Yoshimaru K, Matsuura T, Sanada Y, Tainaka T,
Uchida H, Kubo Y, Tanaka H, Sasaki H, Murai T,
Fujishiro J, Yamashita Y, Nio M, Nittono H,
Kimura A: A Japanese prospective multicenter
study of urinary oxysterols in biliary atresia. Sci
Rep 11: 4986, 2021. Doi: 10.1038/s41598-02184445-w.
Suzuki K, Fujishiro J, Ichijo C, Watanabe E,
Tomonaga K, Sunouchi T, Watanabe Y:
Prophylactic innominate artery transection toprevent tracheoinnominate artery fistula: aretrospective review of single institution
experiences. Pediatr Surg Int 37: 267-273, 2021.
doi: 10.1007/s00383-020-04792-z.
Shinya Takazawa, Akira Nishi, Tetsuya Ishimaru,
Masataka Takahashi, Tomohiro Sunouchi, Kenta
Kikuchi, Ryota Koyama: Face and constructvalidity assessment of training models forintestinal anastomosis in low-birth-weight
infants. Pediatr Surg Int 37: 1765-1772, 2021.
doi: 10.1007/s00383-021-04991-2.
Aiyoshi T, Masumoto K, Tanaka N, Sasaki T,

Chiba F, Ono K, Jimbo T, Urita Y, Shinkai T,
Takayasu H, Hitomi S: Optimal First-Line
Antibiotic Treatment for Pediatric ComplicatedAppendicitis Based on Peritoneal Fluid Culture.
Pediatr Gastroenterol Hepatol Nutr 24: 510-517,
2021(9) Kanako Omata, Noriki Okada, Go Miyahara,
Yuta Hirata, Yukihiro Sanada, Yasuharu Onishi,
Shinya Fukuda, Hideki Kumagai, Alan K Lefor,
Yasunaru Sakuma, Naohiro Sata: Peliosis Hepatis
in a Child with X-Linked Myotubular Myopathy
Treated with Living-Donor Liver Transplant: A
Case Report. Transplantation Proceeding 53:
1317-1321, 2021
(10) Ogawa S, Nishihara M, Nakanishi T, Maeda T,
Hirota S: A rare case of extraluminallypedunculated gastrointestinal stromal tumor withpostoperative metastasis to pancreas. J Surg Case
Rep 2021: rjab422, 2021
(11) C Ichijo, S Takami, K Suzuki, J Fujishiro, M
Watanabe: Retroperitoneal lymphatic malformation causing scrotal swelling a useful diagnostic
work-up with two-phase MRI to differentiate
from scrotal lymphatic malformation or
abdomino-scrotal hydrocele. JPS case reports, 64,
2021, 101701(12) Yamada K, Ishikawa T, Ohno E, Iida T, Suzuki H,
Uetsuki K, Yashika J, Yoshikawa, Takami H,
Inokawa Y, Uchida H, Kawashima H, Fujishiro
M: Double common bile duct associated withpancreaticobiliary maljunction. Nagoya Journalof Medical Science 83: 655-661, 2021
(13) Amano H, Shirota C, Tainaka T, Sumida W,
Yokota K, Makita S Takimoto A, Tanaka Y,
Hinoki A, Kawashima H, Uchida H: Latepostoperetive complication of congenital biliary
dilatation in pediatric patients: single-center
experience of managing complications for over
20 years. Surgery Today 37: 1675-1682, 2021
(14) Yohei Sanmoto, Tetsuya Ishimaru, Kentaro
Hyashi, Osamu Tomita, Koichi Oshima, Atsuko
Nakazawa, Katuyoshi Koh, Hiroshi Kawashima:
Scrlerosing angiomatoid nodukar transformetionin a child. Juounal of Peditric Surgery Case
Report. (2021). Doi:https//doi,org/10.1016/j.epsc.
2021.101836(15) Ishimaru T, Kawashima H, Hayashi K, Omata K,

204

Sanmoto Y, Inoue M: Laparoscopically assisted
anorectoplasty-Surgical procedures and outcomes: A literature review. Asian J Endosc Surg
14: 335-345, 2021
(16) Ishimaru T, Kawashima H, Hayashi K, Oiki H,
Omata K, Sanmoto Y, Inoue M: A Comparison of
Sexual Function in Male Patients with Anorectal
Malformations Between the Conventional andLaparoscopic Approaches. J Laparoendosc Adv
Surg Tech A 31: 1420-1423, 2021
(17) M Takahashi, Y Kanamori, T Kobayashi, M
Kobayashi, K Tsukamoto, S Yamagishi, R
Furugane, M Kutsukake, T Mori, M Kano, A
Yoneda, Y Ito, A Fujino: Triple duodenal
obstruction” complicated with intestinal malrotation and several cardiovascular malformations.
JPS case reports. 2021; 75: 102078.
(18) Sakamoto T, Fujiogi M, Matsui H, Fushimi K,
Yasunaga H: Comparing Perioperative Mortality
andMorbidityof
Minimally
Invasive
Esophagectomy Versus Open Esophagectomy for
Esophageal Cancer: A Nationwide Retrospective
Analysis. Ann Surg 274: 324-330, 2021. doi: 10.
1097/SLA.0000000000003500.
(19) Patregnani JT*, Fujiogi M*, Camargo CA,
Brooks BA, Hoptay CE, Mansbach JM, Teach SJ,
Freishtat RJ, Hasegawa K: Serum Soluble
Receptor for Advanced Glycation End Productsin Infants With Bronchiolitis: Associations With
Acute Severity and Recurrent Wheeze. Clin
Infect Dis 73: e2665-e2672, 2021. doi: 10.1093/
cid/ciaa1700. * J. T. P. and M. F. contributed
equally to this work(20) Fujiogi M, Camargo CA Jr, Raita Y, Zhu Z,
Celedón JC, Mansbach JM, Spergel JM,
Hasegawa K: Integrated associations of
nasopharyngeal and serum metabolome withbronchiolitis severity and asthma: A multicenterprospective cohort study. Pediatr Allergy
Immunol 32: 905-916, 2021. doi: 10.1111/pai.
13466.
(21) Fujiogi M, Camargo CA Jr, Raita Y, Toivonen L,
Freishtat RJ, Mansbach JM, Piedra PA,
Hasegawa
K:
Associationofendemic
coronaviruses with nasopharyngeal metabolome
and microbiota among infants with severe
bronchiolitis: a prospective multicenter study.

Pediatr Res 89: 1594-1597, 2021. doi: 10.1038/
s41390-020-01154-2.
(22) Hayashi K, Ishimaru T, Lee J, Hirai S, Ooke T,
Hosokawa T, Omata K, Sanmoto Y, Kakihara T,
Kawashima H: Identification of Appendicitis
Using Ultrasound with the Aid of Machine
Learning. J Laparoendosc Adv Surg Tech A. 2021
Nov 5. doi: 10.1089/lap.2021.0318.

Reproductive, Developmental andAging Sciences
3. Aging Sciences

206

Department of Geriatric Medicine
Department of Aging Research
Professor
Masahiro Akishita, MD, PhD.

Associate Professor
Sumito Ogawa, MD, PhD.

Lecturer
Taro Kojima, MD, PhD.

Masaki Ishii, MD, PhD.

Kotaro Azuma, MD, PhD.

Research Associate
Yumi Kameyama, MD, PhD.

Mitsutaka Yakabe, MD, PhD.

Michiko Nanao, MD, PhD.

Yoshitaka Kase, MD, PhD.

Yoko Yamada, MD, PhD.

Homepage http://www.h.u-tokyo.ac.jp/geriatrics/
Introduction and Organization
The Department of Geriatric Medicine wasestablished in 1962, as the first geriatric department
in Japan.
Since older adult patients tend to have multiple
organ disorders, these patients should be taken cared
as a whole from multiple points of view. In addition,
symptoms, signs and responses to the treatment in
the older adult patients could be quite different fromthe younger counterparts. Specific knowledge on thephysiological and metabolic changes with aging isnecessary when these older adult patients are treated.
Quality of life of the patients is another point of viewwhich should be emphasized. The department
belongs to the division of Internal Medicine. The
staff includes one professor, one associate professor,
three lecturers, and five assistant professors.
Our sub-specialty includes pneumology, cardiology,
neurology, hematology, endocrinology, and bonemetabolism, besides geriatrics. The main objective ofour research is to elucidate the pathophysiology of

aging process and to understand older adult patientsfrom viewpoints of basic aging science using
molecular biology technique and clinical aspects
using the recent advancement of technology andgeriatric assessment.

Clinical activities
The Department of Geriatric Medicine specialized
in the diagnosis and treatment of dementia, frailty,
geriatric syndrome and polypharmacy in older adults.
We provide Comprehensive Geriatric Assessment(CGA) and manages multiple diseases in older
patients who have physical and/or mental disabilities.
The Department of Geriatric Medicine belongs toInternal Medicine. In the outpatient setting, we
accept patients every day in the three outpatient
wards (#207, #208, and #209). We also provide
specialized outpatient treatment on dementia, frailty
and sarcopenia, osteoporosis, chronic obstructive
pulmonary disease (COPD), and sleep apnea. As a‘second opinion outpatient clinic’, we accept

207

consultation on polypharmacy. Since 2003, we
provide ‘women’s general outpatient clinic’ byfemale physicians for treatment of gender sensitive
conditions. In the inpatient setting, we have ourproper wards in the 13th floor of our hospital, andgenerally accept approximately 10 patients who aretreated by junior, senior, and chief residents of ourstaff. Older patients often suffer from a variety of
diseases and clinical problems. To deal with them,our department forms multi-disciplinary teams
composed of geriatricians and related specialists
such as psychologists and pharmacists to provide
comprehensive medical care.

Education
Clinical education is provided for fifth and sixthyear medical students on a man-to-man basis with afaculty staff member. During the period, the student
studies one or two cases, through which the student
learns the techniques of interrogation and physicalexamination, interpretation of laboratory tests, andactual medical procedures. Interpretation of theresults of geriatric assessment is studied throughlectures in a case-oriented manner with an emphasis
placed on the multidisciplinary basis of geriatricpatients.

Research
The purpose of our study is to fulfill the society
where older adult people enjoy healthy independent
life. We are engaged in studies on various topics
including epidemiological studies, clinical studies,and basic molecular studies to contribute to our
research aim. Our main research themes are as
follows.
1) Research on the molecular mechanism ofvascular calcification
2) Regulation of vascular function by sex hormone
3) Molecular biology for the control of aging:
Association of vascular and neuronal senescence and the role of Sirt1
4) Molecular biology and treatment of sarcopenia5) Multicenter-investigation of the optimal treatment strategy for hypertension or lipid disorder in the older adult patients
6) Clinical study on metabolic syndrome in theolder adult patients
7) Biomarkers of dementia, caregiver’s stress andgeriatric syndromes8) Research on appropriate healthcare for theolder adult patients including pharmacotherapy9) Expression and regulation of nuclear receptors
in osteoblast and osteoclast10) Molecular mechanism under the treatment of
osteoporosis11) Genetic analysis of osteoporosis and osteoarthritis
12) Identification and functional analysis of thetarget gene networks associated with hormone
responsiveness in prostate and breast cancers13) Roles of nuclear receptors in age-relateddiseases and cancers14) Molecular mechanism of vitamin K function
and its roles in aging
15) Novel roles of antimicrobial peptide, defensin16) Adrenomedullin and airway hyperresponsiveness17) Klotho protein and vitamin D in lung18) Clinical investigation of sleep-related breathing
disorder19) Observational study on medical treatment/careprovided in the end-of-life stage of life20) Observational study on the outcome of frail
patients
21) Clinical study on the relationship between
metabolic diseases and pulmonary aging

Publications (Original Articles)
1.

2.

Akishita M, Suzuki S, Inoue H, Akao M, Atarashi
H, Ikeda T, Koretsune Y, Okumura K, Shimizu W,
Tsutsui H, Toyoda K, Hirayama A, Yasaka M,
Yamaguchi T, Teramukai S, Kimura T, Morishima
Y, Takita A, Yamashita T. Frailty and outcomes inolder adults with non-valvular atrial fibrillationfrom the ANAFIE registry. Arch Gerontol Geriatr.
2022 Jul-Aug;101:104661. doi: 10.1016/j.archger.
2022.104661.
Azuma K, Ikeda K, Suzuki T, Aogi K, HorieInoue K, Inoue S. TRIM47 activates NF-κB
signaling via PKC-ε/PKD3 stabilization andcontributes to endocrine therapy resistance inbreast cancer. Proc Natl Acad Sci U S A. 2021

208

3.

4.

5.

6.

7.

8.

9.

Aug
31;118(35):e2100784118.
doi:
10.1073/pnas.2100784118.
Azuma K, Osuka Y, Kojima N, Sasai H, Kim H,
Inoue S. Association of Vitamin K Insufficiency
With Cognitive Dysfunction in CommunityDwelling Older Adults. Front Nutr. 2022 Jan 31;
8:811831.
doi:10.3389/fnut.2021.811831.
eCollection 2021.
Cherbuin N, Iijima K, Kalula S, Malhotra R,
Rasmussen L, Chan A, Lafortune L, Harper S,
Zheng X, Lindeman D, Walsh E, Hussain R,
Burns R, Kristiansen M, Sugawara I, Son BK,
Tanaka T, Buckner S, Hoffman J, Combrinck M.
SOCIETAL NEED FOR INTERDISCIPLINARY
AGEINGRESEARCH
An
International
Association of Research Universities “Ageing,
Longevity, and Health” Stream (IARU-ALH)
position statement. Biomed Hub. 2021;6:42-47.
Fitriana I, Setiati S, Rizal EW, Istanti R, Rinaldi I,
Kojima T, Akishita M, Azwar MK. Malnutritionand depression as predictors for 30-day unplanned
readmission in older patient: a prospective cohort
study to develop 7-point scoring system. BMC
Geriatr. 2021;21(1):256.
Gong Q, Ishii M, Numata O, Xie W, Hirata T.
Utility of a shortened Hasegawa Dementia Scale
Revised questionnaire to rapidly screen anddiagnose Alzheimer's disease. Aging Med. 2021
Jun 8;4(2):109-114. doi: 10.1002/agm2.12152.
eCollection 2021.
Hamada S, Kojima T, Hattori Y, Maruoka H, Ishii
S, Okochi J, Akishita M. Use of psychotropic
drugs and drugs with anticholinergic properties
among residents with dementia in intermediatecare facilities for older adults in Japan: a cohort
study. BMJ Open. 2021;11(4):e045787.
Handa N, Mitsutake S, Ishizaki T, Nakabayashi T,
Akishita M, Tamiya N, Yoshie S, Iijima K.
Associations of coprescribed medications forchronic comorbid conditions in very old adults
with clinical dementia: a retrospective cohort
study using insurance claims data. BMJ Open.
2021;11:e043768. doi: 10.1136/bmjopen-2020043768. PMID: 34266835; PMCID: PMC8286766.
Iijima K, Arai H, Akishita M, Endo T, Ogasawara
K, Kashihara N, Hayashi K. Y, Yumura W,
Yokode M, Ouchi Y. Toward the development of

10.

11.

12.

13.

14.

15.

a vibrant, super-aged society: The future of
medicine and society in Japan, Geriatr Gerontol
Int. 2021.5 doi: 10.1111/ggi.14201
Iki M, FujimoriK, Nakatoh S, Tamaki J, Ishii S,
Okimoto N, Kamiya K, Ogawa S. Delayed
initiation of anti-osteoporosis medications
increases subsequent hip and vertebral fractures inpatients on long-term glucocorticoid therapy: anationwide health insurance claims database study
in Japan. Bone. 2022 Mar 26:116396. doi: 10.
1016/j.bone.2022.116396. Online ahead of print.
Iki M, FujimoriK, Nakatoh S, Tamaki J, Ishii S,
Okimoto N, Ogawa S. Guideline adherence byphysicians for management of glucocorticoidinduced osteoporosis in Japan: a nationwide healthinsurance claims database study. Osteoporosis Int.
2022 Jan 13. doi: 10.1007/s00198-021-06265-y.
Online ahead of print.
Ishii M, Yamaguchi Y, Hamaya H, Iwata Y,
Takada K, Ogawa S, Imura M, Akishita M.
Influence of oral health on frailty in patients with
type 2 diabetics aged 75 years or older. BMC
Geriatr. 2022 Feb 19;22(1):145. doi: 10.1186/
s12877-022-02841-x.
Ito T, Mori T, Takahashi H, Shimafuji N, Iijima K,
Yoshie S, Tamiya N. Prevention services via
public long-term care insurance can be effective
among a specific group of older adults in Japan.
BMC Health Services Research. 2021.5 21:531
https://doi.org/10.1186/s12913-021-06495-0
Iwasaki M, Ohara Y, Motokawa K, Hayakawa M,
Shirobe M, Edahiro A, Watanabe Y, Awata S,
Okamura T, Inagaki H, Sakuma N, Obuchi S,
Kawai H, Ejiri M, Ito K, Fujiwara Y, Kitamura A,
Nofuji Y, Abe T, Iijima K, Tanaka T, Son BK,
Shinkai S, Hirano H. Population-based reference
values for tongue pressure in Japanese older
adults: a pooled analysis with over 5,000
participants. J Prosthodont Res. 2022 Jan 27. doi:
10.2186/jpr.JPR_D_21_00272. Online ahead ofprint.
Jung HW, Lim WS, Cesari M, Auyeung TW,
Kojima T, Ga H, Cameron ID, Lim JY.
Challenges and Opportunities for Academic
Journals to Serve the Older Population in Western
Pacific Region. Ann Geriatr Med Res.
2021;25(4):231-236.

209

16. Kazawa K, Akishita M, Ikeda M, Iwatsubo T, Ishii
S. Experts' perception of support for people withdementia and their families during the COVID-19
pandemic. Geriatr Gerontol Int. 2022 Jan;22(1):26-31. doi: 10.1111/ggi.14307.
17. Kikuchi K, Tatebe T, Sudo Y, Yokoyama M,
Kidana K, Chiu YW, Takatori S, Arita M, Hori Y,
Tomita T. GPR120 signaling controls amyloid-βdegrading activity of matrix metalloproteinases.
Journal of Neuroscience. 2021;41(28):6173-6185.
18. Konno D, Ikegaya Y, Sasaki T. Weakrepresentation of awake/sleep states by local fieldpotentials in aged mice. bioRxiv. https://doi.org/
10.1101/2021.10.13.464191, 2021.
19. Konno D, Nishimoto S, Suzuki T, Ikegaya Y,
Matsumoto N. Multiple states in ongoing neuralactivity in the rat visual cortex. PLoS One. 16(8):e0256791., 2021.
20. Kunieda K, Fujishima I, Wakabayashi H, Ohno T,
Shigematsu T, Itoda M, Mori T, Machida N,
Ogawa S. Relationship between tongue pressure
and pharyngeal function using high resolution
manometry in older dysphagia patients withsarcopenia. Dysphargia. 36:33-40,2021.
21. Mori T, Wakabayashi H, Kishima M, Itoda M,
Fujishima I, Kunieda K, Ohno T, Shigematsu T,
Oshima F, Ogawa N, Nishioka S, Momosaki R,
Shimizu A, Saito Y, Yamada M, Ogawa S.
Association between inflammation and functional
outcome in patients with sarcopenic dysphagia. J.
Nutr Health Aging. 2022 Mar 30. Online ahead ofprint.
22. Mori T, Wakabayashi H, Ogawa N, Fujishima I,
Oshima F, Itoda M, Kunieda K, Shigematsu T,
Nishioka S, Tohara H, Yamada M, Ogawa S. The
mass of the geniohyoid muscle is associated withmaximum tongue pressure and tongue area inpatients with sarcopenic dysphagia. J. Nutr Health
Aging. 25:356-360,2021.
23. Nakamura M, Okajima K, Matsumoto Y, Tanaka
T, Iijima K, Nihei M. Effectiveness of Continuous
Grip Strength Measurement using Social Assistive
Robots on Older adults at Home. Journal of
Robotics and Mechatronics. 33(4):719-729. doi:
10.20965/jrm.2021.p0719
24. Nakatoh S, Fujimori K, Ishii S, Tamaki J,
Okimoto N, Ogawa S, Iki M. Insufficient increase

25.

26.

27.

28.

29.

30.

31.

in bone mineral density testing rates andpharmacotherapy after hip and vertebralfracture:
Analysis from National Database of Health
Insurance Claims in Japan. Arch Osteoporos.
16:130,2021.
Nakatoh S, Fujimori K, Ishii S, Tamaki J,
Okimoto N, Ogawa S, Iki M. Insufficientpersistence of and adherence to osteoporosis
pharmacotherapy: Analysis from National
Database of Health Insurance Claims in Japan.
Arch Osteoporos. 16:131,2021.
Nakatoh S, Fujimori K, Tamaki J, Okimoto N,
Ogawa S, Iki M. Insufficient persistence andadherence to osteoporosis pharmacotherapy inJapan. J Bone Miner Metab. 39:501-509,2021.
Ogawa N, Wakabayashi H, Mori T, Fujishima I,
Oshima F, Itoda M, Kunieda K , Shigematsu T,
Nishioka S, Tohara H, Ohno T, Nomoto A,
Shimizu A, Yamada M, Ogawa S. Digastricmuscle mass and intensity in older patients withsarcopenic dysphagia by ultrasonography. Geriatr.
Gerontol. Int. 21:14-19,2021.
Ogura T, Azuma K, Sato J, Kinowaki K,
Takayama KI, Takeiwa T, Kawabata H, Inoue S.
OCT1 Is a Poor Prognostic Factor for Breast
Cancer Patients and Promotes Cell Proliferation
via Inducing NCAPH. Int J Mol Sci. 2021 Oct
25;22(21):11505. doi: 10.3390/ijms222111505.
Ogura T, Azuma K, Takeiwa T, Sato J, Kinowaki
K, Ikeda K, Kawabata H, Inoue S. TRIM39 is apoor prognostic factor for patients with estrogen
receptor-positive breast cancer and promotes cell
cycle progression. Pathol Int. 2022 Feb;72(2):96106. doi: 10.1111/pin.13190.
Okamoto S, Ishii M, Hibi S, Akishita M,
Yamaguchi Y. Breathing irregularities before
sleep onset on polysomnography in patients withheart diseases. Sleep Breath. 2022 Jun;26(2):605612. doi: 10.1007/s11325-021-02403-2.
Sato J, Azuma K, Kinowaki K, Ikeda K, Ogura T,
Takazawa Y, Kawabata H, Kitagawa M, Inoue S.
Combined Use of Immunoreactivities of RIG-I
with Efp/TRIM25 for Predicting Prognosis ofPatients With Estrogen Receptor-positive Breast
Cancer. Clin Breast Cancer. 2021 Oct;21(5):399407.e2. doi: 10.1016/j.clbc.2020.12.001.

210

32. Sawada M, Kubota N, Sekine R, Yakabe M,
Kojima K, Umeda-Kameyama Y, Akishita M,
Ogawa S. Sex-related differences in the effects ofnutritional status and body composition on
functional disability in the elderly. PLOS ONE.
16:e0246276,2021.
33. Shibasaki K, Asahi T, Kuribayashi M, Tajima Y,
Marubayashi M, Iwama R, Akishita M, Ogawa S.
Potential prescribing omissions of antiosteoporosis drugs is associated with rehabilitation
outcomes after fragility fracture: Retrospective
cohort study. Geriatr Gerontol Int. 2021 May;
21(5):386-391. doi: 10.1111/ggi.14145.
34. Shirobe M, Watanabe Y, Tanaka T, Hirano H,
Kikutani T, Nakajo K, Sato T, Furuya J,
Minakuchi S, Iijima K. Effect of an Oral Frailty
Measures Program on Community-Dwelling
Elderly People: A Cluster-Randomized Controlled
Trial, Gerontology, 2022;68(4):377-386. doi:
10.1159/000516968.
35. Son BK, Akishita M, Yamanaka T, Toyoshima K,
Tanaka T, Suthutvoravut U, Iijima K. Association
between inflammatory potential of the diet andsarcopenia/its components in communitydwelling older Japanese men. Arch Gerontol
Geriatr.
2021;97:104481.
doi:
10.1016/j.archger.2021.104481.
36. Son BK, Imoto T, Inoue T, Nishimura T, Tanaka T,
Iijima K. Social detachment influenced muscle
mass and strength during the COVID-19 pandemic
in Japanese community-dwelling older women. J
Frailty Aging. 2022;11(2):231-235. doi: 10.14283/
jfa.2022.4.
37. Takamatsu K, Tanaka J, Katada R, Azuma K,
Takakura I, Aota K, Kamatani T, Shirota T, Inoue
S, Mishima K. Aging-associated stem/progenitor
cell dysfunction in the salivary glands of mice.
Exp Cell Res. 2021 Dec 1;409(1):112889. doi:
10.1016/j.yexcr.2021.112889.
38. Tamiya H, Yasunaga H, Hosoi T, Yamana H,
Matsui H, Fushimi K, Akishita M, Ogawa S.
Association between protein intake and mortality
in older patients receiving parenteral nutrition: aretrospective observational study. Am J Clin Nutr.
2021 Sep 28:nqab292. doi: 10.1093/ajcn/nqab292.
39. Tanaka T, Hirano H, Ohara Y, Nishimoto M,
Iijima K. Oral Frailty Index-8 in the risk

40.

41.

42.

43.

44.

45.

46.

assessment of new-onset oral frailty and functional
disability among community-dwelling older adults.
Arch Geront Geriatr. May-Jun 2021; 94: 104340.
doi: 10.1016/j.archger.2021.104340.
Tanaka T, Son BK, Iijima K. Poor healthbehaviorsamonghouseboundJapanese
community-dwelling older adults due to prolonged
self-restraint during the first COVID-19 pandemic:
A cross-sectional survey. J Frailty Aging 2022
Mar 17: 1–5. doi: 10.14283/ jfa.2022.20.
Tanaka T, Son BK, Lyu W, Iijima K. Impact ofsocial engagement on the development ofsarcopenia among community-dwelling older
adults: A Kashiwa cohort study. Geriatr Gerontol
Int. First published: 23 March 2022 https://doi.org/
10.1111/ggi.14372
Wakabayashi H, Kishima M, Itoda M, Fujishima I,
Kunieda K, Ohno T, Shigematsu T, Oshima F,
Mori T, Ogawa N, Nishioka S, Momosaki R,
Yamada M, Ogawa S. Prevalence of hoarsenessand its association with severity of dysphagia inpatients with sarcopenic dysphagia. J. Nutr Health
Aging. 26:266-271,2022.
Yakabe M, Shibasaki K, Hosoi T, Matsumoto S,
Hoshi K, Akishita M, Ogawa S. Effectiveness of
the Questionnaire for Medical Checkup of OldOld (QMCOO) to diagnose frailty in communitydwelling older adults. Geriatr Gerontol Int. 2022
Feb;22(2):127-131. doi: 10.1111/ggi.14328.
Yamada Y, Kojima T, Umeda-Kameyama Y,
Ogawa S, Eto M, Akishita M. Outcomes ofanticoagulant prescribing for older patients withatrial fibrillation depends on disability levelprovided by long-term care insurance. Arch
Gerontol Geriatr. 2021;96:104434.
Yamamoto H, Sazuka M, Ishibashi M, Nogimori
C, Takada K, Hamaya H, Yamada H, Awata.
DASC-21: a novel geriatric assessment fordiscriminating best supportive care in older
patients with inoperable advanced non-small celllung cancer. S.Jpn J Clin Oncol. 2021 Nov
1;51(11):1628-1635.
Yamamoto K, Akasaka H, Yasunobe Y, Shimizu
A, Nomoto K, Nagai K, Umegaki H, Akasaki Y,
Kojima T, Kozaki K, Kuzuya M, Ohishi M,
Akishita M, Takami Y, Rakugi H; Cherry Study
Group. Clinical characteristics of older adults with

211

hypertension
andunrecognizedcognitive
impairment. Hypertens Res. 2022;45:612-619. doi:
10.1038/s41440-022-00861-z.
47. Yamasaki T, Ikawa F, Hidaka T, Kuwabara M,
Matsuda S, Ozono I, Chiku M, Kitamura N,
Hamano T, Akishita M, Yamaguchi S, Tomimoto
H, Suzuki M. Prevalence and risk factors for brain
white matter changes in young and middle-aged
participants with Brain Dock (brain screening): a
registry database study and literature review.
Aging (Albany NY). 2021;13:9496-9509. doi:
10.18632/aging.202933.
48. Yoshizawa Y, Tanaka T, Takahashi K, Mahiro
Fujisaki-Sueda-Sakai M, Son BK, Iijima K.
Impact of Health Literacy on the Progression of
Frailty after Four Years among Communitydwelling Older Adults. Int J Env Res Pub Health.
2022;19(1): 394. doi: 10.3390/ijerph19010394.

Surgical Sciences
1. Surgery

213

Department of Thoracic Surgery
Professor
Nakajima, Jun

Associate Professor
Sato, Masaaki

Assistant Professor
Kitano, Kentaro
Konoeda, Chihiro
Nagano, Masaaki
Nakao, Keita
Ohtoshi, Ryota

Homepage http://cts.m.u-tokyo.ac.jp/
History
Study on thoracic surgery has begun since 1916
when symposium on lung surgery was held at annual
meeting of Japan Surgical Society. Clinical and basic
research of the thoracic surgery have been performed
since the prewar era at the Second department ofSurgery in this university. Professor Tsuduki, Masao
adopted the modified Coryllos’s thoracoplasty for thetreatment of the pulmonary tuberculosis in 1934. In
1942, they initiated thoracoscopy for the treatment of
the tuberculosis in our country. Before the World War
II, thoracic surgery had been performed underspontaneous breathing. Since 1950 safer anesthesia
with endotracheal intubation has been started in thisuniversity.
After the successful application of theantituberculosis drugs, surgical treatment of thethoracic malignant neoplasms was the major concernof the thoracic surgery. Case reports on surgicaltherapy for lung cancer has been present since 1920’s
in our country. In 1950, successful rightpneumonectomy for the primary lung cancer in thisuniversity was reported. Surgical therapy for the
mediastinal tumor was also begun in 1950. In 1954,

thymectomy through median sternotomy has begun inour department.
The Department of Cardiothoracic Surgery, The
University of Tokyo, was established on December 15,
1964, as the first department of this field along withthe cardiovascular surgery in the Japanese national
universities. It has played an internationally leadingrole and contributed to development of the field in ourcountry.
Professors and Chairs in the history of thedepartment are as follows: Kimoto, Seiji (1964.12.15~ 1968.3.31), Saigusa, Masahiro (1968.4.1 ~ 1981.
3.31), Asano, Ken-ichi (1981.4.1 ~ 1986.3.31), Furuse,
Akira (1986.4.1 ~ 1997.3.31) and Takamoto, Shinichi(1997.6.1 ~ 2009.3.31). Nakajima, Jun has taken overthe mission of the department since April 2011.
The Department of Cardiothoracic Surgery has been
divided into two departments, Department of
Cardiovascular Surgery and Department of Thoracic
Surgery in 1995.
The mission of the Department of Thoracic Surgery
is to cure the patients with diseases of the thoracic
organs through clinical works, basic and clinicalresearch, and education of the medical students,

214

postgraduates, and the surgical residents in our
university.

Clinical activities
Five staffs (Nakajima J, Sato M, Konoeda C,
Nagano M, and Nakao K), who are certificated as
members of the Japanese Board of General Thoracic
Surgery, are in charge of the Department of Thoracic
Surgery, University of Tokyo Hospital. They
specialize in surgical treatment for diseases of therespiratory and the mediastinal organs and the chest
wall, except for diseases of the esophagus andmammary glands.
Lung cancer is the leading cause of cancer death inour country: In 2020, Ministry of Health, Labour andWelfare documented that number of deaths frommalignant neoplasms was approximately 390 thousandout of 1.37 million total deaths in Japan. Of them, 76
thousand people were killed by malignant tracheal /pulmonary neoplasms. Surgical therapy for non-small
cell lung cancer (NSCLC) is thus the most important
issue in our department. By the practice of treatment
based on EBM, we perform basic training of thoracic
surgery for medical school students, graduate students
and clinical residents, as well as doing theprofessional education for training physicians whowish to become board-certified thoracic surgeons.
We have performed video-assisted thoracoscopy forthe diagnosis and treatment of the thoracic disease
with less surgical invasiveness since 1992 for safer
treatment of older patients with cardiovascular and/or
respiratory complications. We currently conduct a
standard surgery for clinical stage I non-small celllung cancer (NSCLC), that is, lobectomy andlymphadenectomy through thoracoscopy: Since 2015,
more than 90% of patients with NSCLC has
undergone thoracoscopic surgery in our department.
Research on less-invasiveness, oncological advantageof the thoracoscopic surgery is thus actively done.
Robot-assisted lobectomy/segmentectomy with Da
Vinci has applied to lung cancer patients since January
2021.
Pulmonary metastasis represents far advanced
malignant neoplasms of extrathoracic organs.
Pulmonary resection is an option for the treatment of
pulmonary metastasis. We actively perform pulmonary
resection through thoracoscopy on patients withpulmonary metastasis who are eligible for surgicaltherapy through thoracoscopy
Thymic epithelial neoplasms, such as thymoma andthymic carcinoma, show broad spectrum in the degreeof malignancy. They also associated with paraneoplastic syndromes, such as the myasthenia gravis
and the pure red cell aplasia. Although they are
relatively rare diseases, we sought to establish thestrategies on diagnosis and treatment of these diseases,
which are still yet to be determined, from our clinicalexperiences of more than 200 cases with the diseases
in our department. We are now actively participating a
multiinstitutional study on malignant thymic epithelial
neoplasms database led by Japanese Association forresearch on the thymus (JART).
Our hospital has been certified as a lung transplant
centers since March 2014. We have started to registerpatients who are eligible for lung transplantation. We
successfully performed the first case in Tokyo ofliving donor lung transplantation in April 2015: The
patients had suffered from the interstitial pneumonia.
In July 2015, we also succeeded in performing
brain-dead donor bilateral lung transplantation on apatient who had suffered from the pulmonary
hypertension. We have performed 113 lung transplants(including 24 living related donor lung transplantations) to date.

Academic education
Medical students in the fifth grade have three-weekprogram on the clinical training of the thoracic and the
cardiovascular surgery. They are also able toparticipate the clinical clerkship of the thoracic
surgery, an elective course for 4 weeks. We also
conduct a further research training for medical
students who like to study thoracic surgery. The
Department of Thoracic Surgery also offers the 4-year
postgraduate program for qualified surgeons who arewilling to specialize in the thoracic surgery. We have a
training program for surgeons who wish to be a boardcertified thoracic surgeon after 4-year residency.

Current research
Main subjects of current research at present include
basic and clinical studies on the malignant neoplasmsin the thorax including lung cancer and thymic tumors,and transplantation of the thoracic organs. The

215

following items are the major themes under researchin our department:(1) Minimally invasive surgeries for thoracic
malignant neoplasms.
(2) Navigation techniques for finding out small
pulmonary lesions through thoracoscopy.
(3) Imaging analysis of lung lung adenocarcinoma(4) Global analysis of oncogenes and suppressor
genes associated with lung cancer.
(5) Application of new fluorescent agents fordiagnosis of lung cancer.
(6) Immunotherapy for lung cancer.
(7) Analysis on mechanisms of acute or chronic
rejection of the allogeneic lung and trachea after
allogeneic transplantation.
(8) Regeneration of the acellularized allogeneic lungwith autologous cell seeding(9) Research on extracorporeal membranous oxygenation for bridge use to lung transplantation

Selected publications (2021)
1.

2.

3.

4.

Konoeda C, Sato M, Nagayama K, Nakajima J.
Simultaneous single lobar lung transplantationand contralateral lung volume reduction. Eur J
Cardiothorac Surg. 2021; 59(6):1342-1344
Shiono S, Matsutani N, Hashimoto H, Yamauchi
Y, Matsuguma H, Mun M, Kuroda H, Funai K,
Nakajima J, Kawamura M; Metastatic Lung
Tumor Study Group of Japan. Prospective studyof recurrence at the surgical margin after wedge
resection of pulmonary metastases. Gen Thorac
Cardiovasc Surg. 2021; 69(6):950-959
Hirata T, Koga K, Taniguchi F, Takazawa N,
Honda R, Tanaka T, Kurihara M, Nakajima J,
Yoshimura K, Kitade M, Narahara H, Kitawaki J,
Harada T, Katabuchi H, Horie S, Osuga Y.
National survey of bladder endometriosis cases inJapan. J Obstet Gynaecol Res. 2021;
47(4):1451-1461
Yanagie H, Fujino T, Yanagawa M, Terao T,
Imagawa T, Fujihara M, Morishita Y, Mizumachi
R, Murata Y, Dewi N, Ono Y, Ikushima I,
Seguchi K, Nagata M, Nonaka Y, Furuya Y, Hisa
T, Nagasaki T, Arimori K, Nakashima T, Sugihara
T, Kakimi K, Ono M, Nakajima J, Eriguchi M,
Higashi S, Takahashi H. Tumor Growth Suppres-sion With Novel Intra-arterial Chemotherapy
Using Epirubicin-entrapped Water-in-oil-in-water
Emulsion In Vivo 2021; 35(1):239-248
5. Yoshiyasu N, Sato M, Konoeda C, Nakajima J.
Management of partial anomalous pulmonary
venous return in lung transplantation. Ann Thorac
Surg. 2021; 112(2):e95-e97
6. Iida T, Sato M, Nakajima J. Resection ofclustered arteriovenous malformations to avoid
lung transplantation. Ann Thorac Surg. 2021;
112(4):e253-e256
7. Shiiya H, Nakajima J, Date H, Chen-Yoshikawa
TF, Tanizawa K, Handa T, Oto T, Otani S,
Shiotani T, Okada Y, Matsuda Y, Shiraishi T,
Moroga T, Minami M, Funaki S, Chida M,
Yoshino I, Hatachi G, Uemura Y, Sato M.
Outcomes of lung transplantation for idiopathic
pleuroparenchymal fibroelastosis. Surg Today.
2021; 51(8):1276-1284.
8. Yoshiyasu N, Sato M, Urushiyama H, Aoyama A,
Date H, Nakajima J. Familial interstitial
pneumonia revealed after living-donor lobar lungtransplantation. Ann Thorac Surg. 2021; 112(5):e365-e368
9. Nobori Y, Sato M, Morota M, Shinohara Y,
Yoshida D, Karasaki T, Kitano K, Nakajima J.
Lung autotransplantation for bronchial necrosis
after radiotherapy: a case report. Surg Case Rep.
2021; 7(1):79
10. Yoshiyasu N, Sato M, Konoeda C, Nakajima J.
Pediatric living-donor lobar lung transplantationin postpneumonectomy-like anatomy caused bypulmonaryhypoplasia
withcongenital
diaphragmatic hernia. Am J Transplant. 2021;
21(10):3461-3464
11. Nobori Y, Sato M, Hirata Y, Yamauchi H,
Konoeda C, Kitano K, Nakajima J. Intrabronchialmigration of hemostatic agent through a
bronchial fistula after lung transplantation: a casereport. Surg Case Rep. 2021; 7(1):116.
12. Yoshiyasu N, Sato M, Nakajima D, Tomioka Y,
Watanabe Y, Shiraishi T, Funaki S, Maeda S,
Tomoshige K, Nakajima T, Tsuchiya T, Sugimoto
S, Yoshino I, Nagayasu T, Chida M, Minami M,
Okada Y, Toyooka S, Date H, Nakajima J.
Current status of inhaled nitric oxide therapy forlung transplantation in Japan: a nationwide

216

13.

14.

15.

16.

17.

18.

19.

survey. Gen Thorac Cardiovasc Surg. 2021;
69(10):1421-1431
Nagayama K, Kitano K, Yoshiyasu N, Nakajima
J. Lobectomy for lung cancer in a patient with
Fontan circulation: A case report. JTCVS Tech.
2021; 6:163-165
Yoshiyasu N, Sato M, Anraku M, Ichiba S,
Nakajima J. Lung transplant after long-termveno-venous extracorporeal membrane oxygenation: a case report. J Cardiothorac Surg. 2021;
16(1):246.
Yanagie H, Yanagawa M, Morishita Y, Shinohara
A, Dewi N, Nonaka Y, Furuya Y, Mizumachi R,
Murata Y, Nakamura H, Suzuki M, Sakurai Y,
Tanaka H, Masunaga S, Ono K, Sugihara T,
Nashimoto M, Yamauchi H, Ono M, Nakajima J,
Takahashi H. Suppression of Tumor Growth in a
Rabbit Hepatic Cancer Model by Boron Neutron
Capture Therapy With Liposomal Boron Delivery
Systems. In Vivo. 2021; 35(6):3125-3135
Sun C, Nagaoka K, Kobayashi Y, Nakagawa H,
Kakimi K, Nakajima J. Neoantigen Dendritic
Cell Vaccination Combined with Anti-CD38 and
CpG Elicits Anti-Tumor Immunity against the
Immune Checkpoint Therapy-Resistant Murine
Lung Cancer Cell Line LLC1. Cancers (Basel).
2021; 13(21):5508
Sun C, Anraku M, Nakajima J. ASO Author
Reflections: An Evolving Skeletal Muscle
Profiling-Towards Precise Host Phenotype andPrognostic Stratification in Non-small Cell Lung
Cancer. Ann Surg Oncol. 2022; 29(3):1825-182
Maeda Y, Wada H, Sugiyama D, Saito T, Irie T,
Itahashi K, Minoura K, Suzuki S, Kojima T,
Kakimi K, Nakajima J, Funakoshi T, Iida S, Oka
M, Shimamura T, Doi T, Doki Y, Nakayama E,
Ueda R, Nishikawa H. Depletion of central
memory CD8+ T cells might impede theantitumor therapeutic effect of Mogamulizumab.
Nat Commun. 2021; 12(1):7280
Saito T, Kurose K, Kojima T, Funakoshi T, Sato
E, Nishikawa H, Nakajima J, Seto Y, Kakimi K,
Iida S, Doki Y, Oka M, Ueda R, Wada H. Phase
Ib study on the humanized anti-CCR4 antibody,
KW-0761, in advanced solid tumors. Nagoya J
Med Sci. 2021; 83(4):827-840

20. Nagano M, Kohsaka S, Hayashi T, Ueno T,
Kojima S, Shinozaki-Ushiku A, Morita S, Tsuda
M, Tanaka S, Shinohara T, Omori Y, Sugaya F,
Kato H, Narita Y, Nakajima J, Suzuki K,
Takamochi K, Mano H. Comprehensive
molecular profiling of pulmonary pleomorphic
carcinoma. NPJ Precis Oncol. 2021
21. Tian D, Shiiya H, Sato M, Nakajima J. Tumor
Maximum Area May Determine the Survival
Outcomes of Patients with Thymic Epithelial
Tumors. Ann Surg Oncol. 2021;28(4):2078-2085
22. Tian D, Yan HJ, Nakajima J. ASO Author
Reflections: Tumor Maximum Area is Better for
Representing Tumor Size in Thymic Epithelial
Tumors. Ann Surg Oncol. 2021; 28(4):2086-2087
23. Tian D, Nakajima J. Reply to "Euclidean
Geometry Versus Metabolic Biochemistry in the
Prognostic Evaluation of the Thymic Epithelial
Tumours". Ann Surg Oncol. 2021; 28(7):40604061
24. Konoeda C, Sato M, Hirata Y, Nakajima J. Native
Lung Pulmonary Artery Banding After SingleLung Transplant for Obliterative Bronchiolitis.
Ann Thorac Surg. 2021;111(4):e253-e255.
25. Yanagiya M, Kitano K, Yotsumoto T, Asahina H,
Nagayama K, Nakajima J. Transplantation of
Bioengineered Lungs Created From RecipientDerived Cells Into a Large Animal Model. Semin
Thorac Cardiovasc Surg. 2021; 33(1):263-271

217

Department of Cardiac Surgery
Professor
Minoru Ono, M.D., Ph.D.

Associate Professor
Yasutaka Hirata, M.D., Ph.D.

Lecturer
Haruo Yamauchi, M.D., Ph.D., Osamu Kinoshita, M.D., Ph.D.,
Mitsutoshi Kimura, M.D., Ph.D.

Associate
Shogo Shimada, M.D., Ph.D., Masahiko Ando, M.D., Ph.D., Yoshifumi Itoda, M.D., Ph.D.,
Hyoe Komae, M.D., Ph.D., Miyuki Shibata, M.D., Ph.D., Yasuhiro Hoshino, M.D., Ph.D.,
Takayuki Gyoten, M.D., Kazuki Yakuwa, M.D.

Homepage

http://cts.m.u-tokyo.ac.jp/

Introduction and Organization
Cardiac surgery in the Department was initiated by
Dr. Seiji Kimoto, who performed ligation of patentductus arteriosus in June, aortic arch aneurysm
resection in July and first-in-Japan Blalock-Taussig
operation for Tetralogy of Fallot in October in 1951.
He also started implantation of alcohol-preserved
aortic homograft for abdominal aortic aneurysm in
1952, and closed commissurotomy for mitral valve
stenosis in 1954. The first open heart surgery (atrial
septal defect closure) was performed in 1955, using
selective brain perfusion cooling method that wasdeveloped in the Department.
Establishment of Department of Thoracic Surgery
in the University of Tokyo Hospital was approved by
the government first in Japan December 15, 1964.
Under the leadership of Professor Kimoto excellent
research works were created especially on pacemakerand artificial heart, and many opinion leaders were
produced. Dr. Masahiro Saigusa, the second Professor,
endeavored to make open heart surgery safer byintroducing new- generation heart-lung machines tothe Department. Dr. Kenichi Asano, the third

Professor, started posterior-leaflet preserving mitralvalve replacement first in Japan. He also dramatically
improved surgical results of Tetralogy of Fallot. Dr.
Akira Furuse, the fourth Professor, modernizedmanagement of extremely busy clinical works. During
this time, the Department was divided into two
Divisions, Cardiovascular and General thoracic, due
to the University policy of Graduate-school.
Dr. Shinichi Takamoto assumed the fifth Professor
in June 1997. He rearranged clinical teams into threegroups (adult cardiac disease, thoracic aortic diseaseand congenital heart disease) to adapt the rapid
progress of cardiovascular surgery.
Dr. Minoru Ono was elected as the sixth Professor
in November 2009. Advanced Heart Failure Center
was open on the 5th Floor of Hospital Building B,
January 2018 to cope with an increasing number ofpatients who require ventricular assist device andheart transplantation treatment. Present staffs are one
Chief Professor, one Associate Professor and three
Lecturer and seven Associates.

218

Clinical Activities
Clinical conference starts at 7:15 am in weekdays.
Regular surgery is scheduled on every weekday. Adult
patients are hospitalized in the South Wing of 5th floor,
and pediatric patients in the South Wing of 2nd floor.
Clinics are open Monday through Friday for thefollow-up visit as well as for patient referral.
Case volume in recent years has been over 380,
which is one of the highest in Japan. We are leading inJapan by showing excellent surgical results. There are
10 Board-certified cardiovascular surgeons, each ofwhom has his own subspecialty among adult cardiac,thoracic aortic or congenital heart disease. We are
famous for off- pump coronary artery bypass surgery,mitral valve plasty, heart transplantation, ventricularassist device implantation, aortic valve sparing root
replacement, arch replacement, treatment of extended
thoracic aortic aneurysm and repair of complex
congenital heart diseases, such as Jatene, Fontan and
Norwood operations. Transcatheter aortic valve
replacement was initiated in 2015. Many high-riskvery old patients with aortic valve stenosis weresuccessfully treated.
The University of Tokyo Tissue Bank was founded
in 1997, based on the Department of Cardiovascular
Surgery. The Bank has been actively promoting
procurement, preservation and shipping of humanvalve and blood vessel allograft in Japan. We take thelead in surgical treatment using allograft for severe
active endocarditis or infection of aortic aneurysm or
vascular prosthesis. Surgical treatment using allograft
was approved for health insurance coverage by theGovernment in 2018. As of March 2022, 176 cases ofheart transplantation including 15 pediatric patientsand 382 cases of ventricular assist device (VAD)
implantation
including262
implantable
continuous-flow VADs were performed in The
University Hospital with excellent long-term survival.

Teaching Activities
We have the chair of systematic review of cardiovascular surgery in the spring term at the 2nd grade of
medical course. We expose the students to dailyclinical works as well as research works during thecourse of “Free Quarter” and “Research Lab Visit”,
which are scheduled in the summer and springvacations at 1st and 2nd grade. Joint lectures with the
Cardiology Department are scheduled 3rd through 4th
grades. Each student is assigned one or two
cardiovascular surgical cases in the Regular ClinicalClerkship, in which he/she is required to learn
preoperative patient evaluation and management,
surgical treatment and postoperative care, based onparticipatory practice. There are also fifteen small
key-lectures on cardiovascular surgery. Hands-on
practice is provided during the Advanced ClinicalClerkship one-month course in the last months of 3rd
grade.
We take charge in core surgical curriculum in the“Super-rotation” postgraduate training. We offer a
program in which each resident can learn basic
knowledge of cardiovascular disease and surgery, andhemodynamic and respiratory evaluation as well asbasic surgical techniques and patient management.
Residents who take the course of cardiovascularsurgery are required three-year general surgicaltraining for General Surgery Board certification. We
have well-developed specialty/subspecialty training
programs to allow the residents to pass Cardiovascular
Board Examination by 9-10th postgraduate year.

Research Activities
In order to achieve excellent clinical results and toseek for new possibilities of surgical treatments, it isessential for cardiothoracic surgical department of the
University to have active research programs in clinicaland basic subjects. The Cardiothoracic Department of
the University of Tokyo has created highly active
research programs in the every field of cardiothoracic
surgery, played an internationally leading role andcontributed to its development. A research meeting isheld once a month on a research project for every
member of the department to understand and to makefree thorough discussions of the subject.
Basic and/or clinical research activities are focusedon 1) establishment of recovery and weaning
protocols of left ventricular assist device, 2) basic andclinical research on cryopreserved allograft, 3)application of regenerative medicine to end-stage
heart failure, 4) analysis of cardiomyocytes matured
and differentiated from iPS cells, 5) mechanism
analysis of right heart failure and development of219

effective pharmacological and mechanical therapy, 6)
development of versatile suture device, 7) clinicalresearch to test the safety and efficacy of artificial
pancreas during open heart surgery.

References
1.

2.

3.

4.

5.

Bujo C, Amiya E, Hatano M, Tsuji M, Maki H,
Ishida J, Ishii S, Narita K, Endo M, Ando M,
Shimada S, Kinoshita O, Ono M, Komuro I.
Association between infectious event and denovo malignancy after heart transplantation.
Heart Vessels. 2021 Apr;36 (4): 499-508. PMID:
33140148.
Kohno H, Matsumiya G, Sawa Y, Fukushima N,
Saiki Y, Shiose A, Ono M. Can the intermittent
low-speed function of left ventricular assist
device prevent aortic insufficiency? J Artif
Organs. 2021 Jun; 24(2): 191-198. PMID:
33420874.
Tsuji M, Amiya E, Bujo C, Hara T, Saito A,
Minatsuki S, Maki H, Ishida J, Hosoya Y, Hatano
M, Imai H, Nemoto M, Kagami Y, Endo M,
Kimura M, Ando M, Shimada S, Kinoshita O,
Ono M, Komuro I. Carbon Monoxide Diffusing
Capacity Predicts Cardiac Readmission in
Patients Undergoing Left Ventricular Assist
Device Implantation in Japan. ASAIO J. 2021
Oct 1;67(10):1111-1118. PMID: 33470633.
Goto H, Komae H, Sekine H, Homma J, Lee S,
Yokota T, Matsuura K, Someya T, Ono M,
Shimizu T. Continuous measurement of surface
electricalpotentials
fromtransplanted
cardio-myocyte
tissuederivedfromhuman-induced pluripotent stem cells underphysiological conditions in vivo. Heart Vessels.
2021 Jun;36(6):899-909. PMID: 33683408.
Yanagie H, Yanagawa M, Morishita Y,
Shinohara A, Dewi N, Nonaka Y, Furuya Y,
Mizumachi R, Murata Y, Nakamura H, Suzuki M,
Sakurai Y, Tanaka H, Masunaga S, Ono K,
Sugihara T, Nashimoto M, Yamauchi H, Ono M,
Nakajima J, Takahashi H. Suppression of Tumor
Growth in a Rabbit Hepatic Cancer Model by
Boron Neutron Capture Therapy With Liposomal
Boron Delivery Systems. In Vivo. 2021
Nov-Dec;35(6):3125-3135. PMID: 34697143

6.

Chang D, Fan T, Gao S, Jin Y, Zhang M, Ono M.
Application of mesenchymal stem cell sheet totreatment of ischemic heart disease. Stem Cell
Res Ther. 2021 Jul 7;12(1):384. PMID:
34233729
7. Shimamura J, Nishinaka T, Mizuno T, Tsukiya T,
Inatomi A, Kobayashi F, Katagiri N, Takewa Y,
Nishimura T, Ono M, Tatsumi E. Assessment ofocular blood flow in continuous-flow ventricularassist device by laser speckle flowgraphy.
J Artif Organs. 2021 Dec;24(4):419-424. PMID:
33825101.
8. Takeda N, Inuzuka R, Yagi H, Morita H, Ando M,
Yamauchi H, Taniguchi Y, Porto KJ, Kanaya T,
Ishiura H, Mitsui J, Tsuji S, Toda T, Ono M,
Komuro I. Clinical Impact of Copy Number
Variation on the Genetic Diagnosis of Syndromic
Aortopathies. Circ Genom Precis Med. 2021
Aug; 14(4): e003458. PMID: 34325513.
9. Yakuwa K, Miyaji K, Kitamura T, Miyamoto T,
Ono M, Kaneko Y. Neutrophil-to-lymphocyte
ratio is prognostic factor of prolonged pleural
effusion after pediatric cardiac surgery. JRSM
Cardiovasc Dis. 2021 Apr 19;10:2048004021100
9438. doi: 10.1177/20480040211009438. PMID:
34262699
10. Kinugawa K, Sakata Y, Ono M, Nunoda S, Toda
K, Fukushima N, Shiose A, Oishi S, Yumino D,
Imamura T, Endo M, Hori Y, Kashiwa K, Aita K,
Kojin H, Tejima Y, Sawa Y. Consensus Reporton Destination Therapy in Japan - From the DT
Committee of the Council for Clinical Use ofVentricular Assist Device Related Academic
Societies. Circ J. 2021 Sep 24;85(10): 1906-1917.
PMID: 34433758.
11. Bujo C, Amiya E, Hatano M, Ishida J, Tsuji M,
Kakuda N, Narita K, Saito A, Yagi H, Ando M,
Shimada S, Kimura M, Kinoshita O, Ono M,
Komuro I. Long-Term renal function after
implantation of continuous-flow left ventricularassist devices: A single center study. Int J Cardiol
Heart Vasc. 2021 Nov 1;37, PMID: 34765720
12. Ikeda N, Yamamoto H, Taketomi A, Hibi T, Ono
M, Niikura N, Sugitani I, Isozumi U, Miyata H,
Nagano H, Unno M, Kitagawa Y, Mori M. The
impact of COVID-19 on surgical procedures inJapan: analysis of data from the National Clinical

220

13.

14.

15.

16.

17.

18.

19.

Database. Surg Today. 2022 Jan; 52(1): 22-35.
PMID: 34783905.
Aoyama G, Zhao L, Zhao S, Xue X, Zhong Y,
Yamauchi H, Tsukihara H, Maeda E, Ino K,
Tomii N, Takagi S, Sakuma I, Ono M, Sakaguchi
T. Automatic Aortic Valve Cusps Segmentationfrom CT Images Based on the Cascading
Multiple Deep Neural Networks. J Imaging. 2022
Jan 14;8(1):11. doi: 10.3390/jimaging8010011.
PMID: 35049852.
Terakawa K, Yamauchi H, Lee Y, Ono M. A
Novel Knitted Polytetrafluoroethylene Patch for
Cardiovascular Surgery. Int Heart J. 2022;63(1):122-130. PMID: 35095061.
Ando M, Yamauchi H, Gyoten T, Komae H,
Hoshino Y, Itoda Y, Shimada S, Kimura M,
Kinoshita O, Ono M. Association between left
ventricular ejection fraction and mortality after
Bentall procedure. Heart Vessels. 2022 Feb 5.
doi: 10.1007/s00380-022-02028-9. Epub ahead ofprint. PMID: 35124729.
Tsuji M, Kakuda N, Bujo C, Ishida J, Amiya E,
Hatano M, Shimada A, Imai H, Shimada S,
Kinoshita O, Yamauchi H, Ono M, Komuro I.
Sarcopenia and risk of infection in adult hearttransplant recipients in Japan. ESC Heart Fail.
2022 Apr; 9(2): 1413-1423. PMID: 35146960.
Myers PO, Dayan V, Szeto WY, Thourani VH,
Malaisrie SC, Moon MR, Prager RL, Ono M,
Okita Y, Freemantle N, Milojevic M. Joint
surgical associations (EACTS, LACES, ASCVTS,
AATS, and STS) position statement regarding the
VARC-3 definitions for aortic valve clinicalresearch. J Thorac Cardiovasc Surg. 2022 May;
163(5): 1792-1794. PMID: 35307218.
Kida K, Kanaki T, Gao S, Hatanaka D, Iwakami
M, Liu S, Horikawa M, Ono M, Chang D. A
Novel 3D Culture System Using a Chitin-Based
Polysaccharide Material Produces High-Quality
Allogeneic Human UCMSCs with Dispersed
Sphere Morphology. Cells. 2022 Mar 15;11(6):995. PMID: 35326446.
Ono M. Updating guidelines: When is the best
timing of upgrading recommendation for an
emerging technology? Asian Cardiovasc Thorac
Ann.
2021
May;29(4):250-253.
PMID:
34053247.

20. Kitaoka H, Tsutsui H, Kubo T, Ide T, Chikamori
T, Fukuda K, Fujino N, Higo T, Isobe M, Kamiya
C, Kato S, Kihara Y, Kinugawa K, Kinugawa S,
Kogaki S, Komuro I, Hagiwara N, Ono M,
Maekawa Y, Makita S, Matsui Y, Matsushima S,
Sakata Y, Sawa Y, Shimizu W, Teraoka K,
Tsuchihashi-Makaya M, Ishibashi-Ueda H,
Watanabe M, Yoshimura M, Fukusima A, Hida S,
Hikoso S, Imamura T, Ishida H, Kawai M,
Kitagawa T, Kohno T, Kurisu S, Nagata Y,
Nakamura M, Morita H, Takano H, Shiga T,
Takei Y, Yuasa S, Yamamoto T, Watanabe T,
Akasaka T, Doi Y, Kimura T, Kitakaze M,
Kosuge M, Takayama M, Tomoike H; Japanese
Circulation Society Joint Working Group.
JCS/JHFS 2018 Guideline on the Diagnosis andTreatment of Cardiomyopathies. Circ J. 2021 Jul
22. doi: 10.1253/circj.CJ-20-0910. Epub ahead ofprint. PMID: 34305070.
21. Chang D, Fan T, Gao S, Jin Y, Zhang M, Ono M.
Application of mesenchymal stem cell sheet totreatment of ischemic heart disease. Stem Cell
Res Ther. 2021 Jul 7;12(1):384. PMID:
34233729.
22. Tsutsui H, Ide T, Ito H, Kihara Y, Kinugawa K,
Kinugawa S, Makaya M, Murohara T, Node K,
Saito Y, Sakata Y, Shimizu W, Yamamoto K,
Bando Y, Iwasaki YK, Kinugasa Y, Mizote I,
Nakagawa H, Oishi S, Okada A, Tanaka A,
Akasaka T, Ono M, Kimura T, Kosaka S, Kosuge
M, Momomura SI. JCS/JHFS 2021 Guideline
Focused Update on Diagnosis and Treatment of
Acute and Chronic Heart Failure. J Card Fail.
2021 Dec;27(12):1404-1444. PMID: 34600838.
23. Ono M. Durable Ventricular Assist Device for
Bridge to Transplantation. In: Fukushima N,
editor. Heart Transplantation. London: Intech
Open; 2022 [cited 2022 Feb 05]. Available from:https://www.intechopen.com/online-first/80317
doi: 10.5772/intechopen.102467
24. Nakamura M, Yaku H, Ako J, Arai H, Asai T,
Chikamori T, Daida H, Doi K, Fukui T, Ito T,
Kadota K, Kobayashi J, Komiya T, Kozuma K,
Nakagawa Y, Nakao K, Niinami H, Ohno T,
Ozaki Y, Sata M, Takanashi S, Takemura H,
Ueno T, Yasuda S, Yokoyama H, Fujita T, Kasai
T, Kohsaka S, Kubo T, Manabe S, Matsumoto N,

221

25.

26.

27.

28.

29.

30.

Miyagawa S, Mizuno T, Motomura N, Numata S,
Nakajima H, Oda H, Otake H, Otsuka F, Sasaki
KI, Shimada K, Shimokawa T, Shinke T, Suzuki
T, Takahashi M, Tanaka N, Tsuneyoshi H, Tojo
T, Une D, Wakasa S, Yamaguchi K, Akasaka T,
Hirayama A, Kimura K, Kimura T, Matsui Y,
Miyazaki S, Okamura Y, Ono M, Shiomi H,
Tanemoto K; Japanese Circulation Society Joint
Working Group. JCS/JSCVS 2018 Guideline on
Revascularization of Stable Coronary Artery
Disease. Circ J. 2022 Feb 25;86(3):477-588.
PMID: 35095031.
Koizumi J, Iwase T, Tsuji S, Goto T, Oyama K,
Kin H. Intrapulmonary artery septation forunilateral absence of the pulmonary artery. Asian
Cardiovasc
ThoracAnn.
2022
May;30(4):477-479. PMID: 33926269.
Tsuji S, Ikai A, Oyama K, Kin H, Koizumi J.
Outcomes of primary sternal closure forpostoperative mediastinitis in children. Eur J
Cardiothorac Surg. 2021 May 8;59(5):951-957.
PMID: 33576375.
Hirata Y, Hirahara N, Murakami A, Motomura N,
Miyata H, Takamoto S. Status of cardiovascularsurgery in Japan: A report based on the Japan
Cardiovascular Surgery Database 2017-2018. 1.
Congenital heart surgery. Asian Cardiovasc
Thorac Ann. 2021 May;29(4):289-293. PMID:
33375819.
Ide Y, Tachimori H, Hirata Y, Hirahara N, Ota N,
Sakamoto K, Ikeda T, Minatoya K. Risk analysis
for patients with a functionally univentricular
heart
after
systemic-to-pulmonary
shunt
placement. Eur J Cardiothorac Surg. 2021 Jul 30;
60(2):377-383. PMID: 33712829.
Hörer J, Hirata Y, Tachimori H, Ono M, Vida V,
Herbst C, Kansy A, Jacobs JP, Tobota Z,
Sakamoto K, Ebels T, Maruszewski B. Pediatric
Cardiac Surgical Patterns of Practice andOutcomes in Japan and Europe. World J Pediatr
Congenit Heart Surg. 2021 May;12(3):312-319.
PMID: 33942682.
Ota N, Tachimori H, Hirata Y, Miyata H,
Suzuki T, Uchita S, Takamoto S, Izutani H.
Contemporary patterns of the management oftruncus arteriosus (primary versus staged repair):outcomesfromtheJapanese
National

Cardiovascular Database. Eur J Cardiothorac
Surg. 2022 Mar 24;61(4):787-794. PMID:
34329388.
31. Matsui H, Hirata Y, Inuzuka R, Hayashi T,
Nagamine H, Ueda T, Nakayama T. Initialnational investigation of the prenatal diagnosis ofcongenitalheartmalformations
inJapan-Regional Detection Rate and Emergency
Transfer from 2013 to 2017. J Cardiol. 2021
Dec;78(6):480-486. PMID: 34454809.
32. Taniguchi Y, Takeda N, Inuzuka R,
Matsubayashi Y, Kato S, Doi T, Yagi H,
Yamauchi H, Ando M, Oshima Y, Tanaka S.
Impact of pathogenic FBN1 variant types on thedevelopment of severe scoliosis in patients with
Marfan syndrome. J Med Genet. 2021 Dec 16:
jmedgenet-2021-108186. PMID: 34916231.

222

Department of
Gastrointestinal Surgery
Professor
Yasuyuki Seto M.D., Ph.D.

Associate Professor
Sachiyo Nomura M.D., Ph.D.
Susumu Aikou M.D., Ph.D.(The Institute of Medical Science)

Lecturer
Koichi Yagi M.D., Ph.D.

Associates
Takako Wakeda M.D., Ph.D.
Shoh Yajima M.D. Ph.D.
Masayuki Urabe M.D. Ph.D

Homepage

Yasuhiro Okumura M.D., Ph.D.
Motonari Ri M.D., Ph.D.
Shuntaro Yoshimura M.D., Ph.D.

http://gibes.m.u-tokyo.ac.jp/

General Affairs:
Since 1997, the former Third Department ofSurgery, which was located in a branch hospital of the
University of Tokyo, has been divided into two
departments, the Department of Gastrointestinal
Surgery and the Department of Metabolic Care andEndocrine Surgery, in line with the integration of themain and branch hospitals. Department of Metabolic
Care and Endocrine Surgery has been renamed Breastand Endocrine Surgery in April 2017. Under the supports by the Social Medical Corporation Sosaikoseikai,
the Social Medical Corporation Kawakita Medical
Foundation and RIZAP Group Inc., Bariatric &Metabolic care (social cooperation program) was
newly established in April 2017.
With the prolongation of life expectancy, there are
increasing numbers of multi-morbid patients requiring
multi-organ treatment, as well as a greater need for
multidisciplinary approaches to the patients. Our
fundamental principles of patient treatment arecomprehensive patient care which includes pre-, peri-,and postoperative management of the diseases as wellas patient care over long-term postoperative periods
which often extend to the terminal stage. We believethat patient care encompassing the entire lifespanprovides a wealth of valuable information concerning
the appropriateness of current treatment strategy, theestablishment of new surgical designs, the development of new basic research activities which can muchcontribute to clinical fields, and indications ofdesirable modes of terminal care.
Fostering good surgeons as well as scientists whomeet both clinical and academic needs has always
been the guiding principle of our department.

Educational Activities:
The new system of clinical clerkship for medical
students has begun from 2013. During those periods,
the students are educated strictly and gently by staffs.
Clinical exercises, e.g., blood sampling, injection, andligation, etc., are performed. They can attend theoperations as an assistant.

223

They learn general patient care which encompasses
not only perioperative management of diseases but
also non-surgical management of postoperative
disorders and terminal care. Our educational systemprovides medical students with a great deal ofpractical information from the medical point of view
as well as better opportunities to ponder the
implications of life and death.
For the medical students, the clinical clerkshiplectures are held two or three times a week. The
experts (from outside hospital) other than the staff
give special unique and informative lectures, which
are popular among the students.
Intern doctors rotate every three or one and halfmonths. After completion of their initial training
program, they go into a further exclusive clinicaltraining program for several consecutive years andbecome a chief resident.

Research Activities:
Our goal is to cure the cancer patients by muchbetter surgery. The development of better surgicalmethods has the highest priority. Better surgery means
radicality of the cancer control, minimal invasiveness,and good QOL after surgery. Recently, transmediastinal (non-transthoracic) radical esophagectomy with extended lymphadenectomy has been
applied, which shows less pulmonary complications,shorter postoperative hospital stay and better QOL
after surgery. To develop this surgical procedure, we
and other surgeons sharing same will established theJapanese Society for Nontransthoracic Radical
Esophagectomy in 2016. New methods of endoscopic/
laparoscopic full-thickness resection, non-exposedendoscopic wall-inversion surgery (NEWS) has beendeveloped for submucosal gastric tumor as acollaboration of endoscopy and laparoscopy, and now
NEWS is applied for some gastric cancer. Eliminationof the pulmonary complications after esophagectomy
and the detection of minute metastasis for theestablishment of better surgery are also our important
targets.
Another main research activities of the department
of Gastrointestinal Surgery has been focused on
diagnosis and therapy for gastrointestinal diseases andclinical and basic research for gastrointestinal

carcinogenesis from the view point of “Surgery andInflammation”. The department's research activities
have focused on a wide spectrum of research topics,
ranging from basic research topics to clinical ones.
Our research activities have been well organized andultimately achieved by maintaining a close connection
between hospital and laboratory activities. Our
medical staffs make every effort to promote theresearch activities and obtain successful results.

Clinical Activities:
We have outpatient clinics from Monday throughFriday. We have specialized divisions for outpatientmanagement of esophageal, gastric diseases. The ward
is divided into two subgroups, and each of them has
one medical staff for supervision, one assistantsupervisor, one chief resident, and one or two juniorresidents in rotation. They are on duty for daily patientcare under the supervision of medical staffs. Ordinary,each subgroup takes care of 15-25 patients.
The weekly official activities of our department are
Ward Rounds by the Professor on Monday. We havepost- and preoperative case conferences on Wednesday,Thursday, and Friday morning, respectively, and ajournal club on Monday. We also have a specialized
upper gastrointestinal case conference on Wednesday
evening. Further, cancer board is held bi-weekly,
where the radiologists and endoscopists as well as
surgeons attend together and have discussions frankly.
Generally, elective surgery is scheduled on Tuesday，
Wednesday and Thursday. The statistics shows 80
gastric and 70 esophageal cancer surgeries are
performed a year, respectively. Hernia surgery is also
performed. Laparoscopic sleeve gastrectomy formorbid obesity has started in June 2016, and thenumber of cases is steadily increasing. All residents
and medical personnel work with high motivation for
the good of the patients.

References
1.

Mori K, Sugawara K, Aikou S, Yamashita H,
Yamashita K, Ogura M, et al. Esophageal cancer
patients' survival after complete response todefinitive chemoradiotherapy: a retrospective
analysis. Esophagus 2021 Jul;18(3):629-637.

224

2.

Ogane K, Uenomachi M, Shimazoe K, Takahashi
M, Takahashi H, Seto Y, et al. Simultaneous
measurements of single gamma ray of (131)I andannihilation radiation of (18)F with Compton
PET hybrid camera. Appl Radiat Isot 2021 Oct;176:109864.
3. Sato Y, Mori K, Hirano K, Yagi K, Kobayashi Y,
Nagaoka K, et al. Adoptive γδT-cell transfer
alone or combined with chemotherapy for thetreatment of advanced esophageal cancer.
Cytotherapy 2021 May;23(5):423-432.
4. Seto Y. Sarcopenia, muscle quality, and gastriccancer surgery. Ann Gastroenterol Surg 2021 Jul
12;5(4):402-403.
5. Seto Y, Mori K, Yamagata Y, Aikou S, Yagi K,
Nishida M, et al.
. Robot-Assisted Transmediastinal Esophagectomy for Esophageal
Cancer. Gan To Kagaku Ryoho 2021 Sep;48(9):1110-1114
6. Shiomi S, Toriumi T, Yagi K, Asaoka R,
Okumura Y, Wakamatsu K, et al. Trunk fat
volume can be a predictor of postoperativecomplications after gastrectomy: a retrospective
cohort study. BMC Surg 2021 Apr 23;21(1):207021-01221-3.
7. Sugawara K, Iwai M, Ito H, Tanaka M, Seto Y,
Todo T. Oncolytic herpes virus G47Δ works
synergistically with CTLA-4 inhibition via
dynamic intratumoral immune modulation. Mol
Ther Oncolytics 2021 May 19;22:129-142.
8. Sugawara K, Kawaguchi Y, Seto Y, Vauthey JN.
Multidisciplinary treatment strategy for locallyadvanced gastric cancer: A systematic review.
Surg Oncol 2021 Sep;38:101599.
9. Sugawara K, Yamashita H, Urabe M, Okumura Y,
Yagi K, Aikou S, et al. Geriatric Nutrition Index
Influences Survival Outcomes in Gastric
Carcinoma Patients Undergoing Radical Surgery.
JPEN J Parenter Enteral Nutr 2021 Jul;45(5):1042-1051.
10. Sugawara K, Yamashita H, Urabe M, Okumura Y,
Yagi K, Aikou S, et al. The different survival
impacts of body mass index in elderly andnon-elderly patients with gastric carcinoma. Surg
Oncol 2021 Jun;37:101549.
11. Sugawara K, Yamashita H, Yajima S, Oshima Y,
Mitsumori N, Fujisaki M, et al. Prognosis of

12.

13.

14.

15.

16.

hemodialysis patients undergoing surgery for
gastric cancer: Results of a multicenter retrospective study. Surgery 2021 Jul;170(1):249-256.
Yagi K, Toriumi T, Aikou S, Yamashita H,
Seto Y. Salvage treatment after definitive
chemoradiotherapy for esophageal squamous cell
carcinoma. Ann Gastroenterol Surg 2021 Mar 10;
5(4):436-445.
Yajima S, Sugawara K, Iwai M, Tanaka M, Seto
Y, Todo T. Efficacy and safety of athird-generation oncolytic herpes virus G47Δ inmodels of human esophageal carcinoma. Mol
Ther Oncolytics 2021 Oct 30;23:402-411.
Yamashita S, Abe H, Kunita A, Yamashita H,
Seto Y, Ushiku T. Programmed cell death protein
1/programmed death ligand 1 but not HER2 is apotential therapeutic target in gastric neuroendocrine carcinoma. Histopathology 2021 Feb;
78(3):381-391.
Yasukawa Y, Hattori N, Iida N, Takeshima H,
Maeda M, Kiyono T, et al. SAA1 is upregulated
in gastric cancer-associated fibroblasts possibly
by its enhancer activation. Carcinogenesis 2021
Feb 25;42(2):180-189.
Yoshimura S, Mori K, Ri M, Aikou S, Yagi K,
Yamagata Y, et al. Comparison of short-term
outcomes between transthoracic and robotassisted transmediastinal radical surgery foresophageal cancer: a prospective study. BMC
Cancer 2021 Mar 31;21(1):338-021-08075-1.

225

Hepato-biliary-Pancreatic Surgery
Division and Artificial Organ
and Transplantation Division
Professor and Chairman
Kiyoshi Hasegawa, M.D., Ph.D.

Associate Professor
Junichi Arita, M.D., Ph.D.

Lecturers
Nobuhisa Akamatsu, M.D., Ph.D.

Junichi Kaneko, M.D., Ph.D.

Yoshikuni Kawaguchi, M.D., Ph.D.

Homepages

http://www.u-tokyo-hbp-transplant-surgery.jp/

Introduction and Organization
The Hepato-Biliary-Pancreatic (HBP) Surgery
Division, Artificial Organ and Liver Transplantation
Division, Department of Surgery is originated from
Second Department of Surgery (2nd Dept of Surg),
which was established in 1893. This department has ahistory of over 125 years and has made tremendous
contribution to the Japanese surgical advancement,such as the foundation of Japanese Surgical Society.
As departments in the style of graduate school havebeen increasingly founded in The University of Tokyo,
and organ-specific medication has been progressively
recommended, 2nd Dept of Surg has been replaced to
HBP Surg Division since June 1st, 1998.

Clinical Activities
Our division deals with patients with HBPmalignancies, benign diseases and end stage liverdisease. We specialize in hepatectomies forhepatocellular carcinoma and colorectal metastasis.
Laparoscopic or robotic Whipple’s procedure has
started recent year. Living donor liver transplantationachieved international renown. Now we are ranked in
the top three high volume centers in Japan including

deceased donor liver transplantation. Roughly 500
patients undergo surgery every year. Elective
operations are carried out on Monday, Wednesday andFriday. The perioperative management is strictly
controlled, with nearly zero mortality. Adjuvant
chemotherapy is performed in a style of prospective
clinical trials.

Education
Education for medical students includes systematic
lectures of surgery for M2 (senior year) students, andclinical lectures and bed-side practice for M3 andfinal-year students, in accordance with other surgicaland non-surgical departments. Since 2013, The
Clinical Clerkship, more practical medical training
had started. In our division, students actively
participate the surgical activities.
Clinical Clerkship is designed to consist of 2 parts;
2 weeks clinical practice in the University of Tokyoand 1 week practice in other hospitals. Medical
students are expected to join the surgical team and thesurgical operations. They can learn about preoperative
examinations & care of the patients, informed
consents, diagnosis, presentation at the conferences,
operative procedures, and postoperative managements.

226

They also are expected to submit a report on a themeof specific surgical topics.

Research
We have published papers mainly on HBP Surgery
and liver transplantation. The ongoing topics involve
clinical application of ICG fluorescence imaging
enabling visualization of biological structures (biliary
trees, hepatic tumors, hepatic segmental boundaries,etc.), prospective clinical trials of adjuvant
chemotherapy for hepatocellular carcinoma, metastatic colorectal cancer, neoadjuvant chemotherapy forborderline resectable pancreatic cancer, utility ofcontrast-enhanced intraoperative ultrasonography, preoperative navigation for hepatic surgery, and clinicalapplication of artificial intelligence and synthetic
blood vessel graft.

Publications (2021-2022)
1.

2.

3.

Kiritani S, Kaneko J, Arita J, Ishizawa T,
Akamatsu N, Hasegawa K. Radical antegrade
modular pancreatosplenectomy for left-sided
pancreatic ductal adenocarcinoma may reduce thelocal recurrence rate. Dig Surg. 2022 May 9.
Online ahead of print.
Bae SK, Arita J, Akamatsu N, Maki H, Nishioka
Y, Kawahara T, Miyata A, Kokudo T, Nagata R,
Mihara Y, Ichida A, Inagaki Y, Kawaguchi Y,
Ishizawa T, Kaneko J, Tamura S, Tanaka Y,
Moriya K, Hasegawa K. The impact of thecovalently closed circular DNA level onrecurrence of hepatocellular carcinoma after initialhepatectomy: an analysis of patients with resolved
hepatitis B virus infection. HPB (Oxford). 2022
Jul 1. Online ahead of print. PMID: 35863998
Matsumura M, Hasegawa K, Oba M, Yamaguchi
K, Uetake H, Yoshino T, Morita S, Takahashi K,
Unno M, Shimada Y, Muro K, Matsuhashi N,
Mori M, Baba H, Shimada M, Mise Y,
Kawaguchi Y, Kagimura T, Ishigure K, Saiura A,
Sugihara K, Kokudo N. A randomized controlled
trial of surgery and postoperative modified
FOLFOX6 versus surgery and perioperative
modified FOLFOX6 plus cetuximab in patientswith KRAS wild-type resectable colorectal liver
metastases: EXPERT study. Langenbecks Arch

Surg. 2022 Feb 25.. Online ahead of print. PMID:
35211831
4. Watanabe G, Mise Y, Oba M, Saiura A, Inoue Y,
Takahashi Y, Kishi Y, Suyama K, Takayama T,
Noie T, Nishioka Y, Akamatsu N, Arita J, Kokudo
N, Hasegawa K. A multicenter phase II trial
evaluating the efficacy of bevacizumab plus
mFOLFOX6 for R0 surgical resection inadvanced colorectal liver metastases harboring
mutant-type KRAS: NEXTO-mt trial. "HPB
(Oxford). 2022 Aug;24(8):1245-1251.
5. Takahashi R, Akamatsu N, Nakazawa A, Nagata
R, Ichida A, Kawaguchi Y, Ishizawa T, Kaneko J,
Arita J, Hasegawa K. Effect of the response topreoperative treatment for hepatorenal syndromeon the outcome of recipients of living-donor livertransplantation. J Hepatobiliary Pancreat Sci.
2022 Jul;29(7):798-809.
6. Arita J, Ichida A, Nagata R, Mihara Y,
Kawaguchi Y, Ishizawa T, Akamatsu N, Kaneko J,
Hasegawa K. Conversion surgery after
preoperative therapy for advanced hepatocellular
carcinoma in the era of molecular targeted
therapy and immune checkpoint inhibitors. J
Hepatobiliary Pancreat Sci. 2022 Jul;29(7):732740.
7. Komoto I, Kokudo N, Aoki T, Morizane C, Ito T,
Hashimoto T, Kimura W, Inoue N, Hasegawa K,
Kondo S, Ueno H, Igarashi H, Oono T, Makuuchi
M, Takamoto T, Hirai I, Takeshita A, Imamura M.
Phase I/II study of streptozocin monotherapy inJapanese patients with unresectable or metastatic
gastroenteropancreatic neuroendocrine tumors.
Jpn J Clin Oncol. 2022 Jul 8;52(7):708-716.
8. Maki H, Hasegawa K. Advances in the surgicaltreatment of liver cancer. "Biosci Trends. 2022
Jul 20;16(3):178-188.
9. Kazami Y, Kaneko J, Keshwani D, Takahashi R,
Kawaguchi Y, Ichida A, Ishizawa T, Akamatsu N,
Arita J, Hasegawa K. Artificial intelligenceenhances the accuracy of portal and hepatic vein
extraction in computed tomography for virtual
hepatectomy. J Hepatobiliary Pancreat Sci. 2022
Mar;29(3):359-368.
10. Mochida S, Nakayama N, Terai S, Yoshiji H,
Shimizu M, Ido A, Inoue K, Genda T, Takikawa
Y, Takami T, Kato N, Abe M, Abe R, Inui A,

227

11.

12.

13.

14.

15.

16.

Ohira H, Kasahara M, Chayama K, Hasegawa K,
Tanaka A. Diagnostic criteria for acute-onchronic liver failure and related disease
conditions in Japan. Hepatol Res. 2022 May;
52(5):417-421.
Abe H, Yasunaga Y, Yamazawa S, Nakai Y,
Gonoi W, Nishioka Y, Murono K, Sasaki K, Arita
J, Kawai K, Nozawa H, Hasegawa K, Ishihara S,
Ushiku T. Histological growth patterns ofcolorectal cancer liver metastases: a strong
prognostic marker associated with invasive
patterns of the primary tumor and p53 alteration.
Hum Pathol. 2022 May;123:74-83.
Watanabe G, Kawaguchi Y, Ichida A, Ishizawa T,
Akamatsu N, Kaneko J, Arita J, Hasegawa K.
Understanding conditional cumulative incidenceof complications following liver resection to
optimize hospital stay. HPB (Oxford). 2022 Feb;
24(2):226-233.
Ichida A, Akamatsu N, Nagata R, Mihara Y,
Kawaguchi Y, Bae SK, Ishizawa T, Kaneko J,
Arita J, Hasegawa K. Efficacy and Safety ofLenvatinib for the Treatment of Recurrent
Hepatocellular Carcinoma After Living Donor
Liver Transplantation: A Report of Two Cases.
Anticancer Res. 2022 Feb;42(2):1161-1167.
Okada Y, Kawaguchi Y, Matsumura M,
Matsubara S, Nakai Y, Ichida A, Ishizawa T,
Akamatsu N, Kaneko J, Arita J, Koike K,
Hasegawa K. A safe sequential treatment
approach for patients who have acutecholecystitis
withsevereinflammation:
Transmural gallbladder drainage followed bylaparoscopic cholecystectomy under the guidanceof fluorescence imaging. Asian J Endosc Surg.
2022 Jan;15(1):230-234.
Komagome M, Maki A, Nagata R, Masuda W,
Kogure R, Mitsui T, Ninomiya R, Akamatsu N,
Hasegawa K, Beck Y. Refractory Acute Antibody
Mediated Rejection in Liver Transplant After
Desensitization of Preformed Donor Specific
Antibody-ValidityofBortezomib
andEverolimus: A Case Report. Transplant Proc.
2022 Jan-Feb;54(1):147-152.
Kawaguchi Y, Fuks D, Vauthey JN, Kokudo N,
Gayet B, Hasegawa K. A novel simple three-level
liver resection classification without compromis-

17.

18.

19.

20.

21.

22.

ing the performance to predict surgical andpostoperative outcomes. Eur J Surg Oncol. 2022
Jan;48(1):305-306.
Omichi K, Hasegawa K, Kumamaru H, Miyata H,
Konno H, Seto Y, Mori M, Kokudo N.
Association between age and short-term
outcomes of gastroenterological surgeries inolder patients: an analysis using the National
Clinical Database in Japan. Langenbecks Arch
Surg. 2021 Dec;406(8):2827-2836.
Watanabe T, Nakai Y, Mizuno S, Hamada T,
Kogure H, Hirano K, Akamatsu N, Hasegawa K,
Isayama H, Koike K. Prognosis of Primary
Sclerosing Cholangitis According to Age ofOnset. J Hepatobiliary Pancreat Sci. 2021 Dec;
28(12):1115-1120.
Iwano T, Yoshimura K, Watanabe G, Saito R,
Kiritani S, Kawaida H, Moriguchi T, Murata T,
Ogata K, Ichikawa D, Arita J, Hasegawa K,
TakedaS.
High-performance
Collective
Biomarker from Liquid Biopsy for Diagnosis of
Pancreatic Cancer Based on Mass Spectrometry
and Machine Learning. J Cancer. 2021 Nov 4;
12(24):7477-7487.
Kokudo T, Hasegawa K. Evaluating the liverfunction of patients with hepatocellular carcinoma.
Hepatol Res. 2021 Nov;51(11):1095-1096.
Yamaguchi T, Hasegawa K, Sauvain MO, Passoni
S, Kazami Y, Kokudo T, Cristaudi A, Melloul E,
Uldry E, Kobayashi K, Akamatsu N, Kaneko J,
Arita J, Sakamoto Y, Demartines N, Kokudo N,
Halkic N. An aberrant right hepatic artery arisingfrom the gastroduodenal artery: a pitfall
encountered during pancreaticoduodenectomy.
Surg Today. 2021 Oct;51(10):1577-1582.
Yasudo H, Ando T, Maehara A, Ando T, Izawa K,
Tanabe A, Kaitani A, Nomura S, Seki M, Yoshida
K, Oda H, Okamoto Y, Wang H, Kamei A,
Kojima M, Kimura M, Uchida K, Nakano N,
Kaneko J, Ebihara N, Hasegawa K, Shimizu T,
Takita J, Ogawa H, Okumura K, Ogawa S,
Tamura N, Kitaura J. A Possible Association
Betweena
Nucleotide-Binding
DomainLRR-Containing Protein Family PYD-Containing
Protein 1 Mutation and an Autoinflammatory
Disease Involving Liver Cirrhosis. Hepatology.
2021 Oct;74(4):2296-2299.

228

Department of Urology
Professor
Haruki Kume, M.D., Ph.D.

Assistant Professor
Daisuke Yamada, M.D., Ph.D., Yusuke Sato, M.D., Ph.D.,
Yuta Yamada, M.D., Ph.D., Yoshiyuki Akiyama, M.D., Ph.D.

AssociateKenji Yoda, M.D., Jimpei Miyakawa, M.D., Ph.D., Kanae Yoshida, M.D.,
Yoichi Fujii, M.D., Ph.D., Mayuko Tokunaga, M.D., Norihide Shirakawa, M.D.,
Kotaro Takemura, M.D., Maki Kazuki, M.D., Fusako Niimi, M.D.,
Kenichi Hashimoto, Ph.D.

Homepage http://www.h.u-tokyo.ac.jp/urology/
Introduction and Organization

prostatectomy substituting open procedures.

Urology is a special field of clinical medicine
covering the diseases of the adrenal gland, the kidney,
the urinary tract and the male genital system by meansof a surgical procedure as well as an approach ofinternal medicine. In addition, urology encompasses
pediatric urology, neurourology, female urology, renaltransplantation, renal vascular surgery, endocrine
surgery and geriatric urology. For this reason, urology
requires the scientific background of oncology,
nephrology, endocrinology, andrology, immunology,
pediatrics, histology, microbiology, neurology andgerontology. Now we have commenced to utilize
cellular and molecular biology to develop the researchin urology. It is expected for our department to devote
to the scientific progress in the frontier of urology.
In recent years, we have been taking international
leadership in applying the new and minimally invasive
treatment modalities. They are exemplified byendoscopic management of the diseases in the upper
urinary tract, ESWL or laser lithotripsy for urolithiasis,
hyperthermic and laser therapies for BPH, andminimum incision endoscopic or laparoscopic
adrenalectomy, nephrectomy, and robot-assisted

Clinical activities
There are 44 beds in the ward (8th floor of the centralward-building). The professor, associate professors,
lecturers and associates are involved in in-patient andout-patient cares and teaching of the students as well
as research activities. Clinical visiting professors aremainly engaged in the teaching. The residents takecare of all the patients on 24-hour a day basis.
Associate staff members team up with the residents on
a man-to-man basis. Elective operations are performedon every weekday (from Monday to Friday). 1812
operations were performed in 2021. The numbers of
main operations are adrenalectomy 10, nephrectomy
28, partial nephrectomy 55, nephroureterectomy 19,
radical cystectomy 14, radical prostatectomy 121,transurethral resection of the bladder tumor (TUR-Bt)
260, transurethral resection of the prostate (TUR-P)
15, and robot-assisted surgeries 188 (radical
prostatectomy 121, partial nephrectomy 49, radical
cystectomy 14, pyeloplasty 4).
At the weekly professor’s round on Wednesday, dataof all in patients are presented and appropriate

229

treatment strategies are recommended for them. On
Wednesday evening, a clinical conference is held for
discussing cases with difficult problems in detail andthe best treatment is chosen for each case.
In out-patient clinic, services are provided from
Monday to Friday. Patients assigned to specialized
services as renal tumor, adrenal surgery, bladdercancer, prostate cancer, andrology, neurourology,
urolithiasis, kidney transplantation, second opinion,
pediatric urology and female urology receive
sophisticated care on the particular day of the week.
The total number of out-patients was 21,456 patientdays from January 2021 to December 2021.

References1.

2.

Teaching activities
Systematic urological lectures are provided for second
year medical students. Both clinical lectures and bed
side teaching are scheduled for third and fourth year
medical students. Thirteen times of systematic lectures
are performed by professor, associate professors andinstructors concerning their specialties.
Bed side teaching is concentrated on practical care of
the patients. Teachers give lectures mainly regarding
pre- and post-operative management, indication ofoperation, surgical anatomy and surgical techniques.

3.

Research activities

5.

There are 9 research themes for research as below.
The basic principles for research are program insurgical techniques and therapy for incurable diseases,
which include advanced cancer, renal insufficiency,
sexual dysfunction, and interstitial cystitis. We havepublished approximately 50 English papers every
year.
Renal tumor
Urolithiasis
Kidney Transplantation
Prostate diseases
New surgical technique
Urinary disturbance/ Female Urology
Andrology
Virology

4.

6.

7.

8.

Watanabe D, Akiyama Y, Niimi A, Nomiya A,
Yamada Y, Sato Y, Nakamura M, Kawai T,
Yamada D, Suzuki M, Igawa Y, Kume H, Homma
Y. Clinical characterization of interstitial cystitis/
bladder pain syndrome in women based on thepresence or absence of Hunner lesions andglomerulations. Low Urin Tract Symptoms, 13(1),139-143 202.1.
Kamei J, Aizawa N, Nakagawa T, Kaneko S,
Fujimura T, Homma Y, Kume H, Igawa Y.
Lacking transient receptor potential melastatin 2
attenuates lipopolysacchar ide induced bladderinflammation and its associated hypersensitivity
in mice. Int J Urol, 28(1),107-114,2021.1.
Yoshida S, Matsushima H, Fujii Y. Classificationof oligometastatic prostate cancer with additional
consideration for hormone sensitivity. World J
Urol, Online ahead of print,2021.1.
Takemura K, Kawai T, Sato Y, Miyakawa J,
Satoru Taguchi S, Akiyama Y, Yamada Y,
Nakamura M, Yamada D, Suzuki M, Nakagawa T,
Kume H. Impact of Initial Computed
Tomography Findings on Management ofAtypical Urinary Cytology of the Upper Urinary
Tract. Urol Int,105(7-8), 619-623,2021.1.
Takeshima Y, Suzuki M, Miyakawa J, Tsuru I,
Yamada Y, Nakamura M, Sato Y, Kawai T,
Yamada D, Morikawa T, Kume H. Latent prostatecancer among Japanese males: a bibliometricstudy of autopsy reports from 1980-2016. Jpn J
Clin Oncol, 51(1),156-159,2021.1.
Takeuchi T, Maki K, Okuno Y, Hattori-Kato M,
Mikami K. Selection of AVP-shortage patients ascandidates for low-dose oral desmopressin
administration. Res Rep Urol,13,25-30,2021.1.
Taguchi S, Nakagawa T, Uemura Y, Akamatsu N,
Gonoi W, Naito A, Kawai T, Kume H,
Fukuhara H. Comparison of major definitionsof sarcopenia based on the skeletal muscle index
in patients with urothelial carcinoma. Future
Oncology, 17, 197-203, 2021.1.
Inoue T, Okada S, Hamamoto S, Miura H,
Matsuzaki J, Tambo M, Fukuhara H, Fujisawa M,
Matsuda T, Nutahara K. Evaluation of flexible
ureteroscope with an omni-directional bending

230

9.

10.

11.

12.

13.

14.

15.

tip, using a JOYSTICK unit (URF-Y0016); an
ex-vivo study. World Journal of Urology, 39,
209-215, 2021.1.
Akiyama Y, Zaitsu M, Watanabe D, Yoshimura I,
Niimi A, Nomiya A, Yamada Y, Sato Y,
Nakamura M, Kawai T, Yamada D, Suzuki M,
Kume H, Homma Y. Relationship between thefrequency of electrocautery of Hunner lesions
and changes in bladder capacity in patients with
Hunner type interstitial cystitis. Scientific
Reports, 11(1), 105, 2021.1.
Akiyama Y, Yao JR, Kreder KJ, O'Donnell MA,
Lutgendorf SK, Lyu D, Maeda D, Kume H,
Homma Y, and Luo Y. Autoimmunity tourothelial antigen causes bladder inflammation,
pelvic pain and voiding dysfunction: a novel
animal model for Hunner type interstitial cystitis.
AmericanJournalofPhysiology-Renal
Physiology, 320(2), 174-182, 2021.2.
Shimizu T, Sugihara T, Kamei J, Takeshima S,
Kinoshita Y, Kubo T, Shinzato T, Fujimura T,
Yagisawa T. Predictive factors and managementof urinary tract infections after kidneytransplantation: a retrospective cohort study. Clin
exp nephrol, 25(2), 200-206, 2021.2.
Matsumura S, Nakamori M, Tsuji T, Kato T,
Nakamura M, Ojima T, Fukuhara H, Ino Y, Todo
T, Yamaue H. Oncolytic virotherapy with SOCS3
enhances viral replicative potency and oncolysis
for gastric cancer. Oncotarget, 12(4), 344-354,
2021.2.
Negishi T, Furubayashi N, Nakagawa T,
Nishiyama N, Kitamura H, Hori Y, Kuroiwa K,
Son Y, Seki N, Tomoda T, Okajima E, Nakamura
M. Site-specific response to nivolumab in renal
cell carcinoma. Anticancer Res, 41(3), 1539-1545,
2021.3.
Suzuki M, Kodaira M, Suyama K, MurataT,
Kume H. Continence Status and Presence ofPressure Skin Injury Among Special Elderly
Nursing Home Residents in Japan: A Nationwide
Cross-Sectional Survey. Geriatrics(Basel), 6(2),34, 2021.3.
Tsuru I, Niimi F, Honda S, Azuma T. Safety ofsame day administration of gemcitabine plus
cisplatin chemotherapy for urothelial carcinoma.
Mol Clin Oncol, 14(3), 57, 2021.3.

16. Uemura H, Matsushima H, Kobayashi K,
Mizusawa H, Nishimatsu H, Fizazi K, Smith M,
Shore N, Tammela T, Tabata K I, Matsubara N,
Iinuma M, Uemura H, Oya M, Momma T,
Kawakita M, Fukasawa S, Kobayashi T, Kuss I,
Le Berre M. A, Snapir A, Sarapohja T, Suzuki K.
Efficacy and safety of darolutamide in Japanesepatients with nonmetastatic castration-resistant
prostate cancer: a sub-group analysis of the phase
III ARAMIS trial. Int J Clin Oncol, 26(3), 578590, 2021.3.
17. Taguchi S, Tambo M, Watanabe M, Machida H,
Kariyasu T, Fukushima K, Shimizu Y, Okegawa T,
Yokoyama K, Fukuhara H. Prospective
Validation of Vesical Imaging-Reporting andData System Using a Next-Generation Magnetic
Resonance Imaging Scanner-Is Denoising Deep
Learning Reconstruction Useful?. Int J Urol,
205(3), 205(3), 686-692, 2021.3.
18. Takeshima Y, Suzuki M, Ikegaya H, Idota N,
Kawai T, Sato Y, Kume H. A cross-sectionalcadaveric study of the correlation between genitalorgan measurements, serum testosterone, andserum prostate-specific antigen levels in Japanesemale subjects. Int J Physiol Pathophysiol
Pharmacol, 13(2), 36-42, 2021.4.
19. Kakutani S, Takeshima Y, Yamada Y, Fujimura T,
Nagamoto S, Enomoto Y, Hakozaki Y, Kimura N,
Teshima T, Akiyama Y, Sato Y, Kawai T, Yamada
D, Kume H. Clinical significance and risk factors
of urethrovesical anastomotic urinary leakage
following robot-assisted radical prostatectomy: amulti-institutional study. BMC Urol, 21(1), 75,
2021.5.
20. Azuma T, Takeuchi T, Matayoshi Y, Namiki S,
Obara T, Imamura K, Takamori M. Serum
Alanine Aminotransferase as an Early Marker of
Outcomes in Patients Receiving Anti-Pd-1 or
Anti-Ctla-4 Antibody. Scientific Reports, 11(1),10264, 2021.5.
21. Blas L, Onozawa M, Shiota M, Hinotsu S,
Sakamoto S, Kitagawa Y, Kawai K, Eto M, Kume
H, Akaza H, Japan Study Group of Prostate
Cancer (J-CaP). Long-term outcomes of
androgen deprivation therapy in prostate cancer
among Japanese men over 80 years old. Cancer
Sci, Online ahead of print, 2021.5.

231

22. Takahashi S, Takei M, Asakura H, Gotoh M,
Ishizuka O, Kato K, Koyama M, Takeyama M,
Tomoe H, Yamanishi T, Yokoyama O, Yoshida M,
Yoshimura Y, Yoshizawa T. Clinical Guidelines
for Female Lower Urinary Tract Symptoms(second edition). Int J Urol, 28(5), 474-492,
2021.5.
23. Takeshima Y, Yamada Y, Teshima T, Fujimura T,
Kakutani S, Hakozaki Y, Kimura N, Akiyama Y,
Sato Y, Kawai T, Yamada D, Kume H. Clinicalsignificance and risk factors of International
Society of Urological Pathology (ISUP) grade
upgrading in prostate cancer patients undergoingrobot-assisted radical prostatectomy. BMC
Cancer, 21, 105, 2021.5.
24. Kinjo M, Nakamura Y, Taguchi S, Yamaguchi T,
Tambo M, Okegawa T, Fukuhara H. Sex
Differences in Prevalence and Patient Behavior
Regarding Lower Urinary Tract Symptoms
Among Japanese Medical Checkup Examinees.
Urology, 151, 24-30, 2021.5.
25. COVID Surg Collaborative; Global Surg
Collaborative. Timing of surgery following
SARS-CoV-2
infection:aninternational
prospective cohort study. Anaesthesia, 76(6),748-758, 2021.6.
26. Kitamura T, Suzuki M, Shigehara K, Fukuda K.
Prevalence and Risk Factors of Human
Papillomavirus Infection among Japanese Female
People: A Nationwide Epidemiological Survey by
Self-Sampling. Asian Pac J Cancer Prev, 22(6),1843-1849, 2021.6.
27. Manaka K, Sato J, Takeuchi M, Watanabe K,
Kage H, Kawai T, Sato Y, Miyagawa T, Yamada
D, Kume H, Sato S, Nagase T, Iiri T, Nangaku M
and Makita N. Immune checkpoint inhibitor
combination therapies very frequently induce
secondary adrenal insufficiency. Scientific
Reports, Open Access, 2021.6.
28. Fujii Y, Sato Y, Suzuki H, Kakiuchi N, Yoshizato
T, Lenis A, Maekawa S, Yokoyama A, Takeuchi Y,
Inoue Y, Ochi Y, Shiozawa S, Aoki K, Yoshida K,
Kataoka K, Nakagawa M, Nannya Y, Makishima
H, Miyakawa M, Kawai T, Morikawa T, Shiraishi
K, Chiba K, Tanaka H, Nagae G, Sanada M,
Sugihara E, Sato T, Nakagawa T, Fukayama M,
Ushiku T, Aburatani H, Miyano S, Coleman J,

29.

30.

31.

32.

33.

34.

Homma Y, Solit D, Kume H, Ogawa S.
Molecular classification and diagnostics of upper
urinary tract urothelial carcinoma. Cancer Cell,
39(6), 793-809, 2021.6.
Nakamura M, Ambe Y, Teshima T, Shirakawa N,
Inatsu H, Amakawa R, Inoue Y, Yoshimatsu T,
Imai S, Kusakabe M, Morikawa T, Kameyama S,
Shiga Y. Assessment of surgical outcomes ofoff-clamp open partial nephrectomy without
renorrhaphy for ≥T1b renal tumours. Int J Clin
Oncol, Online ahead of print, 2021.6.
Dannno T, Iwata S, Niimi F, Honda S, Okada H,
Azuma T. Nivolumab and Ipilimumab Combination Immunotherapy for Patients with MetastaticCollecting Duct Carcinoma. Nivolumab andIpilimumab Combination Immunotherapy for
Patients with Metastatic Collecting Duct
Carcinoma, Open Access, 2021.6.
Takayama Ki, Kosaka T, Suzuki T, Hongo H,
Oya M, Fujimura T, Suzuki Y, Inoue S.
Subtype-specificcollaborativetranscription
factor networks are promoted by OCT4 in the
progression of prostate cancer. Nature
Communications, 12, 3766, 2021.6.
Tohi Y, Kato T, Yokomizo A, Mitsuzuka K,
Tomida R, Inokuchi J, Matsumoto R, Saito T,
Sasaki H, Inoue K, Kinoshita H, Fukuhara H,
Maruyama S, Sakamoto S, Tanikawa T, Egawa S,
Ichikura H, Abe T, Nakamura M, Kakehi Y,
Sugimoto M. Impact of health-related quality oflife on repeat protocol biopsy compliance on
active surveillance for favorable prostate cancer:
results from a prospective cohort in the PRIASJAPAN study. Urol Oncol, Online ahead of print,
2021.6.
Kinno K, Sekido N, Takeuchi Y, Sawada Y,
Watanabe S, Yoshimura Y. Association between
overactive bladder and pelvic organ mobility as
evaluated by dynamic magnetic resonanceimaging. Sci. Rep, 11, 18148, 2021.7.
Uchihashi T, Nakahara H, Fukuhara H, Iwai M,
Ito H, Sugauchi A, Tanaka M, Kogo M, Todo T.
Oncolytic herpes virus G47Δ injected into tongue
cancer swiftly traffics in lymphatics andsuppresses metastasis. Mol Ther Oncolytics, 22,388-398, 2021.7.

232

35. Kato T, Hirama H, Mitsuzuka K, Maruyama S,
Sasaki H, Saito T, Matsumoto R, Sakamoto S,
Sakai Y, Fukuhara H, Naya Y, Tsukino H, Hara I,
Ogawa O, Hashine K, Fumimasa F, Yokomizo A,
Tohi Y, Kakehi Y, Sugimoto M. Reclassification
prediction of first-year protocol biopsy on active
surveillance of prostate cancer by p2PSA-relatedparameters: from PRIAS-JAPAN. Prostate
Cancer Prostatic Dis, Online ahead of print,
2021.7.
36. COVID Surg Collaborative; Global Surg
Collaborative. SARS-CoV-2 infection and venous
thromboembolism after surgery: an international
prospective cohort study. Anaesthesia, Online
ahead of print, 2021.8.
37. Wada K, Yokoyama T, Uno S, Araki M, SadahiraT, Maruyama Y, Acosta H, Nakajima H, Hiyama
Y, Kunishima Y, Togo Y, Nukaya T, Yamada H,
Shigemura K, Ito S, Tanimura M, Kobayashi K,
Kitano H, Teishima J, Yasuda M, Watanabe T,
Nakagawa T, Hayami H, Miyazaki J, Takahashi S,
Masumori N, Ishikawa K, Kiyota H, Fujisawa M,
Arakawa S, Nasu Y, Yamamoto S. Nationwide
surveillance of bacterial pathogens isolated frompatients with acute uncomplicated cystitis in
2018: conducted by the Japanese Research Groupfor Urinary Tract Infections (JRGU). J InfectChemother, 27(8), 1169-1180, 2021.8.
38. Taguchi S, Kawai T, Nakagawa T, Nakamura Y,
Kamei J, Obinata D, Yamaguchi K, Kaneko T,
Kakutani S, Tokunaga M, Uemura Y, Sato Y,
Fujimura T, Fukuhara H, Enomoto Y, Nishimatsu
H, Takahashi S, Kume H. Prognostic significanceof the albumin-to-globulin ratio for advanced
urothelial carcinoma treated with pembrolizumab: A multicenter retrospective study. Scientific
Reports, 11(1), 15623, 2021.8.
39. Imai S, Nakamura M, Chujo S, Ooki R, Inoue Y,
Horiuchi H, Morikawa T, Uchino K, Igarashi A,
Shiga Y. Immune-related dermatitis during
combined treatment with pembrolizumab andaxitinib in a patient with metastatic renal cell
carcinoma with stasis dermatitis: A case report.
IJU Case Rep, Open Access, 2021.8.
40. Yamada D, Kawai T, Sato Y, Yamada Y, Akiyama
Y, Miyakawa J, Takahashi S, Kume H. Trends
in prostate cancer diagnosis during the

41.

42.

43.

44.

45.

46.

47.

48.

COVID-19 crisis: A report from one high-volume
Japanese center. GHM Open, 1(1), 28-30, 2021.8.
Uemura H, Matsushima H, Yokomizo A,
Kobayashi K, Arai G, Satoh T, Grillo V, Chen Y,
Singh S, Athene Ledesma D. Unmet needs in
non-metastatic castraton-resistant prostate cancerfrom the Japaneses patient perspective: a discrete
choicec experiment. BMJ Open, 11(8), 2021.8.
Fukuhara H, Takeshima Y, Todo T. Triplemutated oncolytic herpes virus for treating both
fast- and slow-growing tumors. Cancer Sci,
112(8), 3293-3301, 2021.8.
Oshina T, Taguchi S, Miyakawa J, Akiyama Y,
Sato Y, Kawai T, Fukuhara H, Nakagawa T,
Kume H. Clinicopathological features andoncological outcomes of urothelial carcinoma
involving the ureterovesical junction. Jpn J Clin
Oncol, Online ahead of print, 2021.9.
Hagiwara K, Sakamoto A, Sasaki K, Kanatani A,
Kimura M, Kaneko T, Takahashi S, Yamada Y,
Nakagawa T. Higher serum alkaline phosphatasevalue indicates the need for bone mineral density
testing in non-metastatic prostate cancer patients
undergoing androgen deprivation therapy. Jpn J
Clin Oncol, Online ahead of print, 2021.9.
COVID Surg Collaborative; Global Surg
Collaborative. SARS-CoV-2 vaccination modelling for safe surgery to save lives: data from aninternational prospective cohort study. Br J Surg,
108(9), 1056-1063, 2021.9.
Takayama T, Fujita A, Sugihara T, Fujisaki A,
Yamazaki M, Kameda T, Kamei J, Ando S,
Kurokawa S, Fujimura T. Natural history ofasymptomatic renal artery pseudoaneurysm after
robot-assisted partial nephrectomy. Transl Androl
Urol, 10(9), 3555-3565, 2021.9.
Kinjo M, Tanba M, Masuda K, Nakamura Y,
Tanbo M, Fukuhara H. Comparison ofeffectiveness between modified transvaginal
mesh surgery and vaginal pessary treatment inpatients with symptomatic pelvic organ prolapse.
Low Urin Tract Symptoms, Online ahead of print,
2021.9.
Kitamura J, Taguchi S, Okegawa T, Honda K, Kii
T, Tomida Y, Matsumoto R, Ninomiya N, Masuda
K, Nakamura Y, Yamaguchi T, Kinjo M, Tambo
M, Isomura A, Hayashi A, Kamma H,

233

49.

50.

51.

52.

53.

54.

55.

Higashihara E, Shibahara J, Fukuhara H.
Genomic analysis of circulating tumor cells inadenosquamous carcinoma of the prostate: a casereport. BMC Med Genomics, 14(1), 217, 2021.9.
Shigemori K, Higashihara E, Itoh M, Yoshida H,
Yamamoto K, Nutahara K, Shiokawa Y, Kaname
S, Tambo M, Yamaguchi T, Taguchi S, Yoshioka
T, Yokoyama K, Fukuhara H. PKD1-AssociatedArachnoid Cysts in Autosomal Dominant
Polycystic Kidney Disease. J Stroke Cerebrovasc
Dis, 30(9), 105943, 2021.9.
Sakaguchi K, Hayashida M, Tanaka N, Oka S,
Urakami S. sk model for detecting clinicallysignificant prostate cancer based on bi-parametricmagnetic resonance imaging in a Japanese cohort.
Scientific Reports, 11(1), 18829, 2021.9.
Kinoshita Y, Katano S, Nishida S, Shimizu T,
Fujimura T, Kume H, Iwami D. Creatinine
reduction ratio on postoperative day 2 predicts
long-term outcomes after living donor kidneytransplantation. Int J Urol, Online ahead of print,
2021.10.
Jimba M, Matsuzawa Y, Suzuki M, Kitamura T,
Carandang R, Sieber N. Risk of increasing thesudden diagnosis of AIDS in Japan during andafter COVID-19 outbreak. JMA Journal, Online
ahead of print, 2021.10.
Akiyama Y, Niimi A, Igawa Y, Nomiya A,
Yamada Y, Sato Y, Kawai T, Yamada D, Kume H,
Homma Y.
Cystectomy for patients with
Hunner type interstitial cystitis at a tertiaryreferral center in Japan. Low Urin Tract
Symptoms. Low Urinary Tract Symptoms,
Online ahead of print, 2021.10.
Yamada Y, Nakagawa T, Miyakawa J, Kawai T,
Tabata M, Kaneko T, Taguchi S, Naito A, Hikatsu
M, Sato Y, Murata T, Matsumoto A, Miyazaki H,
Suzuki M, Enomoto Y, Nishimatsu H, Kondo Y,
Takeuchi T, Tanaka Y, Kume H. Smaller declineof renal function after nephroureterectomy
predicts poorer prognosis of upper tract urothelial
carcinoma: a multicentre retrospective study. Jpn
J Clin Oncol, 51(10), 1577-1586, 2021.10.
Kamei J, Fujisaki A, Saito K, Sugihara T, Ando S,
Miyagawa T, Takayama T, Fujimura T. Less
invasive and equivalent short-term outcomes withsimultaneous en bloc robot-assisted radical

56.

57.

58.

59.

60.

61.

62.

cystectomy
andlaparoscopic
nephroureterectomy: Comparison with conventional
open radical cystectomy and nephroureterectomy.
Asian J Endosc Surg, Online ahead of print,
2021.10.
Tohi Y, Kato T, Nakamura M, Matsumoto R,
Sasaki H, Mitsuzuka K, Inokuchi J, Hashine K,
Yokomizo A, Naito H, Hara I, Kawamura N,
Inoue M, Fukuhara H, Maruyama S, Sakamoto S,
Saito T, Egawa S, Kakehi Y, Sugimoto M.
Deferred radical prostatectomy in patients who
initially elected for active surveillance: amulti-institutional, prospective, observational
cohort of the PRIAS-JAPAN study. Int J Clin
Oncol, Online ahead of print, 2021.10.
Ando S, Kamei J, Yamazaki M, Sugihara T,
Kameda T, Fujisaki A, Kurokawa S, Takayama T,
Fujimura T. Longer preserved urethral length inrobot-assisted radical prostatectomy significantly
contributes to post-operative urinary continence
recovery. BJUI Compass, Online ahead of print,
2021.11.
COVID Surg Collaborative; Global Surg
Collaborative. Effects of pre-operative isolation
on postoperative pulmonary complications after
elective surgery: an international prospective
cohort study. Anaesthesia, 6(11), 1545-1464,
2021.11.
Nomura, Y., Okada, Y., Hiramatsu, A., Matsubara,E., Kato, K., Yoshimura, Y. A new method ofadjusting mesh tension using cystoscopy during
laparoscopic sacrocolpopexy. Int Urogynecology
Journal, 32(11), 3089-3093, 2021.11.
Akiyama Y, Miyakawa J, O’Donnell MA, Kreder
KJ, Luo Yi, Maeda D, Ushiku T, Kume H,
Homma Y. Overexpression of HIF1α in HunnerLesionsofInterstitial
Cystitis:
Pathophysiological Implications. J Urol, Online aheadof print, 2021.11.
Yokomizo A, Yonese J, Egawa S, Fukuhara H,
Uemura H, Nishimura K, Nagata M, Saito A, Lee
T, Yamaguchi S, Nonomura N. Real-world use of
enzalutamide in men with nonmetastatic
castration-resistant prostate cancer in Japan. Int J
Clin Oncol, Online ahead of print, 2021.11.
Fujisaki A, Takayama T, Teratani T, Kubo T,
Kamei J, Sugihara T, Ando S, Morita T, Fujimura

234

T. Histological and radiological evaluation ofthermal denaturation depth using soft coagulation
during partial nephrectomy in living pigs. Int J
Urol, 28(12), 1274-1280, 2021.12.
63. Higashihara E, Nutahara K, Itoh M, Okegawa T,
Tambo M, Yamaguchi T, Nakamura Y, Taguchi S,
Kaname S, Yokoyama K, Yoshioka T, Fukuhara
H. Long-term outcomes of longitudinal efficacy
study with tolvaptan in autosomal dominant
polycystic kidney disease. Kidney International
Reports, 7(2), 270-281, 2021.12.

235

Department of Surgical Oncology
Professor
Soichiro Ishihara, M.D., Ph.D.

Associate Professor
Hiroaki Nozawa, M.D., Ph.D., Kazushige Kawai, M.D., Ph.D.

Lecturer
Kazuhito Sasaki, M.D., Ph.D.

Assistant Professor
Shigenobu Emoto, M.D., Ph.D., Koji Murono, M.D., Ph.D., Tsuyoshi Ozawa, M.D., Ph.D.,
Yuichiro Yokoyama, M.D., Ph.D., Shinya Abe, M.D., Ph.D., Yuzo Nagai, M.D., Ph.D.,
Hiroyuki Anzai, M.D., Ph.D., Hirofumi Sonoda, M.D., Pharm.D., Ph.D.,
Yoko Yamamoto, Ph.D.

Homepage

http://all-1su.umin.jp/

Introduction and Organization
In 1995, a new system for postgraduate education
was introduced. The First Department of Surgery was
reorganized to form the Department of Surgical
Oncology and the Department of Vascular Surgery.
The staff of the Department of Surgical Oncology
consists of one Professor, two Associate Professor,
one Lecturers and nine Assistant Professors. The
outpatient office is located on the third floor of the
Outpatient Building. The ward is situated on theeighth floor of the Ward Building. The administrative
office and research laboratories are located in the
Administration and Research Building. Current
activities of the Department of Surgical Oncology inclinical practice, education, and research aresummarized as follows.

Clinical activities
The Department of Surgical Oncology provides
comprehensive evaluation, diagnosis, treatment andmanagement for adult patients with both general andoncologic surgical problems, in the ambulatory as wellas inpatient setting. In particular, we are trying to

identify the best way to treat each patient with theleast surgical stress by minimally invasive surgery
such as laparoscopic surgery and robotic surgery (daVinci Surgical System), and preoperative chemoradiotherapy for rectal cancer. The department is also wellknown for its innovative therapy for inflammatory
bowel disease. Department specialists have expertisein biological cancer immunotherapy, chemotherapy
for a variety of malignancies, and radiotherapy forrectal cancer. The outpatient clinic is open from
Monday through Friday, and twenty-four-hour consultation is available for urgent or emergency problems.
The outpatient clinic is specialized in the lower GI
tract. The Department was responsible for 555
surgically treated inpatients in the year of 2021. On
Monday, Wednesday and Friday mornings, pre- andpost-surgery conferences are held, and the Director'sRound takes place after the conference every
Wednesday. Operating days are Monday, Tuesday andThursday. In addition to the clinical conferences,
research conferences are held every Monday morning.
Each research unit holds its own conference every
week. Over 1200 colonoscopies are performed for ayear. The newest technologies are introduced for236

diagnosis and treatment of colon and rectal cancer andlong-term surveillances for inflammatory bowel
disease are performed.

Teaching activities
The Department of Surgical Oncology also offers afellowship in surgical oncology for well-qualified
surgeons who have completed their training in generalsurgery and wish to further specialize in surgicaloncology. The Department of Surgical Oncology has a
Surgical Oncology Training Program and provides
broad reaching experience in technical aspects ofdiagnosis, treatment and management for adultpatients with both surgical and oncologic problems,development of surgical judgment, and increasing
knowledge about routine and complex conditions. In
addition, the dedicated staff allows multiple
opportunities for academic development both along
clinical and basic scientific lines.
In the undergraduate education program, ourdepartment plays a role in the systemic lecture and in
the clinical introduction lecture for the 2nd year
medical students. We offer the clinical lectures and thebedside learning program for 3rd year medical
students, in cooperation with other departments ofsurgery. In the systemic lectures on surgery, various
fields were covered such as surgical oncology andimmunology, injury, somatic reaction to surgery,
infectious diseases, shock, pre- and post-surgicalmanagement and nutrition. In the clinical lectures, we
presented many diseases such as colon cancer, colonicpolyp, colonic polyposis and inflammatory bowel
disease. In the postgraduate education program, newresidents are trained to become qualified surgeons. In
addition to pre- and post-surgery clinical conferences,
the residents are expected to attend research
conferences and seminars, which are held periodically.
They are also asked to present cases at clinicalmeetings, which are held locally such as the local
meeting of the Japanese Society of Gastroenterology.

Research activities
We apply the techniques used in molecular andcellular biology to our research. The following are themajor themes under research.
1) Preoperative radiotherapy in lower rectal cancer

2)
3)
4)
5)
6)

Cancer surveillance in ulcerative colitis
Carcinogenesis in ulcerative colitis
Laparoscopically assisted colon surgery
Local immunity in colorectal cancer
Genetic analysis of colorectal cancer andadenoma
7) Prognostic factor of early colorectal cancer8) Surveillance program following colectomy forcolorectal cancer
9) Analysis of factors associated with conversion
surgery in initially unresectable/metastatic
colorectal cancer10) Cancer Immunotherapy targeting to the tumor
vessels11) Autophagy in Oncology
12) Lipid metabolism in carcinogenesis and tumor
progression13) Pathological studies in obstructive colorectal
cancer14) Genetic analysis on sensitivity to chemotherapeutic agents15) Hemostasis and fibrinolysis in Oncology16) Intraabdominal chemotherapy for peritoneal
metastasis of gastric cancer17) Pharmacokinetics in intraperitoneal chemotherapy18) Clinical trials of chemotherapeutic drugs inmetastatic colorectal cancer (single- or
multi-institutional)
19) Single nucleotide polymorphisms (SNPs) ininflammatory bowel disease20) Anatomy of vessels feeding the colon and rectum21) High Frequency Ultrasonography (HIFU) for
solid cancer22) Quantitative analysis of intraperitoneal cancer
cells in peritonitis carcinomatosis23) Immunomodulation in chemoradiotherapy for
locally advanced rectal cancer24) Robot assisted laparoscopic colorectal surgery
25) Postoperative defecation function, urinary
function, and sexual function after rectal cancer
surgery26) Application of 3D images and 3D printers incolorectal surgery27) Navigation surgery28) AI endoscopic diagnosis
29) AI pathological diagnosis30) Microbiome in colorectal cancer

237

References
1.

2.

3.

4.

5.

6.

7.

8.

9.

Arakawa T, Ishihara S. Omental Endometriosis.
The New England journal of medicine. 2021;
384(7):e21.
Emoto S, Hata K, Nozawa H, Kawai K, Tanaka T,
Nishikawa T, et al. Risk factors for non-reachingof ileal pouch to the anus in laparoscopic
restorative proctocolectomy with handsewn
anastomosis for ulcerative colitis. Intest Res.
2021.
Fukui R, Nozawa H, Hirata Y, Kawai K, Hata K,
Tanaka T, et al. Low preoperative maximum
squeezing pressure evaluated by anorectal
manometry is a risk factor for non-reversal ofdiverting stoma. Langenbecks Arch Surg. 2021;
406(1):131-9.
Fukui R, Sasaki K, Kawai K, Taira T, Nozawa H,
Kaneko M, et al. Establishing a novel method forassessing elasticity of internal anal sphincter
using ultrasonic real-time tissue elastography.
ANZ journal of surgery. 2021;91(6):E360-e6.
Harada Y, Kazama S, Morikawa T, Sonoda H,
Ishi H, Emoto S, et al. Clinical significanceof CD8(+) and FoxP3(+) tumor-infiltrating
lymphocytes and MFG-E8 expression in lower
rectal cancer with preoperative chemoradiotherapy. Molecular and clinical oncology.
2021;14(5):87.
Hojo D, Kawai K, Murono K, Nozawa H, Hata K,
Tanaka T, et al. Establishment of deformable
three-dimensional printed models for laparoscopic right hemicolectomy in transverse coloncancer. ANZ journal of surgery. 2021;91(7-8):
E493-e9.
Hojo D, Murono K, Nozawa H, Kawai K, Hata K,
Tanaka T, et al. Improvement in Surgical
Outcomes Using 3D Printed Models for Lateral
Pelvic Lymph Node Dissection in Rectal Cancer.
Dis Colon Rectum. 2021.
Iida T, Murono K, Shiratori H, Nozawa H, Kawai
K, Sasaki K, et al. Impact of Inferior Mesenteric
Artery Occlusion on the Calibre of Collateral
Arteries of the Colon. Anticancer research. 2021;
41(10):5189-93.
Inagaki Y, Kawai K, Nishikawa T, Ishii H, Emoto
S, Murono K, et al. Analysis of the Positional

10.

11.

12.

13.

14.

15.

16.

17.

Relationship Among the Operator, Camera, andMonitor: Overcoming the Difficulties of
Mirror-image Conditions During Laparoscopic
Surgery. Surgical laparoscopy, endoscopy &percutaneous techniques. 2021.
Inoue H, Sasaki K, Nozawa H, Kawai K, Murono
K, Emoto S, et al. Therapeutic significance of D3
dissection for low rectal cancer: a comparison ofdissections between the lateral pelvic lymph
nodes and the lymph nodes along the root of theinferior mesenteric artery in a multicenter
retrospective cohort study. Int J Colorectal Dis.
2021;36(6):1263-70.
Ishimaru K, Kawai K, Nozawa H, Sasaki K,
Murono K, Emoto S, et al. Hazard function
analysis of metastatic recurrence after colorectal
cancer surgery-A nationwide retrospective study.
Journal of surgical oncology. 2021;123(4):101522.
Kamada Y, Hida K, Yonemura Y, Sugarbaker PH,
Ghabra S, Ishihara S, et al. The Characteristics of
206 Long-Term Survivors with Peritoneal
Metastases from Colorectal Cancer Treated withCurative Intent Surgery: A Multi-Center Cohortfrom PSOGI. Cancers (Basel). 2021;13(12).
Kaneko M, Nozawa H, Rokutan H, Murono K,
Ushiku T, Ishihara S. Ectopic decidua of theappendix: a case report. Surgical case reports.
2021;7(1):117.
Kawai K, Nozawa H, Hata K, Tanaka T,
Nishikawa T, Sasaki K, et al. Classification of thecolonic splenic flexure based on threedimensional CT analysis. BJS open. 2021;5(1).
Kawai K, Nozawa H, Sasaki K, Murono K,
Ishihara S. Hazard function analysis fordevelopment of second primary colorectal cancer
after surgery for primary colorectal cancer.
Journal of gastroenterology and hepatology.
2021.
Kawai K, Shiratori H, Hata K, Nozawa H,
Tanaka T, Nishikawa T, et al. Optimal Size
Criteria for Lateral Lymph Node Dissection After
Neoadjuvant Chemoradiotherapy for Rectal
Cancer. Dis Colon Rectum. 2021;64(3):274-83.
Kitamura C, Sonoda H, Anzai H, Nagai Y, Abe S,
Yokoyama Y, et al. Expression of Lysophosphatidylinositol Signaling-relevant Molecules

238

18.

19.

20.

21.

22.

23.

24.

25.

26.

in Colorectal Cancer. Anticancer research. 2021;
41(5):2349-55.
Kobayashi T, Ikeda M, Ohama Y, Murono K,
Ikeuchi K, Kitaura S, et al. First human case ofcatheter-related blood stream infection caused by
Staphylococcus schleiferi subspecies coagulans:a case report and literature review. Ann Clin
Microbiol Antimicrob. 2021;20(1):68.
Kokudo T, Saiura A, Takayama T, Miyagawa S,
Yamamoto J, Ijichi M, et al. Adjuvant
chemotherapy can prolong recurrence-freesurvival but did not influence the type ofrecurrence or subsequent treatment in patientswith colorectal liver metastases. Surgery. 2021.
Miyake H, Kawai K, Nozawa H, Sasaki K,
Kaneko M, Murono K, et al. Less intensive
surveillance after radical surgery for stage I-III
colorectal cancer by focusing on the doublingtime of recurrence. Surg Today. 2021;51(4):55060.
Murai S, Kawai K, Sonoda H, Nozawa H, Sasaki
K, Murono K, et al. Computed tomographic
colonography versus double-contrast barium
enema for the preoperative evaluation of rectal
cancer. Surg Today. 2021.
Murono K, Nozawa H, Kawai K, Sasaki K,
Emoto S, Kishikawa J, et al. Vascular anatomy of
the splenic flexure: a review of the literature.
Surg Today. 2021.
Nozawa H, Emoto S, Sonoda H, Kawai K, Sasaki
K, Kaneko M, et al. Liver Injury AmongJapanese Patients Treated Using Prophylactic
Enoxaparin After Colorectal Surgery. Dig Dis Sci.
2021;66(8):2805-15.
Nozawa H, Ishizawa T, Yasunaga H, Ishii H,
Sonoda H, Emoto S, et al. Open and/or
laparoscopic one-stage resections of primarycolorectal cancer and synchronous liver
metastases: An observational study. Medicine.
2021;100(11):e25205.
Nozawa H, Kawai K, Sasaki K, Murono K,
Emoto S, Yokoyama Y, et al. Women are
predisposed to early dose-limiting toxicities
during adjuvant CAPOX for colorectal cancer. Int
J Clin Pract. 2021:e14863.
Ochiai K, Kawai K, Nozawa H, Sasaki K,
Kaneko M, Murono K, et al. Prognostic Impact

27.

28.

29.

30.

31.

32.

33.

34.

and Clinicopathological Features of Multiple
Colorectal
Cancers
andExtracolorectal
Malignancies: A Nationwide Retrospective Study.
Digestion. 2021:1-10.
Ochiai K, Kobayashi E, Tsukihara H, Nozawa H,
Kawai K, Sasaki K, et al. Stereotactic Navigation
System for Laparoscopic Lateral Pelvic Lymph
Node Dissection. Dis Colon Rectum. 2021;64(6):e372-e7.
Okada M, Kawai K, Sonoda H, Shiratori H,
Kishikawa J, Nagata H, et al. Epithelialmesenchymal transition and metastatic ability ofCD133(+) colorectal cancer stem-like cells underhypoxia. Oncology letters. 2021;21(1):19.
Okada S, Hata K, Shinagawa T, Noguchi T,
Tanaka T, Kawai K, et al. A Polymorphism inInterleukin-1β Gene Is Associated with theDevelopment of Pouchitis in Japanese Patientswith Ulcerative Colitis. Digestion. 2021;102(3):489-98.
Okamoto K, Emoto S, Sasaki K, Nozawa H,
Kawai K, Murono K, et al. Extended Left
Colectomy with Coloanal Anastomosis by
Indocyanine Green-guided Deloyers Procedure: A
Case Report. J Anus Rectum Colon. 2021;5(2):202-6.
Okamoto K, Nozawa H, Hongo K, Iida Y, Kawai
K, Sasaki K, et al. Risk factors of mFOLFOX6induced hyperammonemia in patients withcolorectal cancer: an observational study.
International journal of clinical oncology. 2021;
26(8):1477-84.
Ozaki K, Kawai K, Nozawa H, Sasaki K, Murono
K, Emoto S, et al. Therapeutic effects andlimitations of chemoradiotherapy in advanced
lower rectal cancer focusing on T4b. Int J
Colorectal Dis. 2021;36(7):1525-34.
Ozaki K, Kawai K, Nozawa H, Sasaki K, Murono
K, Ishihara S. Development of a novel
apoptosis-based tumor regression grade to assess
the efficacy of preoperative chemoradiotherapy
for rectal cancer: a retrospective single-center
study. International journal of clinical oncology.
2021;26(9):1679-88.
Ozawa T, Hashiguchi Y, Ishihara S, Hayama T,
Tsuchiya T, Nozawa K, et al. Proposal for a
post-operative surveillance strategy for stage I

239

35.

36.

37.

38.

39.

40.

41.

colorectal cancer patients based on a novel
recurrence risk stratification: a multicenter
retrospective study. Int J Colorectal Dis. 2021;
36(1):67-74.
Ozawa T, Matsuda K, Ishihara S, Fukushima Y,
Shimada R, Hayama T, et al. The robust
performance of carcinoembryonic antigen levels
after adjuvant chemotherapy for the recurrence
risk stratification in patients with colorectal
cancer. Journal of surgical oncology. 2021;
124(1):97-105.
Saito H, Tanimoto T, Ozawa T, Ishihara S,
Fujishiro M, Shichijo S, et al. Automaticanatomical classification of colonoscopic images
using deep convolutional neural networks.
Gastroenterol Rep (Oxf). 2021;9(3):226-33.
Sakamoto A, Nozawa H, Sonoda H, Hinata M,
Ishii H, Emoto S, et al. Rectal neuroendocrine
tumor with extracapsular lymph node metastasis:a case report. Clinical journal of gastroenterology.
2021.
Sasaki K, Nozawa H, Kawai K, Murono K,
Emoto S, Kishikawa J, et al. Risk of extracolonicmalignancies and metachronous rectal cancer
after colectomy and ileorectal anastomosis in
familial adenomatous polyposis. Asian journal ofsurgery / Asian Surgical Association. 2021.
Sasaki K, Yoshimi F, Kawasaki H, Hayashi H,
Hiyoshi M, Nagai H, et al. Usefulness of thegracilis muscle flap for reconstruction of large
perineal defects following total pelvic
exenteration with sacrectomy. ANZ journal ofsurgery. 2021;91(9):1932-4.
Tachikawa Y, Nozawa H, Hata K, Abe H, Ushiku
T, Ishihara S. Metachronous ileal cancer after
surgery for ascending colon cancer in a patientwith Lynch syndrome: A case report. International journal of surgery case reports. 2021;81:
105714.
Tachikawa Y, Nozawa H, Otani K, Emoto S,
Sonoda H, Mori K, et al. Definition andcharacterization of the descending branch of theleft colic artery. Abdom Radiol (NY). 2021;
46(7):2993-3001.

240

Department of Vascular Surgery
Associate Professor and Chief of Vascular Surgery
Katsuyuki Hoshina, M.D., Ph.D.

Lecturer
Toshio Takayama, M.D., Ph.D.

Assistant Professor
Ryosuke Taniguchi, M.D., Ph.D., Yasuaki Mochizuki, M.D., Ph.D.,
Masamitsu Suhara, M.D., Ph.D., Kazuhiro Miyahara, M.D., Ph.D.

Homepagehttps://vascular-1su.jp/

Introduction and Organization
In 1995, a new system for postgraduate education
was introduced. The First Department of Surgery was
reorganized to form the Department of Vascular
Surgery and the Department of Surgical Oncology.
The staff of the Department of Vascular Surgery
consists of one Associate Professor, one Lecturer, andfour Assistant Professors. The outpatient office islocated on the third floor of the Outpatient Building.
The ward is situated on the eighth floor of the Ward
Building. The administrative office and researchlaboratories are located in the Administration andResearch Building. Current activities of the
Department of Vascular Surgery in clinical practice,education, and research are summarized as follows.

Clinical activities
The Department of Vascular Surgery has anextensive clinical program in both primary and tertiarycare for vascular problems, and manages patients with
peripheral arterial occlusion, abdominal and thoracoabdominal aortic aneurysms, peripheral aneurysm,
visceral arterial occlusion, carotid artery disease andcommon disorders of the venous circulation such asvaricose veins and venous leg ulcers. State-of-the-art
techniques of percutaneous transluminal angioplasty,
angioscopy and intraoperative ultrasonography areavailable for the treatment of peripheral arterial

disease. And endovascular aneurysm repair was alsoavailable for the treatment of abdominal aortic
aneurysm. The outpatient clinic is open from Monday
through Friday, and twenty-four-hour consultation isavailable for urgent or emergency problems.
Included in the department is the non-invasive
Clinical Vascular Laboratory, which sees over 500
patients per year, with broad reaching expertise inperipheral vascular diagnostic modalities. Also thedepartment has an active angiography program, which
encompasses all aspects of diagnostic and therapeuticintervention in over 500 patients per year and a fullrange of other support and collaborative services.
On Monday, Wednesday and Friday mornings, preand post-surgery conferences are held. Operating days
are Monday, Tuesday and Thursday. The vascularclinical conference is held every Tuesday evening.

Teaching activities
The operative procedure should be the basics ofsurgery. In 2017, the Japanese Board of
Cardiovascular Surgery announced that 30 hours of
Off JT experience will be required for new
cardiovascular specialist applicants. Responding tothis announcement and taking into consideration thesocial request for change in recent years, The JapaneseSociety for Vascular Surgery created the Off JT
working group to create a new framework for Off JT.

241

Thus far, there has not been a versatile Off JT systemthat can be used in any institution with young
surgeons. Therefore, in our department, we aimed todevelop a simple and inexpensive Off JT system thatcan be used at any institution with medical students
and young surgeons. We developed a new Off JT
system that is simple and inexpensive and can be used
at any institution with medical students and young
surgeons. The effectiveness and appropriateness of
this system were confirmed by the learning curve,
analysis of the balance of the anastomosis, and scoringby the trainers. In addition, we demonstrated therelationships among time, performance, and skill. We
will set this system as one of the educational methods
for surgeons.
The Department of Vascular Surgery also offers afellowship in vascular surgery for well-qualified
surgeons who have completed their training in generalsurgery and wish to further specialize in vascularsurgery. The Department of Vascular Surgery has a
Vascular Surgery Training Program and provides
broad reaching experience in technical aspects ofvascular surgery, development of surgical judgment,
and increasing knowledge about routine and complex
conditions. In addition, the dedicated staff offers
multiple opportunities for academic development bothalong clinical and basic scientific lines.
In the undergraduate education program, theDepartment of Vascular Surgery plays a role in thesystemic and clinical lectures and the bedside learning
program for 3rd year medical students, in cooperation
with other departments of surgery. In the postgraduate
education program, new residents are trained to
become qualified surgeons in our department. The
Department of Vascular Surgery is involved with theeducation program of the post-graduate education
meeting, which is held monthly. In addition to preand post-surgery clinical conferences, the residents are
expected to attend research conferences and seminars,
which are held periodically.

Research activities
The Department of Vascular Surgery includes major
research laboratories for academic development bothalong clinical and basic scientific lines. The clinicalvascular laboratories are approaching completely non-invasive testing for vascular disorders, analyzing
essential physiologic information about the specificproblems being addressed. The basic vascularlaboratories are actively performing research on
endothelial biology, the mechanism of intimal
hyperplasia, microcirculation, application of genetherapy to vascular surgery and vascular prosthesis
development. Vascular research meeting is held every
month on Saturday morning. The following are themajor themes under research.
1) Navigation system for less invasive vascularsurgery2) Pathophysiology of the development of theaneurysm
3) Pathophysiology of stent restenosis
4) Analyzing the intercellular transmission of thegrowth signal in the vascular smooth muscle cells5) Tissue oxygen dynamics assessed by near infrared
spectroscopy
6) Genome wide-association studies for arteriosclerosis.
7) Pharmacological analysis of microcirculation in
in-vivo model8) Mechanism of arteriogenesis in ischemic limb.
9) Development of a new drug delivery system fortherapeutic angiogenesis10) Hemodynamic analysis after endovascularaneurysm repair11) Introduction of gene into vascular wall cells byelectroporation
12) Application of nano technology for in-vivo genetransfer to vascular wall cells
13) Basic research for arterialization of artificial
organ
14) Development of a new method for evaluation oflimb ischemia
15) Development of a new machine for autoevaluation of in-vivo endothelial function16) Creating strategy for diagnosis of acute aortic
syndrome.
17) Analysis of ambulatory system and muscle
mechanics in claudicants with peripheral arterydisease.
18) Modeling of saccular aneurysm with thecomputational simulation.
19) Development of hemostatic agent using
Tetra-PEG hydrogel.

24220) Prediction of dilated morphology of aortic
aneurysm by airbag simulation.
21) Quantification of hand movements during sutureusing Leap Motion and its clinical feedback.
22) Study of intimal hyperplasia using aorta-inferior
vena cava fistula model.

7.

References

8.

1.

2.

3.

4.

5.

6.

Okata S, Hoshina K, Miyahara K, Matsukura M,
Akai T, Isaji T, Takayama T. Highaneurysm wallenhancement values are associated with late sacshrinkage afterendovascular repair of abdominal
aortic aneurysms. Medicine(Baltimore) 2021
Jan15;100:e24133.
Hoshina K, Kato M, Ishimaru S, Michihata N,
Yasunaga H, Komori K; JapaneseCommittee for
Stentgraft Management (JACSM). Impact of theurgency and the landingzone on rates of inhospital death, stroke, and paraplegia following
thoracic endovascularaortic repair in Japan. J
Vasc Surg 2021; S0741-5214(21)00142-7.
Matsuura S, Takayama T, Yuhn C, Oshima M,
Shirasu T, Akai T, Isaji T, Hoshina K. Carotid
Stump Pressure and Contralateral Internal
Carotid Stenosis Ratio During Carotid
Endarterectomies: 1D-0D Hemodynamic Simulation of Cerebral Perfusion. Ann Vasc Dis 2021;
14:39-45.
Hoshina K, Komori K, Kumamaru H, Shimizu H.
The Outcomes of EndovascularAneurysm Repair
in Japan in 2017: A Report from the JapaneseCommittee for StentgraftManagement. 2021;25;
14:92-98.
Sugawara M, Hoshina K, Chigira M, Suzuki H,
Daimon M, TakayamaT, Ono Y, Yatomi Y.
Usefulness of duplex ultrasonography to detectcollagen sponge misplacementinto the arterial
lumen during the use of Angio-Seal: A casereport. SAGE Open Med CaseRep 2021;9:2050313X211004818
Matsuura S, Takayama T, Oyama TG, Oyama K,
Taguchi M, Endo T, Akai T, IsajiT, Hoshina K. A
Radiation-Crosslinked Gelatin Hydrogel That
Promotes TissueIncorporation of an Expanded
Polytetrafluoroethylene Vascular Graft in Rats.
Biomolecules 2021;11:1105.

9.

Iida T, Murono K, Shiratori H, Nozawa H, Kawai
K, Sasaki K, Emoto S, KishikawaJ, Ishii H,
Yokoyama Y, Abe S, Nagai Y, Anzai H, Sonoda H,
Takayama T, Hoshina K,Ishihara S. Impact ofInferior Mesenteric Artery Occlusion on the
Calibre of CollateralArteries of the Colon.
Anticancer Res 2021;41:5189-5193.
Hoshina K, Komori K, Kumamaru H, Shimizu H.
Theoutcomes of thoracicendovascular aortic
repair in Japanin 2017: A report from theJapanese Committee forStentgraft Management.
Ann Vasc Dis2021;14:281-288.111.
Mo M, Hirokawa M, Satokawa H, Yasugi T,
Yamaki T, Ito T, Onozawa S, Kobata T, Shirasugi
N, Shokoku S, Sugano N, Sugiyama S, Hoshina
K, on behalf of GuidelineCommittee JapaneseSociety of Phlebology, Ogawa T, on behalf ofGuideline Committeeof Endovenous Treatment
for Varicose Veins. Supplement of clinicalpractice guidelinesfor endovenous thermal
ablation for varicose veins: Overuse for the
inappropriateindication. Ann Vasc Dis 2021:14:
323-327.

243

Department ofBreast and Endocrine Surgery
Professor
Yasuyuki Seto M.D., Ph.D.

Associate Professor
Masahiko Tanabe M.D., Ph.D.

Lecturer
Kotoe Nishioka M.D., Ph.D.

Associates
Takayoshi Niwa M.D., Ph.D.

Ayaka Sato M.D., Ph.D.

Asako Sasahara M.D., Ph.D.

Arisa Morizono M.D., Ph.D.

Homepage
Organization
Our section is staffed by one professor, associate
professor, lecturer, and four associates. Official
activities of our units are run on the same schedule as
the Department of Gastrointestinal Surgery.

Clinical Activities
We started our activities in this area in 1987, andour department was established with thereconstruction of our hospital structure in 1997. Thisis a result of the growth of demand nationally andinternationally. It is caused by not only treatment forthe malignant disease but also functional one or giving
more attention to the quality of life.
Professional skills and broader knowledge of theendocrine system are required for this area. Diseases
we treat at our department are breast, thyroid, andparathyroid. In addition to treatment for malignant
cases of these diseases, we perform surgical procedures as well as systemic therapy. We co-work withthe department of internal endocrine medicine andhave about 250 surgical procedures annually.
In breast surgery, more than half of mammary

cancer patients undergo breast-preserving surgery. In
addition, sentinel node navigation surgery has been
adopted, resulting in better postoperative life quality.
Reconstruction surgery for breast cancer is likely toprovide much better QOL. In this field, we havecollaborated with the Department of Plastic Surgery.
Chemotherapy, hormone therapy, and moleculartargeting therapy play essential roles in breast cancer
treatment. We have accumulated a lot of experienceand achievement in this field.
Our clinical themes are 1) establishment of safe
procedures for endocrine surgery without complications; 2) diagnosis and treatment of micro-breast
lesions under ultrasonographic guides; 3) preoperative
diagnosis for thyroid neoplasms and breast tumors.

Research Activities
We investigate broad areas of breast cancer, thyroid
disease, and parathyroid disease. Most of our studies
are performed with other good institutions.
1) Hereditary Breast and Ovarian Cancer syndrome2442) Precision medicine based on Todai OncoPanel
3) Clinical significance of Ki67 in the area of earlybreast cancer.
4) Clinical evaluation for the developing drugs inbreast and thyroid cancer.
5) Studies in the area of sentinel node biopsy inbreast cancer.
6) Studies about the management of the toxic effects
of chemotherapies.
7) Cover makeup studies for cancer patients.
8) Epigenetic changes critical for breast cancer
development.
9) Cancer stem cells in breast cancer.
10) Quantification of HER2 expression using Digital
PCR.
11) Development of molecular target drugs in the areaof TGF beta
12) Analysis of MED12 mutation and TERT promoter
mutation in breast fibroadenoma and phyllodes
tumor.
13) Loss of BRCA1 expression and morphologicalfeatures associated with BRCA1 promoter
methylation status in triple-negative breast cancer.
14) Epidemiological study using nationwide databases
to resolve clinical questions

Publications
1.

2.

3.

4.

Sato A, Tanabe M, Tsuboi Y, Niwa T, ShinozakiUshiku A, Seto Y, Murakami Y. Circulating
Tumor DNA Harboring the BRAFV600E
Mutation May Predict Poor Outcomes of Primary
Papillary Thyroid Cancer Patients. Thyroid. 2021
Dec;31(12):1822-1828.
Konishi T, Goto T, Fujiogi M, Michihata N,
Kumazawa R, Matsui H, Fushimi K, Tanabe M,
Seto Y, Yasunaga H. New machine learning
scoring system for predicting postoperative
mortality in gastroduodenal ulcer perforation: A
study using a Japanese nationwide inpatient
database. Surgery. 2022 Apr;171(4):1036-1042.
Otsuji K, Sasaki T, Tanabe M, Seto Y.
Quantitative assessment of HER2 gene
amplification of breast cancer using droplet
digital PCR. Pathol Int. 2021 Aug;71(8):538-547.
Konishi T, Fujiogi M, Michihata N, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,

5.

6.

7.

8.

9.

Yasunaga H. Comparisons of postoperative
outcomes after breast cancer surgery in patientswith and without renal replacement therapy: amatched-pair cohort study using a Japanesenationwide inpatient database. Breast Cancer.
2021 Sep;28(5):1112-1119.
Konishi T, Fujiogi M, Michihata N, Kumazawa R,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Outcomes of Nonoperative
Treatment for Gastroduodenal Ulcer Perforation:a Nationwide Study of 14,918 Inpatients in Japan.
J Gastrointest Surg. 2021 Nov;25(11):2770-2777.
Morizono A, Tanabe M, Ikemura M, Sasaki T,
Ushiku T, Seto Y. Loss of BRCA1 expression andmorphological features associated with BRCA1
promoter methylation status in triple-negative
breast cancer. J Hum Genet. 2021 Aug;66(8):785-793.
Konishi T, Fujiogi M, Michihata N, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Comparison of short-term surgicaloutcomes between men and women with breast
cancer: a retrospective study using nationwide
inpatient data in Japan. Breast Cancer Res Treat.
2021 Apr;186(3):731-739.
Konishi T, Fujiogi M, Michihata N, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga
H.
Comparingoutcomesofnonoperative treatment for adhesive small bowel
obstruction with and without antibiotics. J InfectChemother. 2021 May;27(5):690-695.
Murayama T, Takeuchi Y, Yamawaki K, Natsume
T, Li M, Marcela RN, Nishimura T, Kogure Y,
Nakata A, Tominaga K, Sasahara A, Yano M,
Ishikawa S, Ohta T, Ikeda K, Horie-Inoue K,
Inoue S, Seki M, Suzuki Y, Sugano S, Enomoto T,
Tanabe M, Tada KI, Kanemaki MT, Okamoto K,
Tojo A, Gotoh N. MCM10 compensates for
Myc-induced DNA replication stress in breast
cancer stem-like cells. Cancer Sci. 2021 Mar;112(3):1209-1224.

Surgical Sciences
2. Sensory and Motor System Medicine

246

Department of Dermatology
Professor
Shinichi Sato, M.D., Ph.D.

Associate Professor
Yoshihide Asano, M.D., Ph.D.

Sayaka shibata, M.D.,PhD.

Lecturer
Ayumi Yoshizaki, M.D., Ph.D.

Hayakazu Sumida, M.D., Ph.D.

Takuya Miyagawa, M.D., Ph.D.

Takashi Yamashita, M.D., Ph.D.

Hospital Lecturer
Tomomi Miyake,M.D.

Associate
Miki Miyazaki, M.D., Ph.D.

Hikari Boki, M.D., Ph.D.

Satoshi Ebata, M.D., Ph.D.

Takemichi Fukazawa, M.D., Ph.D.

Ai kuzumi, M.D., Ph.D.

Satoshi Toyama, M.D., Ph.D.

Kojiro Nagai, M.D.

Home pagehttps://dermatology.m.u-tokyo.ac.jp/

Introduction and Organization

Clinical Activities

The Department of dermatology celebrated its
100th anniversary in 1990. Originally it was foundedas the Department of Dermatology and Urology,
which also encompassed venereology. In 1946, theDepartment of Dermatology was separated from thatof Urology. Regarding venereology, sexually transmitted diseases only related to skin manifestations are
now dealt with in our department.
The professor, two associate professors, four
lecturers, one hospital lecturer and seven associatestake part in inpatient and outpatient cares as well as
research and teaching activities. Fifty-two doctors
who basically belong to our department are currently
out in affiliated hospitals mainly engaged in clinicalworks there. Additionally, eight staff members areabroad at present, mainly involved in advanced
research activities in cell biology and molecularbiology.

In the outpatient clinic we see around 200 patients aday. Incisional and excisional biopsies are frequently
performed under local anesthesia at the outpatient
operation facilities belonging to our department.
Clinical and histological discussions by all staff
members including Professor and Associate Professors
are held regularly, which always gives us invaluablelessons.
Concerning the inpatient clinic, there are about ten
staff members under the supervision of the ward-chief.
Surgical operations such as removal of malignancies
and skin grafting that require general anesthesia arealso performed weekly in the central surgical facilities.

Education
We have twenty dermatologists who are studying in
the postgraduate course under the guidance of staff
members of our department.

247

In addition to series of lectures, clinical education isprovided for fifth- and sixth- grade medical students,
which aims at giving a general introduction for how tomake dermatological approaches for diagnosis andtreatment, with a stress on learning how to observeand describe a variety of skin eruptions. Actually thestudents are supposed to see patients in outpatient
clinic every day for an entire week, as well as toparticipate in the inpatient clinic.

Research
Each specialized outpatient service reflects its own
research field in a disease-oriented manner. However,those specialized groups performing their own clinicaland research activities are never exclusive, and there
are increasing communications with other departments
such as internal medicine and blood transfusion
service as well as intergroup communications. Recent
advanced techniques in cellular, molecular biology
and our newly established laboratories, will enable us
to organize optimal research conditions.

Publications
1.

2.

3.

Miura S, Watanabe Y, Saigusa R, Yamashita T,
Nakamura K, Hirabayashi M, Miyagawa T,
Yoshizaki A, Trojanowska M, Sato S, Asano Y.
Fli1 deficiency suppresses RALDH1 activity ofdermal dendritic cells and related induction ofregulatory T cells: a possible role in scleroderma.
Arthritis Res Ther. 2021;23(1):137.
Awaji K, Miyagawa T, Omatsu J, Numajiri H,
Kawai T, Funamizu K, Saigusa R, Yamada D,
Asano Y, Sato S.The prognostic relevance ofpretreatment peripheral neutrophil counts andneutrophil-to-lymphocyte ratio in primary
cutaneous angiosarcoma. Acta Dermato Venereol.
2021;101(8):adv00527.
Minami Sakamoto, Tomomitsu Miyagaki,
Hiroaki Kamijo, Tomonori Oka, Hikari Boki,
Naomi Takahashi-Shishido, Hiraku Suga,
Makoto Sugaya, Shinichi Sato. CD147cyclophilin A interactions promote proliferationand survival of cutaneous T-cell lymphoma
International. Int Journal of Molecular Sciences.
2021;22(15):7889.

4.

Hayakazu Sumida, Kiyoshi Migita, Hiroaki Ida,
Yoshihide Asano, Jun Shimizu, Shinji Kagami,
Makoto Sugaya, Takafumi Kadono, Shinichi Sato.
Dermatomyositis-like eruptions and fasciitis withnovel compound heterozygous MEFV mutations:newly recognized features of a variant of familial
Mediterranean
fever.
The
Journalof
Dermatology. 2021;48(9):1453-1456.
5. Shibata Sayaka. Chromatin dynamics andepigenetics in skin stress adaptation. The Journalof Dermatological Science. 2021;103(2):66-72.
6. Hikari Boki, Takayuki Kimura, Tomomitsu
Miyagaki, Hiraku Suga, Andrew Blauvelt,
Hitoshi Okochi, Makoto Sugaya, Shinichi Sato.
Lymphatic dysfunction exacerbates cutaneoustumorigenesis and psoriasis-like skin inflammation through accumulation of inflammatory
cytokines. Journal of Investigative Dermatology.
2022;142(6):1692-1702.
7. Hiroko Numajiri, Ai Kuzumi, Takemichi
Fukasawa, Satoshi Ebata, Asako YoshizakiOgawa, Yoshihide Asano, Yutaka Kazoe,
Kazuma Mawatari, Takehiko Kitamori, Ayumi
Yoshizaki, and Shinichi Sato. B cell depletion
inhibits fibrosis via suppressing pro-fibrotic
macrophage differentiation in a mouse model ofsystemic sclerosis. Arthritis & Rheumatology.
2021;73(11):2086-2095.
8. Ai Kuzumi, Ayumi Yoshizaki, Kazuki M
Matsuda, Hirohito Kotani, Yuta Norimatsu,
Maiko Fukayama, Satoshi Ebata, Takemichi
Fukasawa, Asako Yoshizaki-Ogawa, Yoshihide
Asano, Kyojiro Morikawa, Yutaka Kazoe,
Kazuma Mawatari, Takehiko Kitamori, Shinichi
Sato. Interleukin-31 promotes fibrosis and T
helper 2 polarization in systemic sclerosis.
Nature Communications. 2021;12(1):5947.
9. Ikawa T, Ichimura Y, Miyagawa T, Fukui Y,
Toyama S, Omatsu J, Awaji K, Norimatsu Y,
Watanabe Y, Yoshizaki A, Sato S, Asano Y.
The contribution of LIGHT to the developmentof systemic sclerosis by modulating IL-6 and Th1
chemokine expression in dermal fibroblasts.
J Invest Dermatol. 2022;142(6):1541-1551.
10. Satoshi Ebata, Ayumi Yoshizaki, Takemichi
Fukasawa, Asako Yoshizaki-Ogawa, Yoshihide
Asano, Kosuke Kashiwabara, Koji Oba, Shinichi

248

11.

12.

13.

14.

15.

16.

Sato. The Percentage of Residual B-Cells after 2
Weeks of Rituximab Treatment Predicts the
Improvement of Systemic Sclerosis-associatedInterstitial Lung Disease.The Journal of
Dermatology. 2022;49(1):179-183.
Ikawa T, Miyagawa T, Fukui Y, Toyama S,
Omatsu J, Awaji K, Norimatsu Y, Watanabe Y,
Yoshizaki A, Sato S, Asano Y. Endothelial
CCR6 expression due to FLI1 deficiency contributes to vasculopathy associated with systemicsclerosis.Arthritis Res Ther. 2021;23(1):283
Ai Kuzumi, Ayumi Yoshizaki, Kazue Chiba,
Shunki Mitsuo, Kazuki M Matsuda, Yuta
Norimatsu, Kojiro Nagai, Jun Omatsu, Tomomi
Miyake, Shinichi Sato. Genital necrosis withcutaneous thrombosis after COVID-19 mRNA
vaccination. Journal of The European Academyof Dermatology and Venereology. 2022;36(3):e185-e186.
Takemichi Fukasawa, Ayumi Yoshizaki, Satoshi
Ebata, Asako Yoshizaki-Ogawa, Yoshihide
Asano, Atsushi Enomoto, Kiyoshi Miyagawa,Yutaka Kazoe, Kazuma Mawatari, TakehikoKitamori, Shinichi Sato. Single cell level protein
analysis revealing the roles of autoantigenreactive B lymphocytes in autoimmune disease
and the murine model. eLife. 2021;10:e67209.
Yuki Kawana, Hiraku Suga, Hiroaki Kamijo,
Tomomitsu Miyagaki, Makoto Sugaya, Shinichi
Sato. Roles of OX40 and OX40 ligand in
cutaneous T-cell lymphoma. International
Journal of Molecular Sciences. 2021;22(22):12576.
Mariko Urano-Takaoka, Hayakazu Sumida,
Takuya Miyagawa, Kentaro Awaji, Kojiro Nagai,
Jun Omatsu, Tomomi Miyake, Shinichi Sato.
Serum Cytokeratin 18 as a Metastatic andTherapeutic Marker for Extramammary Paget’s
Disease. Acta Derm Venereol. 2022;102:
adv00636.
Kazuki Mitsuru Matsuda, Ayumi Yoshizaki, Kei
Yamaguchi, Eriko Fukuda, Taishi Okumura, Koji
Ogawa, Chihiro Ono, Yuta Norimatsu, Hirohito
Kotani, Teruyoshi Hisamoto, Ruriko Kawanabe,
Ai Kuzumi, Takemichi Fukasawa, Satoshi Ebata,
Takuya Miyagawa, Asako Yoshizaki-Ogawa,
Naoki Goshima, Shinichi Sato. Autoantibody

17.

18.

19.

20.

landscape revealed by wet protein array: sum of
autoantibody levels reflects disease status.
Frontiers in Immunology. 2022;13:893086.
Satoshi Ebata, Ayumi Yoshizaki, Koji Oba,
Kosuke Kashiwabara, Keiko Ueda, Yukari
Uemura,Takeyuki
Watadani,
Takemichi
Fukasawa, Shunsuke Miura, Asako YoshizakiOgawa, Naoko Okiyama, Masanari Kodera,
Minoru Hasegawa, Shinichi Sato. Safety andefficacy of rituximab in systemic sclerosis(DESIRES): open-label extension of a doubleblind,
investigators-initiated,
randomized,
placebo-controlled trial. Lancet Rheumatology.
2021;3(7):e489-e497.
Ruriko Kawanabe, Ayumi Yoshizaki, Kazuki M.
Matsuda, Hirohito Kotani, Teruyoshi Hisamoto,Yuta Norimatsu, Ai Kuzumi, Takemichi
Fukasawa, Satoshi Ebata, Asako YoshizakiOgawa and Shinichi Sato. Serum C-X-C
chemokine ligand 1 levels in patients withsystemic sclerosis: relationship of clinical andlaboratory observations to anti-CD20 monoclonal
antibody administration. Life. 2022;12(5):646.
Ayumi Yoshizaki, Shinichi Sato. Predictors ofRituximab Effect on Modified Rodnan Skin
Score in Systemic Sclerosis: a machine learning
analysis of the DESIRES trial. Rheumatology. inpress.
Kenta Oka, Takuya Miyagawa, Hiraku Suga,
Tomomitsu Miyagaki, Yuka Mizuno, Hiroaki
Kamijo, Teruyoshi Hisamoto, Issei Omori, Hikari
Boki, Tomonori Oka, Naomi Takahashi-Shishido,
Makoto Sugaya, and Shinichi Sato. Increased
Expression of Squamous Cell Carcinoma Antigen
1 and 2 in Mycosis Fungoides and Sézary
Syndrome. European Journal of Dermatology. inpress.

249

Department of Plastic andReconstructive Surgery
Professor
Mutsumi Okazaki, M.D.

Associate Professor
Shimpei Miyamoto, M.D.

Project Lecturer
Shuji Yamashita, M.D., Masakazu Kurita, M.D.

Associate
Yoko Tomioka, M.D.,

Koji Kanayama, M.D.,

Mika Watanabe M.D.,

Hitomi Matsutani M.D.

Homepage

Kou Fujisawa, M.D.,https://plastic.m.u-tokyo.ac.jp/english/

Organization
The present faculty of the Department of Plastic andReconstructive Surgery consists of 1 professor, 1
associate professor, 2 project lecturers, 5 associates, 6physicians, and 5 residents. There are about 100
doctors in the department, but most are serving inrotation at affiliated hospitals.
The outpatient clinic is located on the 3rd floor of
the outpatients building, while there are wards with
about 16 available beds on the 10th floor in the New
Ward. Our faculty room is located in the Medical
Laboratory Building and laboratory rooms in the East
Laboratory Building.
The present status of the educational, research andclinical activities of the department is as follows.

Clinical Activities
The outpatient clinic is opened every morning from
Monday to Friday. There are several specialized
clinics for facial paralysis, breast reconstruction, headand neck reconstruction, congenital anomalies,
vascular malformations, critical limb ischemia,
lymphedema, keloid, abdominal hernia, and cosmetic

surgery including cosmetic dermatology. Over 1,000
new patients visited our department, including about
800 patients in emergency. About 1,400 surgeries were
performed. Each week, preoperative and postoperative
conferences that all members of the department should
attend are held on Tuesday and Wednesday evening
respectively.

Teaching Activities
In regard to pregraduate education, the department
has the duty of lecturing to 2nd and 4th year medical
students, and also of instructing 4th medical students
in bed side practice. The subjects taken up in thelectures include general concepts of plastic surgery,wound healing, congenital malformations, skin grafts
and flaps, microsurgery, head and neck reconstruction,
hand surgery, craniomaxillofacial surgery, burn andtrauma, cosmetic surgery, and regenerative medicine.
In the bed side practice the students have theopportunity of seeing various diseases and disorders in
the field of plastic surgery and attending inpatientsand surgical operations and clinical lectures by faculty
members. For graduate school students, microsurgical250

training program is undertaken in the laboratory room.
In the postgraduate course, after completing the 6-yeartraining program, a trainee can sit for the board
examination of the Japan Society of Plastic andReconstructive Surgery.

Research Activities
Basic and clinical researches are performed ingroups. The major research subjects are as follows:
1) Blink examination for appropriate closing-eye
function in patients with facial paralysis.
2) Studies on monitoring tissue circulation using
flexible optical probe.
3) ICG examination for evaluating blood and lymph
flow.
4) In vivo reprogramming of wound-resident cells
generates skin epithelial tissue
5) Clinical studies on fat regeneration using suctioned fat tissue and adipose stromal progenitor
cells.
6) Studies on hair regrowth using epidermal stem
cells, dermal papilla cells and dermal sheath cells.
7) Basic studies on free tissue transfer using
microsurgery.

References (2021)
1.

2.

3.

4.

Hidaka T, Ogawa K, Tomioka Y, Yoshii K,
Okazaki M. The Impact of Brow-Lift on Eyelid
Closure in Patients with Facial Paralysis. Facial
Plast Surg Aesthet Med. 2021 Dec 3. doi: 10.
1089/fpsam.2021.0120.
Tanaka K, Sugawara T, Asakage T, Okazaki M. A
Concept of "Boundary Determination" by the
Combination of a Local Flap and Free Tissue
Transfer Useful for the Prevention of
Postoperative Complications After Complex andWidespread Skull Base Reconstruction. J
Craniofac Surg. 2021 Nov-Dec 01;32(8):e820e822.
Yamashita S, Nakazato M, Hirata T. SizeAnalysis of Small Metal Nanoparticles Using
Single Particle ICP Mass Spectrometry. Anal Sci.
2021 Nov 10;37(11):1637-1640.
Fujisawa K, Miyamoto S, Saito Y, Fukuoka O,
Okazaki M. Total Maxillectomy and Free Flap

Reconstruction in Hemodialysis Patients: Reportof Two Cases. Plast Reconstr Surg Glob Open.
2021 Nov 4;9(11):e3922.
5. Hidaka T, Miyamoto S, Ogawa K, Tomioka Y,
Okazaki M. Factors Associated With Late
Admission to Facial Plastic Surgery Among
Patients With Long-Standing Facial Paralysis.
Ann Plast Surg. 2021 Nov 1;87(5):547-551.
6. Kanayama K, Oba J, Yoshii K, Tomioka Y, Kurita
M, Miyamoto S, Okazaki M. Potentially serious
incidental findings on medical imaging in plastic
surgery patients: A single-institution retrospective
cohort study. J Plast Reconstr Aesthet Surg. 2021
Oct;74(10):2776-2820.
7. Kato M, Kurita M, Mito D, Nakamura R, Li K,
Yamashita S, Okazaki M. Establishing a
Lymphatic Venous Anastomotic Training Modelin Pig Trotters. J Reconstr Microsurg. 2021 Oct;37(8):682-686.
8. Kanayama K, Kato H, Mori M, Sakae Y, Okazaki
M. Robotically Assisted Recipient Site
Preparation in Hair Restoration Surgery: Surgical
Safety and Clinical Outcomes in 31 Consecutive
Patients. Dermatol Surg. 2021 Oct 1;47(10):1365-1370.
9. Kagaya Y, Arikawa M, Akazawa S, Miyamoto S.
A Quantitative Evaluation of the Flow-Increasing
Effect of Flow-Through Arterial Anastomosis in
the Vascular Pedicle of Free Flaps: A Prospective
Clinical Before-and-After Study. Plast Reconstr
Surg. 2021 Oct 1;148(4):871-881.
10. Ogawa K, Okazaki M, Tanaka K, Uemura N,
Homma T. Chimeric Latissimus Dorsi Flap in
One-Stage Reconstruction of Depressor Muscle
Dysfunction and Depression Deformity in the
Perimandibular Area. J Craniofac Surg. 2021 Oct
1;32(7):2512-2515.
11. Yoshida S, Koshima I, Imai H, Uchiki T, Sasaki
A, Fujioka Y, Nagamatsu S, Yokota K, Yamashita
S. Modified intraoperative distal compression
method for lymphaticovenous anastomosis withhigh success and a low venous reflux rates. J
Plast Reconstr Aesthet Surg. 2021 Sep;74(9):2050-2058.
12. Moriwaki Y, Kurita M, Hongo H, Okazaki M. In
Vitro Comparative Cytotoxicity Assessment of
Sclerosants Used for Venous Malformations.

251

13.

14.

15.

16.

17.

18.

19.

20.

Plast Reconstr Surg Glob Open. 2021 Sep 17;
9(9):e3814.
Kagaya Y, Arikawa M, Sekiyama T, Mitsuwa H,
Takanashi R, Taga M, Akazawa S, Miyamoto S.
The concept of "whole perforator system" in thelateral thoracic region for latissimus dorsi
muscle-preserving large flaps: An anatomical
study and case series. PLoS One. 2021 Sep 2;
16(9):e0256962.
Iida T, Isozaki Y, Numahata T, Okazaki M. Sacral
defect reconstruction using a sensate superior
gluteal artery perforator flap based on the
superior cluneal nerves: A report of two cases.
Microsurgery. 2021 Jul;41(5):468-472.
Miyamoto S, Arikawa M, Kagaya Y. Response toletter commenting on "The use of lower
abdominal perforator flaps in soft-tissuereconstruction
aftersarcomaresection".
Microsurgery. 2021 May;41(4):396-397.
Hidaka T, Yamashita S, Okazaki M. A Possible
Distal End for Perforasome of the Superficial
Circumflex Iliac Artery Perforator Flap. Plast
Reconstr Surg Glob Open. 2021 May 28;9(5):e3602.
Ogawa K, Okazaki M, Tanaka K, Uemura N,
Homma T. One-Stage Simultaneous Augmentation of 2 Regions of 3 Facial Reanimations After
Mid Skull Base Surgery by Using a
Neurovascular Latissimus Dorsi Chimeric Flap. J
Craniofac Surg. 2021 Mar-Apr 01;32(2):730-733.
Roh S, Miyamoto S, Kitamura Y, Mito D,
Okazaki M. Secondary Vulvar Reconstruction
Using Bilateral Gluteal Fold Flaps after Radical
Vulvectomy with Direct Closure. Plast Reconstr
Surg Glob Open. 2021 Apr 20;9(4):e3550.
Hattori Y, Kurita M, Yokoyama T, Yamashita S,
Okazaki M. Arteriovenous Malformation of the
Head and Neck in a Hemodialysis Patient. Plast
Reconstr Surg Glob Open. 2021 Mar 24;9(3):e3485.
Mashiko T, Kanayama K, Saito N, Shirado T,
Asahi R, Mori M, Yoshimura K. Selective
Proliferation of Highly Functional AdiposeDerived Stem Cells in Microgravity Culture with
Stirred Microspheres. Cells. 2021 Mar 4;10(3):560.

21. Miyamoto S, Kageyama D, Arikawa M, Kagaya
Y, Fukunaga Y. Combined use of ipsilateral
latissimus dorsi flap and anterolateral thigh flap
to reconstruct extensive trunk defects.
Microsurgery. 2021 Feb;41(2):175-180.
22. Fujisawa K, Ito T, Aoyama S, Kiuchi T, Araki J,
Nakao J, Nakagawa M. Thorax anthropometricposition index: a simple evaluation of theinframammary fold position in the thorax. J Plast
Surg Hand Surg. 2021 Feb;55(1):21-24.
23. Matsumoto M, Nakagami G, Kitamura A, Kurita
M, Suga H, Miyake T, Kawamoto A, Sanada H.
Ultrasound assessment of deep tissue on thewound bed and periwound skin: A classification
system using ultrasound images. J Tissue
Viability. 2021 Feb;30(1):28-35.
24. Fujisawa K, Kitatsuji M, Yamamoto Y. Open
Abdomen Negative Pressure Device Applied for
Two-stage Closure of Enterocutaneous Fistula.
Plast Reconstr Surg Glob Open. 2021 Feb 1;9(2):e3369.
25. Kagaya Y, Arikawa M, Higashino T, Miyamoto S.
Letter of response to comments on publication:"Autologous abdominal wall reconstruction using
anterolateral thigh and iliotibial tract flap after
extensive tumor resection: A case series study of
50 consecutive cases''. J Plast Reconstr Aesthet
Surg. 2021 Jan;74(1):223-243.
26. Matsutani Hitomi, Kamochi Hideaki, Ishikawa
Yohei. Use of Surgical Tape Strips to Eliminate
Hair Fragments from Split-thickness Skin Grafts
from the Scalp:A Simple and Quick Technique.
International Journal of Surgical Wound Care,2(1) 32-35, 2021.

252

Department of Oral-Maxillofacial
Surgery
Professor
Kazuto Hoshi, M.D., Ph.D.

Associate Professor
Hideto Saijo, D.D.S., Ph.D.

Masashi Shiiba, D.D.S., Ph.D. (from October)

Lecturer
Toru Ogasawara, D.D.S., Ph.D.

Kazumi Ohkubo, D.D.S., Ph.D.

Hideyuki Suenaga, D.D.S., Ph.D.

Masanobu Abe, D.D.S., Ph.D.

Associate
Mari Okayasu, D.D.S., Ph.D.

Natsuko Uchino, D.D.S., Ph.D.

Asako Taniguchi, D.D.S., Ph.D.

Rika Narita, D.D.S., Ph.D.

Noriko Komatsu, D.D.S., Ph.D. (until June)
Yoko Uchida, D.D.S., Ph.D.

Kenichi Kumagai, D.D.S., Ph.D.

Makiko Ishibashi, D.D.S., Ph.D.

Miki Kashiwagi, D.D.S., Ph.D. (from July)

Homepage http://plaza.umin.ac.jp/%7Eoralsurg/
Introduction and Organization
Department of Oral and Maxillofacial Surgery,commenced by Dr. Hisashi Ishihara in 1900, is oneof the oldest departments in Graduate School of
Medicine, the University of Tokyo. This department
consists of wide variety of specialists, such as oral
surgeons, orthodontists and prosthodontists. We
handle all diseases in the oral-maxillofacial region,such as congenital anomalies, jaw deformities,
benign and malignant tumors, trauma andinflammation. In particular, we have established andpracticed medical system for cleft lip and palate
since around 2000. In November 2016, weestablished the Cleft Lip and Palate Center, which
we become the center for oral surgeons,orthodontists, and others. Specialists such as
prosthodontists, otolaryngologists, anesthesiologists,obstetricians, pediatricians, pediatric surgeons,speech therapists, nurses, dental hygienists, anddental technicians form a team to deal with illnesses
from all directions and provide multidisciplinary
treatment. Dental care for the patients who havesystemic disorders or under medical control isanother field of our department. Multidisciplinary
treatment teamed by these specialists is characteristicand has performed excellent results in clinical works.
In research fields, all staffs participate in the clinicaland basic research to support the treatment
scientifically and to develop new treatment
protocols, and we have mainly performed theexperimental studies on the regenerative abilities oftissues such as bone, periosteum, cartilage,
perichondrium, vessels, nerve, and skin. At present,
we are focusing on tissue engineering in researchworks especially in bone, cartilage and vessels. The
Department of Tissue Engineering was established at
the University of Tokyo Hospital in October 2001,

253

and at present Professor Kazuto Hoshi of ourdepartment is concurrently serving as its director.
The Department of Oral and Maxillofacial Surgery
has Cartilage and Bone Regenerative Medicine and a
Tissue Engineering Department, where assistantprofessors, and graduate students are conducting
basic research on regenerative medicine in the
maxillofacial region.

Clinical activities
In the outpatient clinic, we have 12 dental treatment
booths, one operation room and one speech therapy
room. Average number of patients treated at
outpatient clinic is approximately 100 per day.
Our department has two sections mainly; one is oral
and maxillofacial surgery and another is dental andorthodontic dentistry.
In outward dispensary, oral surgery section performs
dental surgeries such as extraction of impacted teeth,
amputation of infected dental root and gingivoplasty
in the operation room. Patients who had been performed surgical treatment are also followed up after
release from the hospital.
Dentistry and orthodontic dentistry performs facial
growth control and tooth movements for patientswith congenital orofacial anomalies such as cleft lip
and palate, jaw deformities and other congenital
deformities. Speech therapy for the patients withcleft lip and palate is also performed by speechtherapists in our department.
Special section for patients of congenital deformities
is on Monday afternoon examined by plastic
surgeon,oral
andmaxillofacial
surgeons,
orthodontists. We also have special sections forpatients with oral cancer and temporomandibular
joint disorder.
In the ward, we have approximately 400 new
inpatients and surgical treatment is performed on
approximately 300 cases per year. The main surgicaltreatments are chiloplasty and palatoplasty for cleft
lip and palate patients, bone grafting in alveolar
cleft, orthognatic surgery of orofacial deformities,
fixation of orofacial fractures, resection of malignant
tumors combined with reconstruction surgery.
Peculiarity of our treatment strategy is teamapproach that consists of oral and maxillofacial

surgeons, orthodontists and prosthodontists. In our
department, patients with congenital dento-facial
deformity are treated by utilizing several techniquessuch as distraction technique, autologous bone graft
technique, and the original artificial bone graft
technique in addition to orthognatic surgery. The
original bone graft is made from patient’s three
dimensional images of CT data and this technique is
now applied for patients.

Education
Teaching activities are divided into two parts; forundergraduate medical students and for postgraduate
dental students. For undergraduate students, we make5 systematic lectures in their second year of
specialized course, and one lecture and one week
bedside learning in final year. Through thesecurriculums, we demonstrate the characteristics andtreatments of the diseases in oral-maxillofacial
region. Teaching is focused on following points;
congenital anomalies such as cleft lip and palate andbranchial arch syndromes, dentofacial deformities
caused by developmental and acquired problems,
surgical resection and functional reconstruction of
benign and malignant tumors, temporomandibular
joint disorders, inflammation and maxillofacial
trauma. Minimum dental knowledge concerning jaw
movement, tooth pain, periodontal disease,malocclusion and dental restorations are instructed.
For postgraduate dental students, we have two-yearresident course. This course aims to train for a wide
range of dental treatments and to learn about medical
cares. Various specialists instruct dental treatments
for them in outpatient clinic. Dental caries
treatments, periodontal cares and applications ofdentures are instructed. Tooth extractions andorthodontic treatment are instructed by oral surgeons
and orthodontists. Medical cares in the ward aretaught by medical doctors and oral surgeons.
After two-year residential course, research training at
postgraduate school is positively recommended. Ouraim for education of clinician is to raise up
specialists mastered both clinic and research skills.

254

Research
Our research project consists of clinic and basic
sections. Each research themes are closely related on
the aim of clinical improvement.
The main projects are as follows.
Clinical research:
1. Treatment of facial deformities and malocclusionin patients with cleft lip/ palate
2. Research on facial growth in patients withcraniofacial anomalies
3. Reconstruction of oral and maxillofacial area bycustom-made artificial bone (CT bone) (clinical
trial)
4. Transplantation of implant-type tissue-engineered
cartilage for cleft lip-nose patients
5. QOL study of oral health care system inpreparative cancer patients
6. Overcoming eating loss (eat-loss)
7. The association between oral disorders andsystemic diseases
8. Development of surgical assisted systems using
artificial intelligence, computer vision, andaugmented reality
9. Research on the treatment of temporo-mandibular
joint disorder using autologous adipose-derived
mesenchymal stem cells
Basic and experimental research:
1. Regeneration of bone and cartilage with tissueengineering approach
2. Molecular biology of cartilage repair and its
application to cartilage regenerative medicine
3. Development of novel scaffolds for cartilage andbone regeneration
4. In vivo evaluation of tissue-engineered cartilage
and bone
5. Study on the control of mesenchymal celldifferentiation
6. Elucidation of epigenetic abnormalities in oral
cancers and oral premalignant lesions
7. Functional analysis of microRNAs in humandental pulp stem cells
8. Study on the cleft lip and osteonecrosis of thejaw using animal models
9. Elucidation of mechanisms of tissue repair byadipose-derived stem cells and macrophages
10. Analysis of regulatory mechanisms of bone using
a reconstitution system of the cellular network inbone metabolism

Publication(Original articles，Case report)
1. Mori T, Kumagai K, Nasu K, Yoshizawa T,
Kuwano K, Hamada Y, Kanazawa H, Suzuki R.
Clonal Expansion of Tumor-Infiltrating T Cells
and Analysis of the Tumor Microenvironment
within Esophageal Squamous Cell Carcinoma
Relapsed after Definitive Chemoradiation
Therapy. Int J Mol Sci. 2021 Jan 22;22(3):1098. doi: 10.3390/ijms22031098.【査読有】2. Koseki J, Abe T, Miyamoto Y, Kashiwagi M,
Ishibashi M, Taniguchi A, Suenaga H, Abe H,
Abe M, Hoshi K. Use of application ofnavigation system to odontogenic benign tumors
with maxilla. Biomed Res, 2021; 32(2): 37-41,
Accepted Feb 9, 2021 (Online)
3. Fujihara Y, Abe T, Asawa Y, Nishizawa S, Saijo
H, Hikita A, Hoshi K. Influence of DamageAssociatedMolecular
Patterns
fromChondrocytes in Tissue- Engineered Cartilage.
Tissue Eng Part A. 2021 Jan; 27(1-2):1-9. doi:
10.1089/ten.TEA.2019.0185. Epub 2020 Feb 19.
PMID: 31724485.【査読有】4. Nakamura M, Hakozaki Y, Iwata S, Sato Y,
Makino K, Kawai T, Yamada Y, Yamada D,
Suzuki M, Omatsu J, Abe M, Hoshi K, Kume H,
Igawa Y. Novel operative technique of advancement urethral meatoplasty utilizing buccal
mucosa for Vulvar Paget’s disease with urethral
invasion, Case reports. Journal of Medical Case
Reports. 2021 Mar 28; 15(1):136, doi:
10.1186/s13256-021-02729-1,
PMID:
33773597, PMCID: PMC8005229, Free PMC
Article. 【査読有】5. Abe M, Mitani A, Yao A, Zhang C, Hoshi K,
Yanagimoto S. Awareness of Teeth-Alignment
Disorder is Closely Associated with Gum
Bleeding and Pollinosis in Late Adolescence.
Healthcare. 9(4):370, 2021. Published 26
March, 2021 【査読有】

255

6.

KanataTonosaki,Kazumichi
Yonenaga,
Tetsuhiko Mikami, Takashi Mizuno, Shigeto
Oyama. Acute Cholecystitis, Sepsis, andDisseminated Intravascular Coagulation Causedby Edwardsiella tarda in an Elderly Woman. The
Tokai journal of experimental and clinicalmedicine 46(1) 51-53 2021.4.20. PMID:
34859417.【査読有】7. Kanata Tonosaki, Kazumichi Yonenaga, SachikoOno, Shunsuke Itai, Shigeto Oyama, Takashi
Mizuno, Rinji Watanabe, Kazuto Hoshi.
Swallowing evaluation by the Kuchikara Taberu
Balance Chart and videoendscopic examination
reveals that respiratory conditions, chewing, andposition are strongly related to dysphagia.
Odontology 109(2) 448-452 2021.Apr. Epub2020 Oct 27. doi: 10.1007/s10266-020-00561-5.
PMID: 33108554.【査読有】8. Kanazawa S, Okada H, Hojo H, Ohba S, Iwata J,
Komura M, Hikita A, Hoshi K. Mesenchymal
stromal cells in the bone marrow niche consistofmulti populations
withdistincttranscriptional and epigenetic properties. Sci
Rep.
2021
Aug
4;11(1):15811.
doi:
10.1038/s41598-021-94186-5. PMID: 34349154【査読有】9. Ning F, N Zhang N, Wang J, Jin Y, Quan H, Pei
J, Zhao Y, Zeng X, Abe M, Zhang C. Prognostic
value of modified Lauren classification in
gastric cancer. World Journal of Gastrointestinal
Oncology. 13(9):1184-1195, 2021 Sep 15. 【査読有】
10. Miyamoto Y, Kubota K, Asawa Y, Hikita A,
Hoshi K. M1-like macrophage contributes tochondrogenesis in vitro. Sci Rep, 2021 Oct 29,
11:21307 (Online), doi.org/10.1038/s41598021-7 【査読有】11. Pei J, Zhang R, Zhang N, Zeng Y, Sun Z, Ma S,
Zhou J, Li X, Fan J, Zhu J, Abe M, Mei Z, Shi
G, Zhang C. Screening and Validation of a
Novel T Stage-Lymph Node Ratio Classification
for Operable Colon Cancer. Annals ofTranslational Medicine. 9(20):1513, 2021.Oct.
【査読有】
12. Ono S, Abe T, Abe M, Kubota K, Hoshi K.
Squamous cell carcinoma at the oral
commissure in a patient with Behçet's disease. J

Oral Maxillofac Surg Med Pathol, 2021
Nov;33(6): 610-613.【査読有】13. Kanata
Tonosaki,Kazumichi
Yonenaga,
Shunsuke Itai, Takashi Mizuno, Shigeto Oyama.
Familial Mediterranean fever with psychiatricdisorder which have not been diagnosed over 30
years: A case report. The Tokai Journal of
Experimental and Clinical Medicine 46(4) 180183 2021.12. PMID: 34859417．【査読有】(Review articles)
1. Abe M, Mitani A, Zong L., Hoshi K,
Yanagimoto S.
The Challenge of Early
Prevention of Periodontal Diseases in Japan.
Journal of Advanced Oral Research, online, doi:
10.1177/ 23202068211022586, 2021 June. 【査読有】
2. Abe M, Mitani A, Zong L, Zhang C, Hoshi K,
Yanagimoto S. High Frequency and Long
Duration of Toothbrushing Can Potentially
Reduce the Risk of Common Systemic Diseasesin Late Adolescence. Special Care in Dentistry
42(3):317-318, 2022 May, Epub 2021 Oct 22
doi: 10.1111/scd.12670. 【査読有】3. Hoshi K, Ikebe T, Ota Y, Kishimoto H, Kurata
T, Kurita H, Sakamaki K, Takenobu T, Harada
S, Ogasawara T, Tei K, Kirita T. Guide for
Surgical Procedures in Oral And Maxillofacial
Areas during Coronavirus Disease 2019
Pandemic. J Oral Maxillofac Surg Med Pathol.
2021 Oct 28. doi: 10.1016/j.ajoms.2021.10.007.
Epub ahead of print. PMID: 34729347; PMCID:
PMC8552586. 【査読有】(Patents)

256

Department ofOrthopaedic Surgery
Professor
Sakae Tanaka, M.D., Ph.D.

Associate Professors
Taku Saito, M.D., Ph.D.

Yasushi Oshima, M.D., Ph.D.

Lecturers
Shuji Taketomi, M.D., Ph.D.

Hiroshi Inui, M.D., Ph.D.

Takumi Matsumoto, M.D., Ph.D.

Hiroshi Kobayashi, M.D., Ph.D.

Associates
Takeyuki Tanaka, M.D.

Keita Okada, M.D., Ph.D.

Yoshitaka Matsubayashi, M.D.

Kousuke Uehara, M.D.

So Kato, M.D., Ph.D.

Hideki Nakamoto, M.D., Ph.D.

Chan Sonnho, M.D., Ph.D.

Maenohara Yuji, M.D., Ph.D.

Ryuji Sakamoto, M.D.

Samejima Shin, M.D.

Hiroaki Nakarai, M.D.

Shin Asai, M.D.

Zhang Liuzhe, M.D.

Takafumi Miyake, M.D.

Homepage

http://www.u-tokyo-ortho.jp/

Introduction and Organization
In 1906 our department was established as the firsteducational institute of orthopedic surgery in Japan,
by the first professor Yoshinori Tashiro who hadlearned orthopedic surgery in Germany and Austria.
Initially, the department treated patients with
infectious disorders and congenital malformations,such as poliomyelitis, tuberculosis of the spine,congenital clubfoot and hip dislocation. The numberof outpatients visiting our department in 1910 was
estimated to be no more than 3.3% of that of the twosurgical departments in the University of Tokyo
Hospital.
The number and characteristics of the patients,
however, have changed dramatically in these 100

years. This is because our department addressed theacute needs of society from the beginning. Prof.
Tashiro believed that trauma should be treated byorthopedists, so he provided his pupils with thistraining. Since 1950’s, the department has increasingly been involved in the treatment of traffic andindustrial accident victims. Prof. Tashiro and his
successor professor Kenji Takagi devoted themselvesto the establishment of an institute for children withdisabilities. The arthroscopy was developed by Prof.
Takagi, and is now considered to represent a breakthrough in the development of minimally invasive
surgery. We have recently been conducting manystudies related to the ossification of spinal ligaments(OPLL), rheumatoid arthritis, biomechanics, and thedegenerative skeletal disorders such as osteoporosis

257

and osteoarthritis in response to the progressive agingof our society.
Our department is now adept in the entire field of
medical science and medical practice related to thehuman locomotor system, the importance of which is
now clearly recognized not only in Japan, but also all
over the world. To meet the expanding needs ofsociety, we have been conducting the teaching,clinical, and research activities described below.
Faculty members of the department are one
professor, two associate professors, four lecturers, 14
associates, nine medical staff members, and sevensenior residents.

Teaching activities
As for undergraduate education, our department
provides a comprehensive series of lectures, physicalassessment classes and problem-based learning (PBL)
program to 4th year medical students, clinicalclerkship programs to 5th year students and elective
clinical clerkship programs to 6th year medical
students.
A comprehensive series of lectures provides basic
knowledge of the physiology, pathology, diagnosis
and treatment of various musculoskeletal disorders.
Twelve consecutive lectures in total cover a whole
field of orthopaedics: basic science, pediatricdisorders, rheumatic diseases, metabolic bone diseases,
musculoskeletal neoplasm, trauma and regional
disorders of the musculoskeletal system (spine,
shoulder, elbow, hand, hip, knee, ankle and foot). In
the physical assessment classes, we have provided
physical diagnostic maneuvers and the radiologicalassessment of a variety of musculoskeletal diseases.
PBL has been introduced to a small group of students
to learn medical humanity and to develop a practicalmethodology to resolve clinical problems.
During the 3-week period of clinical clerkshipprogram, students have opportunities to join one ofclinical teams and experience patient care andorthopaedic practice with residents and faculty
members. We have developed an original text for the
students to learn on-site orthopedics effectively. They
are encouraged to participate in clinical conferences
and surgeries. They are also required to submit
reports on the cases they are involved in. They learn

how to conduct a medical interview, check physicalfindings and draw up actual plans for a diagnosis andtreatment including surgery.
Elective clinical clerkship provides 4 weeks ofmore intensive exposure to the clinical practice. The
students are attached to a clinical team and are
involved in most of the clinical activities performedby the team.
For postgraduate education, junior residents join
our department for 1-8 months. In 8 doctors-intraining completed our program during this fiscal year.
Since the training period is short, they are encouraged
to experience emergency cases as often as possible tolearn primary care. For senior residents, 1-year
clinical programs were conducted in corporation with
our affiliated hospitals. A postgraduate seminar and abasic research conference are held weekly.
Including the postgraduate training, an eight-year
course has been adopted with clinical and researchtraining taking place either in the University of Tokyo
Hospital or in our 40 affiliated hospitals.

Clinical activities
We have the outpatient clinic open from Monday
through Friday, with specialized divisions for spine,
hip, rheumatoid arthritis, tumor, scoliosis, limb
reconstruction and bone lengthening, knee, hand,elbow, shoulder, sports, peripheral nerves, bonesystemic disorders, and foot. A total of 36,291 patients
visited the outpatient clinic in fiscal 2019.
The ward has approximately 60 to 70 beds available
and is divided into the subgroups above. The members
are on duty for daily patient care under the supervisionof faculty members. The weekly official activities ofour department include ward rounds by the professoron Thursday. Post- and preoperative case conferences
are held on Monday evening, Wednesday evening andThursday morning.
1,464 operations were performed in fiscal 2019.
These include 364 spine surgeries, 73 surgeries forrheumatoid arthritis patients, 115 hip surgeries, 313
knee surgeries (including 31 computer-assisted ACL
reconstructions, 140 computer-assisted TKA, 21
UKA), 237 hand surgeries, 52 foot and ankle surgeries,
44 pediatric surgeries, 153 surgeries for bone and soft
tissue tumor, and 177 trauma surgeries.

258

The main disorders of cervical spine surgery weremyelopathy due to spondylosis or OPLL. We
successfully adopted double-door open laminoplasty
by splitting the spinal processes for most of thesecases. This procedure was invented and developed inour department and is now used nationwide. Difficult
operations such as subluxation of the cervical spine
due to rheumatoid arthritis, Down’s syndrome or
cerebral palsy were treated using a navigation systemthat has been officially approved as a high-leveladvanced medical treatment.
The spine group is now converting open surgeries
to minimum invasive surgeries using endoscopic
technique.
The scoliosis group used the navigation systemespecially for patients with complex deformity. In
addition to the conventional correction surgery,
growth-assist techniques such as dual growing rods
are utilized.
Main operations performed by the rheumatoid
arthritis clinic group were total joint arthroplasty.
They are using image-free navigation system in total
knee arthroplasty operation, which is useful for theaccurate placement of the implants.
The hip surgery group treated mainly acetabular
dysplasia and osteoarthritis of the hip joint. They
performed not only total hip replacements, but also
several osteotomies including rotational acetabularosteotomy (RAO). The RAO was originated andestablished in our department. They conducted aclinical trial for a new artificial hip joint using the
MPC polymer in collaboration with the Department ofMaterials Engineering in Tokyo University.
The knee clinic group developed a new anterior
cruciate ligament reconstruction technique using thenavigation system based on intraoperative threedimensional fluoroscopic image to realize ideal graft
placement.
The peripheral nerve clinic group has developed"costal nerve transfer to the musculocutaneous nerve"
for brachial plexus injury.
The tumor group managed multidisciplinary treatment for musculoskeletal sarcoma including chemotherapy, limb sparing surgery and radiotherapy incoorporation with other departments.
Limb reconstruction operations using external
fixators included non-union, leg lengthening anddeformity correction. One of the main interests of thisgroup is the development of a system to analyze themechanical properties of a skeletal system. During
this period of analysis, the mechanical properties ofthe fracture site in vivo are to be evaluated bymonitoring the motion of a dynamic pin clamp during
simulated walking.

Research activities
Our research activities cover the full range of themusculoskeletal system medicine, using the in-depthsciences of biology and technology. Especially in thefield of molecular biology of bone and cartilage
metabolism, we are regarded as being on the leadingedge in the world. Basic research is performed under
the supervision of the faculty staff members. Four
endowment departments take an active role inresearch activities in close collaboration with ourdepartment. They deal with regenerative medicine,clinical research, and material engineering.
As for research of bone resorption, we have been
researching and released some important reports aboutbone metabolism, especially in differentiation,
activation and apoptosis of osteoclast. Recently wehave been getting achievement in the new research
topics such as “Osteoimmunology”, a new research
field studying on signaling cross-talk between bonemetabolism and immunology, or “Epigenetics”, newresearch concept in spotlight using comprehensive
analysis technique.
As for research of cartilage, we have researchedmolecular biology of cartilage with the students of thegraduate school and the members of Bone andCartilage Regenerative Medicine, Division of Tissue
Engineering. Our research activities cover thegeneration and differentiation of chondrocytes, thejoint formation, the degeneration of joint cartilage,
and the regenerative methods.
Our clinical groups also take part in many
multicenter clinical studies conducted by Japan
Musculoskeletal Oncology Group (JMOG), National
Database of Rheumatic Diseases by iR-net in Japan(NinJa), and other multicenter groups.

259

References
1. Shibayama K, Sugaya H, Matsuki K, Takahashi N,
Tokai M, Onishi K, Tanaka S: Repair Integrity
and Functional Outcomes After Arthroscopic
Suture Bridge Subscapularis Tendon Repair.
Arthroscopy 2018,34:2541-2548
2. Tanaka T, Takao M, Sakai T, Hamada H, Tanaka S,
Sugano N: Variations in sagittal and coronal stem
tilt and their impact on prosthetic impingement in
total hip arthroplasty. Artif Organs 2018, Epub
3. Kawaguchi K, Michishita K, Manabe T, Akasaka
Y, Arakawa T, Higuchi J: Mucoid degeneration of
the cruciate ligaments in osteoarthritis underprimary total knee arthroplasty. Asia-Pacific
Journal of Sports Medicine, Arthroscopy,
Rehabilitation and Technology 2018,12:1-4
4. Ono K, Hirose J, Chang SH, Kubota M, Kinkawa
J, Noguchi M, Takedani H: Orthotropic live
transplantation for cirrhosis from hepatitis C virus
leads to correction of factor IX deficiency
allowing for ankle arthroplasty without factor
replacement in a patient with moderate haemophilia B. Blood Coagul Fibrinolysis 2018, 29(1):131-134
5. Tsuda Y, Ogura K, Shinoda Y, Kobayashi H,
Tanaka S, Kawai A: The outcomes and prognostic
factors in patients with osteosarcoma according toage: a Japanese nationwide study with focusing on
the age differences. BMC Cancer 2018, 18(1):614
6. Oka H, Matsudaira K, Takano Y,Kasuya D, Niiya
M, Tonosu J,Fukushima M, Oshima Y, Fujii T,
Tanaka S, Inanami H: A comparative study ofthree conservative treatments in patients withlumbar spinal stenosis: lumbar spinal stenosis
with acupuncture and physical therapy study(LAP study). BMC Complement Altern Med 2018,
Jan 19;18(1)7. Yamada K, Muranaga S, Shinozaki T, Nakamura
K, Tanaka S, Ogata T: BMC Geriatr 2018, Jan 26;
18(1):28
8. Doi T, Inoue H, Arai Y, Shirado O, Doi T,
Yamazaki K, Uno K, Yanagida H, Takeshita K:
Reliability and validity of a novel quality of life
questionnaire for female patients with adolescentidiopathic
scoliosis:
Scoliosis
Japanese

Questionnaire-27: a multicenter, cross-sectional
study. BMC Musculoskelet Disord 2018,19(1):99
9. Fujii T, Oka H, Katsuhira J, Tonosu J, Kasahara S,
Tanaka S, Matsudaira K: Disability due to knee
pain and somatising tendency in Japanese adults.
BMC Musculoskelet Disord 2018, Jan 19; 19(1):23
10. Tonosu J, Inanami H, Oka H, Takano Y, Koga H,
Yuzawa Y, Shiboi R, Oshima Y, Baba S, Tanaka S,
Matsudaira K: Factors related to subjective
satisfaction
following
microendoscopic
foraminotomy for cervical radiculopathy. BMC
Musculoskelet Disord 2018, Jan 24;19(1):30
11. Oshina M, Oshima Y, Matsubayashi Y, Taniguchi
Y, Chikuda H, Riew KD, Tanaka S: Nutrient
foramen location on the laminae provides alandmark for pedicle screw entry: a cadaveric
study. BMC Musculoskelet Disord 2018, 19(1):293
12. Omiya T, Hirose J, Hasegawa T, Amizuka N,
Omata Y, Izawa N, Yasuda H, Kadono Y,
Matsumoto M, Nakamura M, Miyamoto T, Tanaka
S: The effect of switching from teriparatide toanti-RANKL antibody on cancellous and corticalbone in ovariectomized mice. Bone 2018,107:
18-26
13. Chang SH, Matsumoto T, Okajima K, Naito M,
Hirose J, Tanaka S: Heterotopic Ossification of
the Peroneus Longus Tendon in the Retromalleolar Portion with the Peroneus Quartus
Muscle: A Case Report. Case Rep Orthop 2018,
Jul 29
14. Kobayashi H, Ikegami M, Ushiku T, Anraku M,
Ohki T, Shinoda Y, Tanaka S, Kawano H:
Secondary Chondrosarcoma Presenting with
Symptoms Similar to Thoracic Outlet Syndrome.
Case Rep Orthop 2018, Mar 12
15. Matsumoto T, Chang SH, Takeda R, Tanaka S,
Juji T: Bilateral Stress Fractures of the Talus
Associatedwith
Adult-Acquired
Flatfoot
Deformities. Case Rep Orthop 2018, Sep 9
16. Tanaka T, Ito H, Oshima H, Haga N, Tanaka S:
Total Hip Arthroplasty in a Patient with
Oto-Spondylo-Megaepiphyseal Dysplasia Plannedby Three-Dimensional Motion Analyses andFull-Scale Three-Dimensional Plaster Model ofBones. Case Rep Orthop 2018, Jan 23

260

17. Omata Y, Frech M, Primbs T, Lucas S, Andreev D,
Scholtysek C, Sarter K, Kindermann M,
Yeremenko N, Baeten DL, Andreas N, Kamradt T:Group 2 Innate Lymphoid Cells Attenuate
Inflammatory Arthritis and Protect from Bone
Destruction in Mice 2018,24:169-180
18. Ogata T, Ideno Y, Akai M, Seichi A, Hagino H,
Iwaya T, Doi T, Yamada K, Chen AZ, Li Y,
Hayashi K: Effects of glucosamine in patientswith osteoarthritis of the knee: a systematic
review and meta-analysis. Clin Rheumatol 2018,
37(9):2479-2487
19. Oshina M, Horii C, Hirai S, Matsubayashi Y,
Taniguchi Y, Hayashi N, Tanaka S, Oshima Y:
Lewis SJ, Mohanty C, Gazendam AM, Kato S,
Keshen SG, Lewis ND, Magana SP, Perlmutter D,
Cape J: Posterior column reconstruction improves
fusion rates at the level of osteotomy in threecolumn posterior-based osteotomies. Eur Spine J
2018, 27(3):636-643
20. Comparison of Freehand Sagittal Trajectories forInserting Pedicle Screws Between C7) and T5.
Clin Spine Surg 2018, 31(7):E357-E362
21. Ganau M, Kato S, Oshima Y: Letter to the Editor
concerning "Osteoporotic thoracolumbar compression fractures: long-term retrospective
comparison
betweenvertebroplasty
andconservative treatment" by K. Martikos et al. Eur
Spine 2018, J 27(7):1662-1663
22. Oshina M, Tanaka M, Oshima Y, Tanaka S, Riew
KD: Correlation and differences in cervicalsagittal alignment parameters between cervicalradiographs and magnetic resonance images. Eur
Spine J 2018,27(6):1408-1415
23. Maenohara Y, Taniguchi A, Tomiwa K,
Tsuboyama D, Kurokawa H, Kumai T, Tanaka S,
Tanaka Y: Outcomes of Bilateral vs Unilateral
Ankle Arthrodesis. Foot Ankle Int 2018,39:530534
24. Matsumoto T, Gross CE, Parekh SG: Short-Term
Radiographic Outcome After Distal Chevron
Osteotomy for Hallux Valgus Using Intramedullary Plates With an Amended Algorithm for
the Surgical Management of Hallux Valgus. Foot
Ankle Spec 2018, Epub
25. Oshina M, Oshima Y, Tanaka S, Riew KD:
Radiological Fusion Criteria of Postoperative

Anterior Cervical Discectomy and Fusion: A
Systematic Review. Global Spine J 2018, 8(7):739-750
26. Lewis SJ, Keshen SG, Kato S, Dear TE,
Gazendam AM: Risk Factors for Postoperative
Coronal Balance in Adult Spinal Deformity
Surgery. Global Spine J 2018, 8(7):690-697
27. Kobayashi H, Okuma T, Oka H, Okajima K,
Ishibashi Y, Zhang L, Hirai T, Ohki T, Tsuda Y,
Ikegami M, Sawada R, Shinoda Y, Akiyama T,
Kawano H, Goto T, Tanaka S: Body composition
as a predictor of toxicity after treatment witheribulin for advanced soft tissue sarcoma. Int J
Clin Oncol 2018, Epub
28. Kobayashi H, Okuma T, Oka H, Hirai T, Ohki T,
Ikegami M, Sawada R, Shinoda Y, Akiyama T,
Sato K, Abe S, Kawano H, Goto T, Tanaka S:
Neutrophil-to-lymphocyte ratio after pazopanib
treatment predicts response in patients withadvanced soft-tissue sarcoma. Int J Clin Oncol
2018, 23(2):368-374
29. Hosoi I, Kobayashi E, Chang SH, Matsumoto T,
An Q, Anzai E, Ohta Y, Sakuma I: Developmentof intraoperative planter pressure measuringsystem considering weight bearing axis. Int J
Comput Assist Radiol Surg 201830. Hosoi I, Kobayashi E, Chang SH, Matsumoto T,
An Q, Anzai E, Ohta Y, Sakuma I: Developmentof intraoperative plantar pressure measuringsystem considering weight bearing axis. Int J
Comput Assist Radiol Surg. 2018 Epub
31. Taii T, Matsumoto T, Tanaka S, Nakamura I, Ito K,
Juji T: Wrist Arthrodesis in Rheumatoid Arthritis
Using an LCP Metaphyseal Locking Plate versus
an AO Wrist Fusion Plate. Int J Rheumatol 2018,
Jul 1032. Kojima T, Ishikawa H, Tanaka S, Haga N, Nishida
K, Yukioka M, Hashimoto J, Miyahara H, Niki Y,
Kimura T, Oda H, Asai S, Funahashi K, Kojima M,
Ishiguro N: Target setting for lower limb joint
surgery using the Timed Up and Go test in
patients with rheumatoid arthritis: A prospective
cohort study. Int J Rheum Dis 2018,21:1801-1808
33. Kojima T, Ishikawa H, Tanaka S, Haga N, Nishida
K, Yukioka M, Hashimoto J, Miyahara H, Niki Y,
Kimura T, Oda H, Asai S, Funahashi K, Kojima M,
Ishiguro N: Validation and reliability of the Timed261

Up and Go test for measuring objective functional
impairment in patients with long-standing
rheumatoid arthritis: a cross-sectional study. Int J
Rheum Dis 2018, 21:1793-1800
34. Tanaka T, Moro T, Takatori Y, Oshima H, Ito H,
Sugita N, Mitsuishi M, Tanaka S: Evaluation of
the three-dimensional bony coverage before andafter rotational acetabular osteotomy. Int Orthop
2018, 42(11):2527-2534
35. Kyomoto M, Shoyama Y, Saiga K, Moro T,
Ishihara K: Reducing fretting-initiated crevice
corrosion in hip simulator tests using a zirconiatoughened alumina femoral head. J Biomed Mater
Res B Appl Biomater 2018, Nov 106(8)36. Yamane S, Kyomoto M, Moro T, Hashimoto M,
Takatori Y, Tanaka S, Ishihara K: Wear resistanceof poly(2-methacryloyloxyethyl phosphorylcholine)-grafted carbon fiber reinforced poly(ether ether
ketone) liners against metal and ceramic femoral
heads. J Biomed Mater Res B Appl Biomater
2018, 106(3):1028-1037
37. Kodama R, Muraki S, Iidaka T, Oka H, Teraguchi
M, Kagotani R, Asai Y, Hashizume H, Yoshida M,
Kawaguchi H, Nakamura K, Akune T, Tanaka S,
and Yoshimura N: Serum levels of matrix
metalloproteinase-3 and autoantibodies related torheumatoid arthritis in the general Japanese
population
and
their
association
withOsteoporosis and Osteoarthritis: The ROAD
Study 2018,36:246-253
38. Miura T, Ando M, Tanaka S, Uehara K:
Assessment of Dorsal Subluxation in Thumb
Carpometacarpal Osteoarthritis. J Hand Microsurg
2018,10:125-129
39. Inui H, Taketomi S, Yamagami R, Shirakawa N,
Kawaguchi K, Tanaka S: The Relationshipbetween Soft-Tissue Balance and Intraoperative
Kinematics of Guided Motion Total Knee
Arthroplasty. J Knee Surg 2018,32:91-96
40. Taketomi S, Inui H, Yamagami R, Shirakawa N,
Kawaguchi K, Nakagawa T, Tanaka S:
Bone-Patellar Tendon-Bone Autograft versus
Hamstring Tendon Autograft for Anatomical
Anterior Cruciate Ligament Reconstruction withThree-Dimensional Validation of Femoral andTibial Tunnel Positions. J Knee Surg 2018,31:
866-874

41. Kyomoto M, Moro T, Yamane S, Watanabe K,
Hashimoto M, Tanaka S, Ishihara K: A
phospholipid polymer graft layer affords highresistance for wear and oxidation under load
bearing conditions. J Mechan Behav Biomed
Mater 2018,79:203-212
42. Hirose J, Takedani H, Nojima M, Koibuchi T:
Risk factors for postoperative complications oforthopedic surgery in patients with hemophilia:
Second report. J Orthop 2018, 15(2):558-562
43. Fukushima M, Oshima Y, Oka H, Chang C,
Matsubayashi Y, Taniguchi Y, Matsudaira K,
Tanaka S: Potential pathological mechanisms of
L3 degenerative spondylolisthesis in lumbar
spinal stenosis patients: A case-control study. J
Orthop Sci 2018, Dec 27
44. Nagata K, Ando T, Nakamoto H, Kato S, Sasaki K,
Oshima Y: Adaptation and limitation of anterior
column reconstruction for pyogenic spondylitis inlower thoracic and lumbar spine. J Orthop Sci
2018, Epub
45. Taketomi S, Inui H, Yamagami R, Kawaguchi K,
Nakazato K, Kono K, Kawata M, Nakagawa T,
Tanaka S: Surgical timing of anterior cruciate
ligament reconstruction to prevent associatedmeniscal and cartilage lesions. J Orthop Sci 2018,
23:546-551
46. Tanaka S: Emerging anti-osteoclast therapy forrheumatoid arthritis. J Orthop Sci 2018, 23:717721
47. Makii Y, Asaka M, Setogawa S, Fujiki S, Hosaka
Y, Yano F, Oka H, Tanaka S, Fukui N, Yanagihara
D, Saito T: Alteration of gait parameters in amouse model of surgically induced knee
osteoarthritis. J Orthop Surg (Hong Kong) 2018,
May-Aug;26(2)48. Inanami H, Saiki F, Oshima Y: Microendoscopeassisted posterior lumbar interbody fusion: atechnical note. Journal of Spine Surgery 2018,4:
408-413
49. Inomata Y, Oshima Y, Inoue H, Takano Y, Inanami
H, Koga H: Percutaneous endoscopic lumbar
discectomy via adjacent interlaminar space forhighly down-migrated lumbar disc herniation: atechnical report. Journal of Spine Surgery 2018, 4:
483-489
50. Ishibashi K, Oshima Y, Inoue H, Takano Y, Iwai H,

262

Inanami H, Koga H: A less invasive surgery using
a full-endoscopic system for L5 nerve root
compression caused by lumbar foraminal stenosis.
Journal of Spine Surgery 2018,4:594–601
51. Kaneko T, Oshima Y, Inoue H, Iwai H, Takano Y,
Inanami H, Koga H: Successful treatment oflumbar ligamentum flavum hematoma using a
spinal full-endoscopic system. Journal of Spine
Surgery 2018,4
52. Tonosu J, Oka H, Watanabe K, Abe H,
Higashikawa A, Yamada K, Kuniya T, Nakajima
K, Tanaka Matsudaira K: Validation study of adiagnostic scoring system for sacroiliac jointrelated pain. J Pain Res 2018,11:1659-1663
53. Kondo M, Oshima Y, Inoue H, Takano Y, Inanami
H, Koga H: Significance and pitfalls of
percutaneous endoscopic lumbar discectomy forlarge central lumbar disc herniation. J Spine Surg
2018,4:79-85
54. Inui H, Taketomi S, Yamagami R, Kawaguchi K,
Nakazato K, Tanaka S: The relationship between
anteroposterior stability and medial-lateralstability of the bi-cruciate stabilized total knee
arthroplasty. Knee 2018,25:1247-1253
55. Kawaguchi K, Inui H, Taketomi S, Yamagami R,
Nakazato K, Shirakawa N, Tanaka S:
Intraoperative mobile-bearing movement in
Oxford unicompartmental knee arthroplasty. Knee
Surg Sports Traumatol Arthrosc 2018, Jul 21
56. Kawata M, Sasabuchi Y, Taketomi S, Inui H,
Matsui H, Fushimi K, Yasunaga H, Tanaka S:
Atopic dermatitis is a novel demographic risk
factor for surgical site infection after anterior
cruciate ligament reconstruction. Knee SurgSports Traumatol Arthrosc 2018,26:3699-3705
57. Taniguchi Y, Oichi T, Ohya J, Chikuda H, Oshima
Y, Matsubayashi Y, Matsui H, Fushimi K, Tanaka
S, Yasunaga H: In-hospital mortality andmorbidity of pediatric scoliosis surgery in Japan:
Analysis using a national inpatient database.
Medicine (Baltimore) 2018, 97(14):e0277
58. Fujimoto Y, Fujii T, Oshima Y, Oka H, Tanaka S,
Matsudaira K: The association between neckand shoulder discomfort-Katakori-and highsomatizing tendency. Mod Rheumatol 2018, Nov
28:1-1459. Izawa N, Hirose J, Fujii T, Oka H, Uehara K,

Naito M, Matsumoto T, Tanaka S, Tohma S: Theutility of 25-question Geriatric Locomotive
Function Scale for evaluating functional ability
and disease activity in Japanese rheumatoid
arthritis patients: A cross-sectional study using
NinJa database. Mod Rheumatol 2018, Apr 18:1-7
60. Matsumoto T, Maenohara Y, Chang SH, Hirose J,
Juji T, Ito K, Tanaka S: Lateral collapse of thetarsal navicular in patients with rheumatoid
arthritis: Implications for pes planovarus
deformity. Mod Rheumatol 2018, 28(5):800-807
61. Oka H, Kadono Y, Ohashi S, Yasui T, Ono K,
Matsudaira K, Nishino J, Tanaka S: Assessing
joint destruction in the knees of patients withrheumatoid arthritis by using a semi-automatedsoftware for magnetic resonance imaging:therapeutic effect of methotrexate plus etanercept
compared with methotrexate monotherapy. Mod
Rheumatol 2018,28:235-241
62. Oka H, Nomura T, Asada F, Takano K, Nitta Y,
Uchima Y, Sato T, Kawase M, Sawada S,
Sakamoto K, Yasue M, Arima S, Katsuhira J,
Kawamata K, Fujii T, Tanaka S, Konishi H,
Okazaki H, Miyoshi K, Watanabe J, Matsudaira
K: The effect of the "One Stretch" exercise on the
improvement of low back pain in Japanese nurses:
a large-scale, randomized, controlled trial. Mod
Rheumatol 2018, Aug 22:1-17
63. Tanaka S, Tanaka Y, Ishiguro N, Yamanaka H,
Takeuchi T: RANKL: A therapeutic target forbone destruction in rheumatoid arthritis. Mod
Rheumatol 2018,28:9-16
64. Ogura K, Hosoda F, Arai Y, Nakamura H, Hama N,
Totoki Y, Yoshida A, Nagai M, Kato M, Arakawa
E, Mukai W, Rokutan H, Kawai A, Tanaka S,
Shibata T: Integrated genetic and epigenetic
analysis of myxofibrosarcoma. Nat Commun 2018,
Jul 17;9(1):2765
65. Lucas S, Omata Y, Hofmann J, Bottcher M,
Iljazovic A, Sarter K, Albrecht O, Schulz O,
Krishnacoumar B, Kronke G, Herrmann M,
Mougiakakos D, Strowig T, Schett G, Zaiss MM:
Short-chain fatty acids regulate systemic bonemass and protect from pathological bone loss. Nat
Commun 2018,9:55
66. Inoue M, Okamoto K, Terashima A, Nitta T, Muro
R, Negishi-Koga T, Kitamura T, Nakashima T,

263

Takayanagi H: Arginine methylation controls thestrength of γc-family cytokine signaling in T cellmaintenance. Nature Immunology 2018,19:12651276
67. Yoshimura N, Muraki S, Oka H, Iidaka T,
Kodama R, Horii C, Kawaguchi H, Nakamura K,
Akune T, Tanaka S: Do sarcopenia and/or
osteoporosis increase the risk of frailty? A 4-year
observation of the second and third ROAD study
surveys. Osteporos International 2018
68. Fujii T, Oka H, Katsuhira J, Tonosu J, Kasahara S,
Tanaka S, Matsudaira K: Association between
somatic symptom burden and health-related
quality of life in people with chronic low backpain. PLoS One 2018, Feb 20;13(2):e0193208
69. Kawata M, Sasabuchi Y, Taketomi S, Inui H,
Matsui H, Fushimi K, Chikuda H, Yasunaga H,
Tanaka S: Annual trends in arthroscopic meniscus
surgery: Analysis of a national database in Japan.
PLoS One 2018:Apr 3;13(4):e0194854
70. Maeda T, Hashizume H, Yoshimura N, Oka H,
Ishimoto Y, Nagata K, Takami M, Tsutsui S,
Iwasaki H, Minamide A, Nakagawa Y, Yukawa Y,
Muraki S, Tanaka S, Yamada H, Yoshida M:
Factors associated with lumbar spinal stenosis in alarge-scale,population-based
cohort:
The
Wakayama Spine Study. PLoS One 2018,Jul 18;
13(7):e0200208
71. Ogihara S, Yamazaki T, Inanami H, Oka H,
Maruyama T, Miyoshi K, Takano Y, Chikuda H,
Azuma S, Kawamura N, Yamakawa K, Hara N,
Oshima Y, Morii J, Okazaki R, Takeshita Y,
Tanaka S, Saita K: Risk factors for surgical site
infection after lumbar laminectomy and/or
discectomy for degenerative diseases in adults: A
prospective multicenter surveillance study withregistry of 4027 cases. PLoS One 2018, Oct 16;
13(10):e0205539
72. Sasaki T, Yoshimura N, Hashizume H, Yamada H,
Oka H, Matsudaira K, Iwahashi H, Shinto K,
Ishimoto Y, Nagata K, Teraguchi M, Kagotani R,
Muraki S, Akune T, Tanaka S, Kawaguchi H,
Nakamura K, Minamide A, Nakagawa Y, Yoshida
M: MRI-defined paraspinal muscle morphology inJapanese population: The Wakayama Spine Study.
PLoS One 2018,12: e0187765
73. Murahashi Y, Yano F, Kobayashi H, Makii Y, Iba

K, Yamashita T, Tanaka S, Saito T: Intra-articularadministration of I ﾎ ｺ B ﾎ ｱ kinase inhibitor
suppresses mouse knee osteoarthritis via
downregulation of the NF-kB/HIF-2α axis. Sci
Rep 2018,8:16475
74. Oshina M, Oshima Y, Tanaka S, Tan LA, Li XJ,
Tuchman A, Riew KD: Utility of Oblique Sagittal
Reformatted and Three-dimensional Surface
Reconstruction Computed Tomography in
Foraminal Stenosis Decompression. Sci Rep 2018,
8(1):16011
75. Yamada K, Abe H, Higashikawa A, Tonosu J,
Kuniya T, Nakajima K, Fujii H, Niwa K,
Shinozaki T, Watanabe K, Sakae T, Okazaki H:
Evidence-based Care Bundles for Preventing
Surgical Site Infections in Spinal Instrumentation
Surgery. Spine (Phila Pa 1976) 2018, 43:17651773
76. Anno M, Oshima Y, Taniguchi Y, Matsubayashi Y,
Kato S, Soma K, Oka H, Hayashi N, Tanaka S:
Prevalence and Natural Course of Transverse
Ligament of the Atlas Calcification in
Asymptomatic Healthy Individuals. Spine (Phila
Pa 1976) 2018,43(24):E1469-E1473
77. Kato S, Fehlings MG, Lewis SJ, Lenke LG,
Shaffrey CI, Cheung KMC, Carreon LY,
Dekutoski MB, Schwab FJ, Boachie-Adjei O,
Kebaish KM, Ames CP, Qiu Y, Matsuyama Y,
Dahl BT, Mehdian H, Pellis F, Berven SH: An
Analysis of the Incidence and Outcomes of Major
Versus Minor Neurological Decline After
Complex Adult Spinal Deformity Surgery: A
Subanalysis of Scoli-RISK-1 Study. Spine (Phila
Pa 1977) 2018, 43(13):905-912
78. Kato S, Fok KL, Lee JW, Masani K: Dynamic
Fluctuation of Truncal Shift Parameters During
Quiet Standing in Healthy Young Individuals.
Spine (Phila Pa 1978) 2018, 43(13):E746-E751
79. Kato S, Nouri A, Reihani-Kermani H, Oshima Y,
Cheng J, Fehlings MG: Postoperative Resolutionof Magnetic Resonance Imaging Signal Intensity
Changes and the Associated Impact on Outcomesin Degenerative Cervical Myelopathy: Analysis ofa Global Cohort of Patients. Spine (Phila Pa 1979)
2018, 43(12):824-831
80. Kato S, Nouri A, Wu D, Nori S, Tetreault L,
Fehlings MG: Impact of Cervical Spine

264

Deformity on Preoperative Disease Severity andPostoperative Outcomes Following Fusion
Surgery for Degenerative Cervical Myelopathy:
Sub-analysis of AOSpine North America andInternational Studies. Spine (Phila Pa 1980) 2018,
43(4):248-254
81. Kato S, Oshima Y, Matsubayashi Y, Taniguchi Y,
Tanaka S, Takeshita K: Minimum Clinically
Important Difference and Patient Acceptable
Symptom State of Japanese Orthopaedic Association Score in Degenerative Cervical Myelopathy
Patients. Spine (Phila Pa 1981) 2018, Epub
82. Oichi T, Oshima Y, Matsui H, Fushimi K, Tanaka
S, Yasunaga H: Can Elective Spine Surgery be
Performed Safely Among Nonagenarians?
Analysis of a National Inpatient Database in Japan.
Spine (Phila Pa 1982) 2018, Epub
83. Oichi T, Taniguchi Y, Soma K, Chang SH, Yano F,
Tanaka S, Saito T: A Mouse Intervertebral Disc
Degeneration Model by Surgically Induced
Instability. Spine (Phila Pa 1983) 2018, 43(10):E557-E564
84. Fehlings MG, Kato S, Lenke LG, Nakashima H,
Nagoshi N, Shaffrey CI, Cheung KMC, Carreon L,
Dekutoski MB, Schwab FJ, Boachie-Adjei O,
Kebaish KM, Ames CP, Qiu Y, Matsuyama Y,
Dahl BT, Mehdian H, Pellise-Urquiza F, Lewis SJ,
Berven SH: Incidence and risk factors of
postoperative neurologic decline after complex
adult spinal deformity surgery: results of the
Scoli-RISK-1 study. Spine J 2018, 18(10):17331740
85. Horii C, Yamazaki T, Oka H, Azuma S, Ogihara S,
Okazaki R, Kawamura N, Takano Y, Morii J,
Takeshita Y, Maruyama T, Yamakawa K,
Murakami M, Oshima Y, Tanaka S: Does
intrawound vancomycin powder reduce surgicalsite infection after posterior instrumented spinal
surgery? A propensity score-matched. Spine J
2018, 18(12):2205-2212
86. Kato S, Hozumi T, Yamakawa K, Saiki H, Sugita
S, Oshima Y, Tanaka S: Letter to the Editor
concerning "The META score for differentiating
metastatic from osteoporotic vertebral fractures:
an independent agreement assessment" by Besa
etal.. Spine J 2018,18(11):2167-2168
87. Oichi T, Oshima Y, Chikuda H, Ohya J, Matsui H,

Fushimi K, Tanaka S, Yasunaga H: In-hospitalcomplication rate following microendoscopic
versus open lumbar laminectomy: a propensity
score-matched analysis. Spine J 2018, 18(10)88. Emoto S, Kaneko M, Murono K, Sasaki K, Otani
K, Nishikawa T, Tanaka T, Hata K, Kawai K, Imai
H, Saito N, Kobayashi H, Tanaka S, Ikemura M,
Ushiku T, Nozawa H: Surgical management for ahuge presacral teratoma and a meningocele in an
adult with Currarino triad: a case report. Surg
Case Rep 2018, Jan 19;4(1):989. Uehara K, Zhao C, Amadio PC: Fibrin glue as analternative to peripheral sutures does not increase
tendon repair strength in an in vitro model. J Hand
Surg Eur Vol 2018,43:995-997
90. Ogura K, Uehara K, Akiyama T, Shinoda Y, Iwata
S, Tsukushi S, Kobayashi E, Hirose T, Yonemoto
T, Endo M, Tanzawa Y, Nakatani F, Kawano H,
Tanaka S, Kawai A: Development of apatient-oriented disease specific outcome measureof health-related quality of life (HRQOL) formusculoskeletal oncology patients. J Orthop Sci
2018, Nov 13. pii:S0949-2658(18)30317-8
91. Izawa N, Hirose J, Fujii T, Oka H, Uehara K,
Naito M, Matsumoto T, Tanaka S, Tohma S: Theutility of 25-question Geriatric Locomotive
Function Scale for evaluating functional ability
and disease activity in Japanese rheumatoid
arthritis patients: A cross-sectional study using
NinJa database. Mod Rheumatol 2018,18
92. Saita K, Monobe Y, Ogihara S, Kobayashi Y, SatoK, Nishimura K, Tanabe M: A case of vertebral
fracture associated with diffuse idiopathic skeletal
hyperostosis treated by successful conservative
treatment. Spine Surgery and Related Research
2018, Epub

265

Department of Ophthalmology
Professor
Makoto Aihara, M.D., Ph.D.

Associate Professor
Satoshi Kato, M.D., Ph.D., Megumi Honjo, M.D., Ph.D.

Lecturer
Ryo Obata, M.D., Ph.D., Takashi Miyai, M.D., Ph.D., Hitomi Saito, M.D., Ph.D.
Hiromasa Sawamura, M.D., Ph.D., Tomoyasu Shiraya, M.D., Ph.D.

Research Associate
Rei Sakata, M.D., Ph.D., Rie Tanaka, M.D., Ph.D., Takashi Ueta, M.D., Ph.D.,
Takashi Fujishiro, M.D., Ph.D., Keiko Azuma, M.D., Ph.D., Tetsuya Toyono, M.D., Ph.D.,
Kiyohito Totsuka, M.D., Ph.D., Fumiyuki Araki, M.D., Ph.D., Taku Toyama, M.D., Ph.D.,
Kohei Ueta, M.D., Yukako Taketani, M.D., Ph.D., Kohdai Kitamoto, M.D., Ph.D.

Homepagehttps://www.todaiganka.jp

Introduction and Organization
The Department of Ophthalmology, University ofTokyo School of Medicine, was founded in 1889.
Since then, the department has contributed to Japanese
ophthalmology not only by educating many eminent
ophthalmologists in Japan but also by producing
significant basic research in ophthalmology.
The department has been active in collaboration with
ophthalmologists around the world, sponsoring
international ophthalmological meetings, educating
fellows from foreign countries, and sending our staff
and fellows abroad.

Clinical activities
Altogether, approximately 2900 new outpatients areseen every year in our hospital, which has a total of 27
beds. Residents work in the ambulatory section andtake care of inpatients. Special services are provided
in units devoted to ophthalmic subspecialties such as
cornea, glaucoma, retina, uveitis, neuro-ophthalmology, orthoptics, diabetic retinopathy, and genetic

and color blindness problems. The staff members
supervise the ambulatory and special services
depending on each one’s specialty.
Most of the inpatients suffer from cataract, glaucoma,
corneal diseases, retinal detachment, diabetic
retinopathy, age-related macular degeneration, uveitis,
ptosis, dry eye and strabismus. Surgeries are
performed in the operating theater of the hospital
under operating microscopes. Approximately 8610
cases underwent operations in our department.
Surgeries can be monitored by TV system, which ismounted on operating microscopes. Since multiple
observers can watch the same images and sharefindings, this system has great potential in training andpromoting discussion.

Education
As an undergraduate course, we give lectures on
corneal physiology, corneal diseases, and corneal
transplantation. In addition, we are engaged inpractical training for medical students on ophthalmological examinations at the outpatient clinic. As a266

postgraduate course, we give lectures on topics
concerning corneal transplantation, corneal diseases
and new medical therapies.

Publications
1.

ResearchResearch topics in our department cover a variety offields in ophthalmology; e.g. ocular pharmacology inglaucoma, lipid mediators in ocular diseases,
regenerative medicine in the cornea and retina,
aqueous humor dynamics, immunology and molecularbiology. Special laboratories for physiology,
pharmacology and genetic engineering have been
established. Specific fields of research in our
department are as follows.

2.

3.
1.
2.
3.
4.
5.
6.
7.
8.

9.
10.
11.
12.
13.
14.
15.
16.
17.
18.

Lipid mediators in ocular diseases
Clinical investigation of normal tension
glaucoma
Drug development in IOP reduction of glaucoma
Screening method of glaucoma
Pathophysiology and molecular mechanisms of
diabetic retinopathy
Relationship between visual function and qualityof life in patient with low vision
Investigation of molecular mechanisms of retinal
arteritis and phlebitis
Investigation of gene mutations in primary
vitreoretinal lymphoma and development of newtreatment
Study of mechanisms involving disease-specific
HLA in Behcet's disease
Analysis of structure-function relationships inmacular diseases
Molecular analysis of corneal neovascularization
Gene therapy for corneal dystrophies
Analysis of Meibomian gland with Mibography
Analysis of safety of topical eye drops using
human corneal epithelial cell sheets
Clinical trial of corneal crosslinking for
keratoconus and keratoectasia
Ophthalmic examination of patients withcongenital insensitivity to pain with anhydrosis
Assessment of higher visual functions by fMRI
Relevance between ophthalmic diseases andcortical functions

4.

5.

6.

7.

Aihara M, Kubota N, Minami T, Shirakawa R,
Sakurai Y, Hayashi T, Iwamoto M, Takamoto I,
Kubota T, Suzuki R, Usami S, Jinnouchi H,
Aihara M, Yamauchi T, Sakata T, Kadowaki T.
Association between tear and blood glucose
concentrations: Random intercept modelAzuma K, Okubo A, Suzuki T, Igarashi N,
Nomura Y, Soga H, Murata H, Fujino R, Ogawa
A, Matsui H, Nagamatsu T, Iriyama T, Asaoka R,
Inoue T, Maruyama-Inoue M, Kadonosono K,
Obata R. Assessment of the choroidal structure inpregnant women in the first trimester. Sci Rep.
2021 Feb 25;11(1):4629.
Igarashi N, Honjo M, Asaoka R, Kurano M,
Yatomi Y, Igarashi K, Miyata K, Kaburaki T,
Aihara M. Aqueous autotaxin and TGF-βs arepromising diagnostic biomarkers for distinguishing open-angle glaucoma subtypes. Sci Rep. 2021
Jan 14;11(1):1408.
Obata R, Yoshinaga A, Yamamoto M, Komatsu
K, Aoki N, Yamanari M, Sugiyama S, Minami T,
Azuma K, Inoue T, Aihara M, Kato S. Obata R,
Yoshinaga A, Yamamoto M, Komatsu K, Aoki N,
Yamanari M, Sugiyama S, Minami T, Azuma K,
Inoue T, Aihara M, Kato S. Jpn J Ophthalmol.
2021 Jan;65(1):30-41.
Omoto T, Sugiura A, Fujishiro T, Asano-Shimizu
K, Sugimoto K, Sakata R, Murata H, Asaoka R,
Honjo M, Aihara M. Twelve-month surgicaloutcome and prognostic factors of stand-alone abinterno trabeculotomy in Japanese patients with
open-angle glaucoma. PLoS One. 2021 Jan 7;
16(1):e0245015.
Honjo M, Yamagishi R, Igarashi N, Ku CY,
Kurano M, Yatomi Y, Igarashi K, Aihara M.
Effect of postoperative corticosteroids onsurgical outcome and aqueous autotaxin
following combined cataract and microhook abinterno trabeculotomy. Sci Rep. 2021 Jan 12;11(1):747.
Hashimoto Y, Michihata N, Yamana H, Shigemi
D, Morita K, Matsui H, Yasunaga H, Aihara M.
Intraocular pressure-lowering medications during
pregnancy and risk of neonatal adverse
outcomes: a propensity score analysis using a

267

8.

9.

10.

11.

12.

13.

14.

15.

large database. Br J Ophthalmol. 2021 Oct;105(10):1390-1394.
Nakamura N, Honjo M, Yamagishi R, Kurano M,
YatomiY,
WatanabeS,
AiharaM.
Neuroprotective role of sphingolipid rheostat in
excitotoxic retinal ganglion cell death. Exp Eye
Res. 2021 Jul;208:108623.
Fujita A, Amari T, Ueda K, Azuma K, Inoue T,
Komatsu K, Yamamoto M, Aoki N, Yamanari M,
Sugiyama S, Aihara M, Kato S, Obata R.
Three-Dimensional Distribution Of Fundus
Depolarization
andAssociating
Factors
Measured Using Polarization-Sensitive Optical
Coherence Tomography. Transl Vis Sci Technol.
2021 Feb 5;10(2):30.
Kitano M, Fujita A, Asaoka R, Inoue T, Amari T,
Komatsu K, Yamamoto M, Ogawa A, Aoki N,
Yamanari M, Sugiyama S, Aihara M, Kato S,
Azuma K, Maruyama-Inoue M, Kadonosono K,
Obata R. Assessment of macular function inpatients with non-vascularized pigment epithelial
detachment. Sci Rep. 2021 Aug 16;11(1):16577.
Shirahama S, Soga H, Tanaka R, Fukunaga H,
Izawa H, Komae K, Nakahara H, Kawashima H,
Aihara M, Kaburaki T. Clinical features ofuveitis in elderly patients in central Tokyo(2013-2018). Int Ophthalmol. 2021 May;41(5):1671-1679.
Sakata R, Fujishiro T, Saito H, Honjo M, Shirato
S, Aihara M. The Additive Effect of ROCK
Inhibitor on Prostaglandin-Treated JapanesePatients with Glaucoma Indicating 15 mmHg andUnder: ROCK U-15. Adv Ther. 2021 Jul;38(7):3760-3770.
Nakamura N, Honjo M, Yamagishi R, Igarashi N,
Sakata R, Aihara M. Effects of selective EP2
receptor agonist, omidenepag, on trabecularmeshwork cells, Schlemm's canal endothelial
cells and ciliary muscle contraction. Sci Rep.
2021 Aug 10;11(1):16257.
Zhou HP, Ishikawa H, Yasumoto R, Sakurai K,
Sawamura H. Leber hereditary optic neuropathy
harboring a rare m.12811 T>C mitochondrialDNAmutation.
Canadian
JournalofOphthalmology. 2021; 56: 82-84.
Terao R, Matsuda A, Ogawa A, Shimizu K,
Azuma K, Inoue T, Obata R. OPTICAL

16.

17.

18.

19.

20.

21.

22.

COHERENCETOMOGRAPHYANGIOGRAPHY STUDY OF CHOROIDALNEOVASCULARIZATIONASSOCIATED
WITH EARLY-ONSET DRUSEN. Retin Cases
Brief Rep. 2021 Sep 1;15(5):581-587.
M, Ueta T. Fovea-Sparing as Opposed to Total
Peeling of Internal Limiting Membrane for
Myopic Foveoschisis: A Systematic Review andMeta-analysis. Ophthalmol Retina. 2021; 5: 670679.
Ono T, Mori Y, Nejima R, Iwasaki T, Miyai T,
Miyata K. Corneal endothelial cell density andmorphology in ophthalmologically healthy young
individuals in Japan: An observational study of16842 eyes. Sci Rep. 2021; 11: 18224.
Tanaka R, Kaburaki T, Taoka K, Karakawa A,
Tsuji
H,
Nishikawa
M,
YatomiY,
Shinozaki-Ushiku A, Ushiku T, Araki F. More
Accurate Diagnosis of Vitreoretinal Lymphoma
Using a Combination of Diagnostic Test Results:
A Prospective Observational Study. Ocul
Immunol Inflamm. 2021; 1-7.
Takao-Okuma H, Terao R, Nagahara M, Azuma
K, Inoue T, Uemura Y, Obata R. Distribution ofrecurrence time intervals after anti-vascularendothelial growth factor therapy for myopic
choroidal neovascularization. Can J Ophthalmol.
2021 Apr; 56(2): 137-138.
Agata C, Kitamoto K, Ueda K, Azuma K, Inoue
T, Obata R. Rapidly Changing Serous
Detachment During BRAF and MEK Inhibitor
Therapy. Cureus. 2021 Dec 17;13(12):e20491.
Kanda S, Fujishiro T, Omoto T, Fujino R, Ishii K,
Aihara M. The effects of antithrombotic therapy
in ab interno trabeculotomy with a spatulashaped microhook. PLoS One. 2022 Jan 13;17(1): e0262548.
Soga H, Asaoka R, Kadonosono K, MaruyamaInoue M, Igarashi N, Kitano M, Kitamoto K,
Azuma K, Obata R, Inoue T. Association of
Near-Infrared and Short-Wavelength Autofluorescence With the Retinal Sensitivity in Eyes
With Resolved Central Serous Chorioretinopathy.
Invest Ophthalmol Vis Sci. 2021 Mar 1;62(3):36.

268

Department ofOtorhinolaryngology and Head& Neck Surgery
Professor
Tatsuya Yamasoba, M.D., Ph.D.

Associate Professor
Kenji Kondo, M.D., Ph.D.

Akinori Kashio, M.D., Ph.D.

Rumi Ueha, M.D., Ph.D.（Swallowing Center）

Lecturer
Shu Kikuta, M.D., Ph.D.

Yu Matsumoto, M.D., Ph.D.

Yuki Saito, M.D., Ph.D.

Chisato Fujimoto, M.D., Ph.D.

Research Associate
Osamu Fukuoka, M.D.

Hironobu Nishijima, M.D., Ph.D.

Makoto Kinoshita, M.D., Ph.D.

Akihito Yamauchi , M.D., Ph.D.

Takao Goto, M.D.

Kenya Kobayashi, M.D., Ph.D.

Taku Sato, M.D.

Shinji Urata, M.D., Ph. D.

Shintaro Yoshihara, M.D., Ph.D.

Teru Kamogashira, M.D., Ph.D.

Tsukasa Uranaka, M.D.

Hajime Koyama, M.D.

Homepage

http://utokyo-ent.org/

Introduction and Organization
The Department of Otorhinolaryngology was
founded in 1899 by Prof. Waichiro Okada who studiedin Germany. This is the first department ofotorhinolaryngology of the national university inJapan. Our department covers all otorhinolaryngological diseases and associated systemic
diseases, and has specialized clinics in middle ear andinner ear diseases, hearing impaired infant andchildren, adult and elderly patients, facial paresis,
vertigo and balance disorders, olfactory disorders andparanasal diseases, voice and speech disorders, taste
and swallowing respiratory disorders, aphasia, central

auditory disorders and head & neck cancers.
A professor, associate professors, lecturers(assistant professors) and associates participate insurgery, out-patient and in-patient care as well as
research and educational activities. Moreover 8
Japanese graduate students and two Chinese foreign
graduate students participate in basic research.
Weekly preoperative and postoperative conferences
are held to discuss surgical cases in detail. Special
lectures on leading research activities are presented byinvited guests on a regular basis. A weekly journal
club is held to introduce current research papers.

269

Clinical activities
In the out-patient clinic, general and special
services are provided to approximately 150 outpatients on a daily basis in all areas ofotorhinolaryngology and related specialties, andapproximately 300 new patients visit monthly.
In the new inpatient hospital, 33 beds are preparedfor patients under the supervision of lecturers andsenior residents from each subspecialty group
including head & neck surgery, middle ear surgery andcochlear implant surgery; voice and swallowing
surgery, and paranasal surgery and other minor surgery.
Preoperative and postoperative problems are checkedand discussed by each group, the professor’s andassociate professor’s rounds. Approximately 700
operations are performed annually.
Cochlear implant surgery over 400 cases has been
actively performed for infants, children and adultpatients with profound hearing loss and is very
successful to provide new hearing. Head and necksurgery is performed to extirpate malignant tumor
with neighboring tissues and reconstruct upper
respiratory and swallowing functions at one stage
operation cooperating with plastic surgeons.
Reconstructive surgery of microtia and atresia toreconstruct external ear is routinely performed withplastic surgeons.
Auditory brainstem response is routinely examinedin order to diagnose peripheral and central deafness inneonates, infants and children.
Treatment of acoustic tumor using an ɤ-knife andauditory brainstem implant are performed inconsultation with neurosurgeons.

Teaching activities
For the fourth year medical students’ serial lecturesand for the fifth and sixth year medical students
special lectures on current topics are provided by theprofessor and associate professor.
Clinical training is provided for the sixth year classof medical students on a one-to-one basis with staff
doctors. They are requested to write reports on aclinical case or a clinical problem. The students
participate to see surgery, special clinics and clinicalexaminations such as otoscope, fiberscope, pure-toneaudiometry, auditory brainstem response, and caloric

test. Interview with patient is encouraged. They arequestioned on many aspects of clinical problems inseminars by professor and associate professor.

Research activities
Clinical and basic research activities are highly
encouraged. Clinical research, which is supervised bysenior doctors, is very actively pursued even by young
residents. Case reports presentation and writing skills
are regarded as important experience in order todevelop young doctors’ research activity andinvestigate important findings in patients. The clinicalresearch is related to ear surgery, neurotology, audiology, head and neck surgery, laryngology,
broncho-esophagology and rhinology and is related tocase research, clinical statistics and clinical electrophysiology. Basic research is also encouraged to solve
essence of clinical problems and to elucidate basic
phenomena or anatomical and cellular structures. Our
research topics cover:1) Morphology and neurophysiology of the inner ear
focusing on sensory neural deafness2) Speech perception and language development indeaf children3) Liquid biopsy of perilymph via round window
membrane
4) Prediction of hearing outcome in tympanoplasty
using machine learning5) Analysis of balance disorders using vestibularfunction tests6) Development of novel examination methods forbalance disorders
7) Development of novel therapeutic methods forbalance disorders by galvanic vestibular
stimulation
8) Predicting and elucidating the pathogenesis ofvestibular disorders using machine learning9) Elucidation of the pathogenesis of vestibular
migraine
10) Development of novel therapeutic methods for
persistent postural-perceptual dizziness
11) Elucidation of the mechanism of postural controlinpatients
withvestibulopathy
usingmathematical models
12) Hair cell physiology and pathology and270

introduction of hair cell regeneration in theauditory and vestibular end organ
13) Clinical neurophysiology of the facial nerves
focusing on degeneration and regeneration inpatients
14) Analyses of development, regeneration and aging
in olfactory neural system
15) Pathophysiology of olfactory dysfunction16) Computer fluid dynamics of intranasal airflow17) Metabolic conversion of odorant molecules bynasal mucus18) Analysis of eosinophilic chronic sinusitis using
human samples and animal models
19) Pulmonary inflammatory responses by contrast
agent aspiration
20) Swallowing mechanisms using pathological andelectrophysiological analysis and VR system21) Evaluation of swallowing physiology withpharyngo-esophageal high-resolution manometry22) Esophageal Motility in Neuromuscular Disorders23) Gene expression analysis of recurrent respiratory
papillomatosis24) Kinetics of vocal cord movement using
high-speed video system
25) Histochemical, molecular biological, and genome
analysis of head and neck cancer
Various clinical and basic research is conducted bystaffs, residents, and graduate students as well as
doctors at affiliated hospitals.

References
1.

2.

3.

Asakura S, Kamogashira T. Sudden bilateral
hearing loss after vestibular-evoked myogenic
potentials. Clin Case Rep. 9(11):e05025. 2021
Baba S, Kondo K, Yoshitomi A, Kanemaru A,
Nakaya M, Yamasoba T. Efficacy of Mirror
Biofeedback Rehabilitation on Synkinesis in
Acute Stage Facial Palsy in Children. Otol
Neurotol. 42(7):e936-e41. 2021
Eguchi K, Kobayashi K, Takano T, Ito A, Sakai A,
Ikeda A, Matsumoto Y, Omura G, Matsumoto F,
Yoshimoto S. Carotid artery ligation via
sternotomy as a palliative surgery: Case report ofadvanced intramediastinal malignant soft tissue
tumor. Clin Case Rep. 9(8). 2021

4.

Fujimoto C, Kawahara T, Kinoshita M, Ichijo K,
Oka M, Kamogashira T, Sugasawa K, Yamasoba
T, Iwasaki S. Minimally important differences for
subjective improvement in postural stability inpatients with bilateral vestibulopathy. Neurosci
Lett. 747. 135706, 2021
5. Fujimoto C, Kinoshita M, Ichijo K, Oka M,
Kamogashira T, Sugasawa K, Kawahara T,
Yamasoba T, Iwasaki S. Cervical Vestibular
Evoked Myogenic Potentials That Are Absent at
500 Hz But Present at 1000 Hz Are Characteristicof Endolymphatic Hydrops-Related Disease. Ear
Hearing. 42(5):1306-12. 2021
6. Fujisawa K, Miyamoto S, Saito Y, Fukuoka O,
Okazaki M. Total Maxillectomy and Free Flap
Reconstruction in Hemodialysis Patients: Reportof Two Cases. Prs-Glob Open. 9(11). 2021
7. Fukusumi T, Guo TW, Ren SL, Haft S, Liu C,
Sakai A, Ando M, Saito Y, Sadat S, Califano JA.
Reciprocal activation of HEY1 and NOTCH4
under SOX2 control promotes EMT in head andneck squamous cell carcinoma. Int J Oncol.
58(2): 226-37. 2021
8. Igarashi K, Cabral H, Hong TH, Anraku Y,
Mpekris F, Stylianopoulos T, Khan T, Matsumoto
A, Kataoka K, Matsumoto Y, Yamasoba T.
Vascular Bursts Act as a Versatile Tumor Vessel
Permeation Route for Blood-Borne Particles andCells. Small. 17(42). 2021
9. Ijichi C, Wakabayashi H, Sugiyama S, Hayashi K,
Ihara Y, Nishijima H, Touhara K, Kondo K.
Odorant metabolism of the olfactory cleft mucus
in idiopathic olfactory impairment patients andhealthy volunteers. Int Forum Allergy Rhinol.
10.1002/alr.22897, 2021
10. Imoto Y, Sakashita M, Hayama M, Nakamaru Y,
Suzuki M, Miyabe Y, Yamada T, Saito H,
Yonekura S, Kondo K, Higaki T, Kawashima K,
Urashima M, Fujieda S. The clinical features of
intractable allergic rhinitis based on a questionnaire administered to clinicians. Allergology
international: official journal of the JapaneseSociety of Allergology. 70(3):373-5. 2021
11. Inoue Y, Matsumoto Y, Toh K, Miyano K, Cabral
H, Igarashi K, Iwasaki S, Kataoka K, Yamasoba T.
Manipulating dynamic tumor vessel permeability

271

12.

13.

14.

15.

16.

17.

18.

to enhance polymeric micelle accumulation. J
Control Release. 329:63-75. 2021
Iritani O, Okuno T, Miwa T, Makizako H,
Okutani F, Kashibayashi T, Suzuki K, Hara H,
Mori E, Omoto S, Suzuki H, Shibata M, Adachi
H, Kondo K, Umeda-Kameyama Y, Kodera K,
Morimoto
S.
Olfactory-cognitive
index
distinguishes involvement of frontal lobe
shrinkage, as in sarcopenia from shrinkage of
medial temporal areas, and global brain, as in
Kihon Checklist frailty/ dependence, in older
adults with progression of normal cognition to
Alzheimer's disease. Geriatr Gerontol Int.
21(3):291-8. 2021
Ito A, Kobayashi K, Shiotsuka M, Sato T, Omura
G, Matsumoto Y, Ikeda A, Sakai A, Eguchi K,
Takano T, Matsumoto F, Kobayashi O, Iwata S,
Yoshimoto S. Uniform infection screening
allowed safe head and neck surgery during thecoronavirus disease 2019 pandemic in Japan. Jpn
J Clin Oncol. 51(3):400-7. 2021
Ito Y, Nishijima H, Kishimoto S. A Case of Huge
Cutaneous Verrucous Carcinoma of the Neck.
Cureus. 13(5). 2021
Iwaki H, Kamiya M, Kawatani M, Kojima R,
Yamasoba T, Urano Y. Fluorescence Probes for
Imaging Basic Carboxypeptidase Activity in
Living Cells with High Intracellular Retention.
Anal Chem. 93(7):3470-6. 2021
Kagoya R, Kondo K, Kishimoto-Urata M,
Shimizu Y, Kikuta S, Yamasoba T. A murine
model of eosinophilic chronic rhinosinusitis
using the topical application of a vitamin D3
analog. Allergy. 76(5):1432-42. 2021
Kashihara T, Nakamura S, Murakami N, Ito K,
Matsumoto Y, Kobayashi K, Omura G, Mori T,
Honma Y, Kubo Y, Okamoto H, Takahashi K,
Inaba K, Okuma K, Igaki H, Nakayama Y, Kato
K, Matsumoto F, Yoshimoto S, Itami J. Initial
Experience of Intentional Internal High-Dose
Policy Volumetric Modulated Arc Therapy of
Neck Lymph Node Metastases >= 2 cm inPatients With Head and Neck Squamous Cell
Carcinoma. Front Oncol. 11. 2021
Kashio A, Takahashi H, Nishizaki K, Hara A,
Yamasoba T, Moriyama H. Cochlear implants inJapan: Results of cochlear implant reporting

19.

20.

21.

22.

23.

24.

25.

26.

27.

system over more than 30 years. Auris Nasus
Larynx. 48(4):622-9. 2021
Katano A, Takenaka R, Yamashita H, Ando M,
Yoshida M, Saito Y, Asakage T, Abe O,
Nakagawa K. A retrospective analysis ofradiotherapy in the treatment of external auditory
canal carcinoma. Mol Clin Oncol. 14(3). 2021
Kataoka T, Yoshida S, Ueha R. Clicking
Sensation on Swallowing. Jama Otolaryngol.
147(8):762-3. 2021
Kikuta S, Kuboki A, Yamasoba T. Protective
Effect of Insulin in Mouse Nasal Mucus Against
Olfactory Epithelium Injury. Front Neural
Circuits. 15:803769. 2021
Kobayashi K, Yoshimoto S, Ando M, Matsumoto
F, Murakami N, Omura G, Honma Y, Matsumoto
Y, Ikeda A, Sakai A, Eguchi K, Ito A, Ryo E,
Yatabe Y, Mori T. Full-coverage TP53 deep
sequencing of recurrent head and neck squamouscell carcinoma facilitates prognostic assessment
after recurrence. Oral Oncol. 113. 2021
Kobayashi K, Miyatkita Y, Matsumoto F, Omura
G, Matsumura S, Ikeda A, Eguchi K, Ito A,
Narita Y, Akazawa S, Yoshimoto S. Olfactory
Preservation in Craniofacial Resection of Tumor
Invading Hemianterior Skull Base: Operative
Video. J Neurol Surg B Skull Base. doi:
10.1055/s-0041-1727123. 2021
Kobayashi T, Iwamoto S, Shiraishi K, Mori A,
Koyama H, Fujita T, Osaki Y, Doi K. Evaluationof Vestibular Disorder Risk Associated with
Middle Ear Surgery Clinics in Surgery. 1:3063.
2021
Koizumi M, Ishimaru M, Matsui H, Fushimi K,
Yamasoba T, Yasunaga H. Factors associatedwith the occurrence of stomal stenosis aftertracheostomy in adults. Auris Nasus Larynx.
48(5):973-7. 2021
Koyama H, Kashio A, Fujimoto C, Uranaka T,
Matsumoto Y, Kamogashira T, Kinoshita M,
Iwasaki S, Yamasoba T. Alteration of VestibularFunction in Pediatric Cochlear Implant
Recipients. Front Neurol. 12:661302. 2021
Koyama H, Mori A, Nagatomi D, Fujita T, Saito
K, Osaki Y, Yamasoba T, Doi K. Machine
Learning Technique Reveals Prognostic Factorsof Vibrant Soundbridge for Conductive or Mixed

272

28.

29.

30.

31.

32.

33.

34.

35.

Hearing Loss Patients. Otol Neurotol. 42(9):e1286-e92. 2021
Koyama S, Kondo K, Ueha R, Kashiwadani H,
Heinbockel T. Possible Use of Phytochemicals
for Recovery from COVID-19-Induced Anosmia
and Ageusia. International journal of molecularsciences. 22(16). 2021
Koyama S, Ueha R, Kondo K. Loss of Smell andTaste in Patients With Suspected COVID-19:
Analyses of Patients' Reports on Social Media. J
Med Internet Res. 23(4). 2021
Kuboki A, Kikuta S, Otori N, Kojima H,
Matsumoto I, Reisert J, Yamasoba T.
Insulin-Dependent
Maturation
of
Newly
Generated Olfactory Sensory Neurons after
Injury. eNeuro. 8(3):0618-21. 2021
Lin N, Urata S, Cook R, Makishima T. Sex
differences in the auditory functions of rodents.
Hearing research.108271. 2021
Masuda H, Ueha R, Sato T, Goto T, Koyama M,
Yamauchi A, Kaneoka A, Suzuki S, Yamasoba T.
Risk Factors for Aspiration Pneumonia After
Receiving Liquid-Thickening Recommendations.
Otolaryngology--head and neck surgery : official
journalof
AmericanAcademyof
Otolaryngology-Head and Neck Surgery. doi:
10.1177/ 01945998211049114. 2021
Matsumoto F, Miyakita Y, Sakai A, Akamatsu M,
Matsumoto Y, Matsumura S, Omura G,
Kobayashi K, Narita Y, Yoshimoto S. Resectionof carcinoma of the external auditory canal in apatient with a high jugular bulb using temporalcraniotomy. Auris Nasus Larynx. 48(3):535-8.
2021
Meng X, Matsumoto F, Mori T, Miura N, Ino Y,
Onidani K, Kobayashi K, Matsuzaki Y,
Yoshimoto S, Ikeda K, Honda K. BP180 Is a
Prognostic Factor in Head and Neck Squamous
Cell Carcinoma. Anticancer Res. 41(2):1089-99.
2021
Mori A, Takeda H, Kobayashi M, Misawa T,
Watanabe R, Abe S, Kumakawa K, Nishio S,
Usami S, Yamasoba T. Successful cochlear
implantation in a patient with Epstein syndromeduring long-term follow-up. Auris Nasus Larynx
doi: 10.1016/j.anl.2020.09.008. 2020

36. Mori E, Ueha R, Kondo K, Funada S, Shimmura
H, Kanemoto K, Tanaka H, Nishijima H, Otori N,
Yamasoba T, Kojima H. Squamous andRespiratory Metaplasia After Olfactory Mucosal
Resection. Front Neurosci. 15:695653. 2021
37. Namba S, Ueno T, Kojima S, Kobayashi K,
Kawase K, Tanaka Y, Inoue S, Kishigami F,
Kawashima S, Maeda N, Ogawa T, Hazama S,
Togashi Y, Ando M, Shiraishi Y, Mano H,
Kawazu M. Transcript-targeted analysis reveals
isoform alterations and double-hop fusions inbreast cancer. Commun Biol. 4(1):1320. 2021
38. Nativ-Zeltzer N, Ueha R, Nachalon Y, Ma B,
Pastenkos G, Swackhamer C, Bornhorst GM,
Lefton-Greif MA, Anderson JD, Belafsky PC.
Inflammatory Effects of Thickened Water on theLungs in a Murine Model of Recurrent Aspiration.
Laryngoscope. 131(6):1223-8. 2021
39. Ogawa K, Asano K, Yotsumoto S, Yamane T,
Arita M, Hayashi Y, Harada H, Makino-Okamura
C, Fukuyama H, Kondo K, Yamasoba T, Tanaka
M. Frontline Science: Conversion of neutrophils
into atypical Ly6G(+)SiglecF(+)immune cellswith neurosupportive potential in olfactory
neuroepithelium.
J
LeukocyteBiol.
109(3):481-96. 2021
40. Okano M, Kondo K, Takeuchi M, Taguchi Y,
Fujita H. Health-related quality of life and drug
treatment satisfaction were low and correlated
negatively with symptoms in patients having
severe refractory chronic rhinosinusitis withnasal
polyps.
Allergology
International.
70(3):370-2. 2021
41. Okano S, Homma A, Kiyota N, Tahara M, Hanai
N, Asakage T, Matsuura K, Ogawa T, Saito Y,
Sano D, Kodaira T, Motegi A, Yasuda K,
Takahashi S, Tanaka K, Onoe T, Yokota T,
Imamura Y, Ariizumi Y, Akimoto T, Hayashi R.
Induction chemotherapy in locally advanced
squamous cell carcinoma of the head and neck.
Jpn J Clin Oncol. 51(2):173-9. 2021
42. Omura K, Han B, Nishijima H, Aoki S, Ebihara T,
Kondo K, Otori N, Kojima H, Yamasoba T,
Kikuta S. Heterogeneous distribution of matureolfactory sensory neurons in human olfactory
epithelium. Int Forum Allergy Rhinol. 10.1002/
alr.22885, 2021

273

43. Sano N, Kikuta S, Kondo K, Yamasoba T. HighCT values relative to the brainstem differentiate
inverted papillomas from nasal polyps. Auris
Nasus Larynx. 48(5):905-13. 2021
44. Sato D, Hasegawa H, Shin M, Kondo K, Saito N.
Combined endoscopic endonasal transtubercularand transclival approaches for large neurentericcyst in posterior cranial fossa: A case report andliterature review. Surg Neurol Int. 12:554. 2021
45. Sato T, Ueha R, Goto T, Yamauchi A, Kondo K,
Yamasoba T. Expression of ACE2 and TMPRSS2
Proteins in the Upper and Lower Aerodigestive
Tracts of Rats: Implications on COVID 19
Infections. Laryngoscope. 131(3):E932-E9. 2021
46. Sekiguchi Koyama M, Ueha R, Goto T, Sato T,
Tachibana A, Mizumoto Y, Nito T, Yamasoba T.
Aspiration Prevention Surgery under Local
Anesthesia for Palliative Care in Patients with
Head and Neck Cancer: A Report of Two Cases.
ORL J Otorhinolaryngol Relat Spec. 83(1):52-8.
2021
47. Shibasaki H, Kinoh H, Cabral H, Quader S,
Mochida Y, Liu X, Toh K, Miyano K, Matsumoto
Y, Yamasoba T, Kataoka K. Efficacy of
pH-Sensitive Nanomedicines in Tumors withDifferent c-MYC Expression Depends on the
Intratumoral Activation Profile. ACS nano. 15(3):5545-59. 2021
48. Shinya Y, Hasegawa H, Shin M, Sugiyama T,
Kawashima M, Katano A, Kashio A, Kondo K,
Saito N. Long-Term Outcomes of Stereotactic
Radiosurgery for Trigeminal, Facial, and Jugular
Foramen Schwannoma in Comparison with
Vestibular Schwannoma. Cancers. 13(5). 2021
49. Sugaya T, Ueha R, Sato T, Goto T, Yamauchi A,
Yamasoba T. Safety of surgical tracheostomy
undercontinued
antithrombotic
therapy:
A retrospective
cohortstudy.
Clinicalotolaryngology. doi: 10.1111/coa.13861.2021
50. Suzuki T, Maruyama J, Cook R, Urata S, Paessler
S, Makishima T. Auditory function analysis in
immunodeficient STAT1 knock-out mice:
Considerations for viral infection models.
Neurosci Lett. 740:135427. 2021
51. Takabayashi T, Asaka D, Okamoto Y, Himi T,
Haruna S, Yoshida N, Kondo K, Yoshikawa M,
Sakuma Y, Shibata K, Suzuki M, Kobayashi M,

52.

53.

54.

55.

56.

57.

58.

Kawata R, Tsuzuki K, Okano M, Higaki T,
Takeno S, Kodama S, Yonekura S, Saito H,
Nozaki A, Otori N, Fujieda S. A Phase II,
Multicenter, Randomized, Placebo-Controlled
Study of Benralizumab, a Humanized Anti-IL-5R
Alpha Monoclonal Antibody, in Patients With
Eosinophilic Chronic Rhinosinusitis. Am J
Rhinol Allergy. 35(6):861-70. 2021
Takamizawa S, Honma Y, Murakami N, Mori T,
Oka H, Yamamoto S, Kashihara T, Ito K, Kubo Y,
Ikeda A, Matsumoto F, Omura G, Kobayashi K,
Itami J, Kato K, Yoshimoto S. Short-term
outcomes of induction chemotherapy withdocetaxel, cisplatin, and fluorouracil (TPF) in
locally advanced nasopharyngeal carcinoma.
Invest New Drugs. 39(2):564-70. 2021
Ueha R, Kondo K, Kagoya R, Shichino S,
Shichino S, Yamasoba T. ACE2, TMPRSS2, andFurin expression in the nose and olfactory bulb inmice and humans. Rhinology. 59(1):105-9. 2021
Ueha R, Sato T, Goto T, Koyama M, Yamauchi A,
Mizukami A, Yamasoba T. Effects of Aspiration
Prevention Surgery on the Dynamics of the
Pharynx and Upper Esophageal Sphincter. OTO
Open. 5(4):2473974X211048505. 2021
Ueha R, Sato T, Goto T, Yamauchi A,
Nativ-Zeltzer N, Mitsui J, Belafsky PC,
Yamasoba T. Esophageal Dysmotility is Common
in Patients With Multiple System Atrophy.
Laryngoscope. 131(4):832-8. 2021
Uranaka T, Kashio A, Ueha R, Sato T, Bing H,
Ying G, Kinoshita M, Kondo K, Yamasoba T.
Expression of ACE2, TMPRSS2, and Furin in
Mouse Ear Tissue, and the Implications for
SARS-CoV-2
Infection.
Laryngoscope.
131(6):E2013-E7. 2021
Uranaka T, Matsumoto Y, Hoshi Y, Iwasaki S,
Kakigi A, Yamasoba T. Classification of theChorda Tympani: An Endoscopic Study. Otol
Neurotol. 42(3):e355-e62. 2021
Urata S, Maruyama J, Kishimoto-Urata M,
Sattler RA, Cook R, Lin N, Yamasoba T,
Makishima T, Paessler S. Regeneration Profilesof Olfactory Epithelium after SARS-CoV-2
Infection in Golden Syrian Hamsters. ACS Chem
Neurosci. 12(4):589-95. 2021

274

59. Yamauchi A, Imagawa H, Yokonishi H,
Sakakibara KI, Tayama N. Multivariate Analysis
of Vocal Fold Vibrations on Various Voice
Disorders Using High-Speed Digital Imaging.
Appl Sci 11, 2021. https://doi.org/10.3390/
app11146284
60. Yamauchi A, Imagawa H, Yokonishi H,
Sakakibara KI, Tayama N. Multivariate analysis
of vocal fold vibration in normal speakers using
high-speed digital imaging. J Voice. doi:
10.1016/j. jvoice.2021.08.002. 2021
61. Yamakawa K, Kondo K, Unaki A, Saigusa H,
Horikiri K, Yamasoba T. Gustatory rhinitis in
multiple system atrophy. Acta Oto-Laryngol Ca.
6(1):67-70. 2021
62. Yamagishi J, Kagoya R, Saito M, Fujimoto C,
Kikuchi H, Ito K. Acute pharyngitis with theabrupt manifestation of neurological disorders,leading to a diagnosis of Neuro-Behcet's disease.
Acta Otolaryngol Case Rep 6:71-74. 2021
63. Yazaki S, Yoshida T, Kojima Y, Yagishita S,
Nakahama H, Okinaka K, Matsushita H,
Shiotsuka M, Kobayashi O, Iwata S, Narita Y,
Ohba A, Takahashi M, Iwasa S, Kobayashi K,
Ohe Y, Yoshida T, Hamada A, Doi T, Yamamoto
N. Difference in SARS-CoV-2 Antibody Status
Between Patients With Cancer and Health Care
Workers During the COVID-19 Pandemic in
Japan. Jama Oncol. 7(8):1141-8. 2021

275

Department of
Rehabilitation Medicine
Professor
Toru Ogata, M.D.

Homepage

http://todaireh.umin.ne.jp

Introduction and Organization
The Department of Rehabilitation Medicine wasestablished by Ministry of Education, Culture, Sports,
Science and Technology in April 2001. It is one of thenewest fields in Graduate School of Medicine, theUniversity of Tokyo. It belongs to the Sensory andMotor System Science Course of the Surgical Science
Division. Current authorized staff is only one
professor.
This department derives from the establishment of
the physical therapy room in the central diagnostic
and therapeutic sections in order to develop theclinical practice of rehabilitation medicine in 1963.
The chair of professor was set up as a full-time director of the central rehabilitation service in 1984, but theformal title remained a physical therapy department.
Rehabilitation medicine is a newly establishedclinical section which was born in development of themodern principle of the medical health service bywhich it came to value the enhancement of not only
adding years of patient's life but also adding life to theyears. Regardless of the rapid expansion of needs,
acknowledgment of rehabilitation medicine wasdelayed in the frame of the old-fashioned clinicaldepartments. In our country, it was 1996 when the
rehabilitation specialty was authorized as formal
clinical practice by the former Ministry of Health andWelfare.
On the other hand, it was positioned as an
assistance instructor in the sensory and motor system
medicine department with shifting to the graduate
school course systems since 1995 to 97 in the
University of Tokyo. Finally, the rehabilitation

medicine field was installed in the sensory and motor
system medicine department by a budget step of 2001.
We have accepted the graduate school student
formally since fiscal year 2001. However, thearrangement of additional teaching staff is not stillmaterialized. Therefore, the staff of the graduate
school is only one professor. Twenty students haveentered the graduate school by 2020, and fifteen ofthem were granted Ph.D.

Clinical activities
The professor serves as a director of Rehabilitation
Center, the University of Tokyo Hospital. The
Rehabilitation Center and the Department of
Rehabilitation Medicine are united and engage inclinical practice. We have at present no charged ward,
and treat about 4,700 new referrals annually fromalmost all the departments of the university hospital.
We always take charge of 250-300 patients
corresponding about 25-30% of the whole number of
inpatients. We also see 15 people per day at theoutpatient rehabilitation setting. The numerical ratioof outpatient is being reduced in order to give priority
to the clinical service corresponding to needs
expansion of service to inpatients.

Teaching activities
We have provided several clinical curriculums on
rehabilitation medicine for 4th, 5th, and 6th year
medical students since 1973. The systematic lecture
series for 4th year medical students (M2) include thesubjects on rehabilitation for disorders such as276

cerebrovascular disturbances, respiratory disorders,
neuromuscular diseases, bone and joint diseases, andpediatric disorders as well as on outline ofrehabilitation, and amputation/prostheses. We haveprovided a clinical practice in small group, so-calledclinical clerkship for 5th and 6th year students from
Wednesday to Friday every week. They experience a
few patients and learn how to take a patients’ history,
physical findings, functional evaluation, and how toplan rehabilitation programs. We have introduced a
few of elective students for elective clinical clerkshipto our collaborating hospitals with specialized
rehabilitation ward.
In addition, we have provided the training ofstudents including physical therapy, occupational
therapy, and speech therapy. Twenty students or morecome and stay at the university hospital annually as along-term clerkship from several PT/OT/ST training
schools.

Research activities
Our research activities are growing up. In 2006, theRehabilitation Center moved to the new building and a
research laboratory was provided for the first time. As
the motion analysis system was partially renewed, weare planning our researches mainly in the field ofmusculoskeletal disabilities. In addition, we areplanning collaborating researches with otherdepartments in our hospital, other faculties in our
university, and institutions outside the University ofTokyo. The ongoing projects are as follows.
1) 3D Motion analysis of patients with musculoskeletal disorders
2) Prognostic evaluation of patients with metastaticbone tumors
3) Rehabilitation and long-term outcome in patientswith skeletal dysplasias
4) Pathology and treatment for patients withcongenital limb deficiencies
5) Analysis of rehabilitation outcome using DPC
data

2.

3.

4.

5.

6.

7.

8.

References
1.

Goto M, Haga N, Takedani H: Physical activity
and its related factors in Japanese people withhaemophilia. Haemophilia 25: e267-e273, 20199.

Mano H, Fujiwara S, Haga N: Body knowledge inchildren with congenital lower limb deficiency.
Pediatr Int 61(2): 158-165, 2019
Matsushita M, Kitoh H, Mishima K, Yamashita S,
Haga N, Fujiwara S, Ozono K, Kubota T, Kitaoka
T, Ishiguro N: Physical, mental and social
problems of adolescent and adult patients withachondroplasia. Calc Tissue Int 104(4): 364-372,
2019
Nakahara Y, Kitoh H, Nakashima Y, Toguchida J,
Haga N: The longitudinal study of activities ofdaily living and quality of life in Japanese patientswith fibrodysplasia ossificans progressiva. Disabil
Rehabil 41(6): 699-704, 2019
Taya M, Amiya E*, Hatano M, Maki H, Hosoya Y,
Ishida J, Bujo C, Tsuji M, Konishi Y, Yokota K,
Haga N, Komuro I: Inspiratory muscle training foradvanced heart failure with lamin-related muscular
dystrophy. J Cardiol Cases 2019, jccase 20(6):232-234, 2019.9
Yamoto K, Saitsu H, Nishimura G, Kosaki R,
Takayama S, Haga N, Tonoki H, Okumura A,
Horii E, Okamoto N, Suzumura H, Ikegawa S,
Kato F, Fujisawa Y, Nagata E, Takada S, Fukami
M, Ogata T: Comprehensive clinical andmolecular studies in split hand/foot malformation:
identification of two plausible candidate genes(LRP6 and UBA2). Eur J Hum Genet 27: 18451857, 2019
Yoshida M, Matsunaga A, Igawa Y, Fujimura T,
Shinoda Y, Aizawa N, Sato Y, Kamei J, Kume H,
Homma Y, Haga N, Sanada H*: May preoperative
ultrasound-guided pelvic floor muscle training
promote early recovery of urinary continence after
robot-assisted radical prostatectomy? Neurourol
Urodyn 38(1): 158-164, 2019
Ogura K, Uehara K, Akiyama T, Shinoda Y, Iwata
S, Tsukushi S, Kobayashi E, Hirose T, Yonemoto T,
Endo M, Tanzawa Y, Nakatani F, Kawano H,
Tanaka S, Kawai A: Development of a patientoriented disease specific outcome measure ofhealth-related quality of life (HRQOL) formusculoskeletal oncology patients. J Orthop Sci
24(3): 539-547, 2019
Fujimura T, Igawa Y, Aizawa N, Niimi A, Yamada
Y, Sugihara T, Kamei J, Sato Y, Matsunaga A,
Yoshida M, Shinoda Y, Fukuhara H, Nakagawa T,

277

10.

11.

12.

13.

14.

Homma Y, Kume H: Longitudinal change ofcomprehensive lower urinary tract symptoms andvarious types of urinary incontinence during
robot-assisted radical prostatectomy. Neurourol
Urodyn 38(4): 1067-1075, 2019
Shinoda Y, Sawada R, Yoshikawa F, Oki T, Hirai T,
Kobayashi H, Matsudaira K, Oka H, Tanaka S,
Kawano H, Haga N: Factors related to the qualityof life in patients with bone metastases. Clin Exp
Metastasis 36(5): 441-448, 2019
Shinoda Y, Kobayashi H, Kaneko M, Ohashi S,
Bessho M, Hayashi N, Oka H, Imanishi J, Sawada
R, Ogura K, Tanaka S, Haga N, Kawano H:
Prediction of the pathological fracture risk during
stance and fall-loading configurations formetastases in the proximal femur, using acomputed tomography-based finite element
method. J Orthop Sci 24(6): 1074-1080, 2019
Morita K, Miura K, Fujimoto M, Yamamori H,
Yasuda Y, Kudo N, Azechi H, Okada N,
Koshiyama D, Shiino T, Fukunaga M, Watanabe Y,
Ikeda M, Kasai K, Hashimoto R: Eye‐movement
characteristics of schizophrenia and theirassociation with cortical thickness. Psychiatry Clin.
Neurosci. 73: 508–9, 2019
Morita K, Miura K, Kasai K, Hashimoto R: Eyemovement characteristics in schizophrenia: A
recent update with clinical implications. Neuropsychopharmacol Rep. Epub ahead of print, 2019
Morita K, Miura K, Fujimoto M, Yamamori H,
Yasuda Y, Kudo N, Azechi H, Okada N,
Koshiyama D, Ikeda M, Kasai K, Hashimoto R:
Eye movement abnormalities and their association
with cognitive impairments in schizophrenia.
Schizophr. Res. 209: 255–62, 2019

Surgical Sciences
3. Vital Care Medicine

279

Department of Anesthesiology
Professor
Kanji Uchida, M.D., Ph.D.

Associate Professor
Masahiko Sumitani, M.D., Ph.D.

Project Associate Professor
Maiko Hasegawa, M.D., Ph.D.

Lecturer
Nobuko Ito, M.D., Ph.D.,

Masahiko Bougaki, M.D., Ph.D.,

Gaku Kawamura, M.D., Ph.D.,

Taro Kariya, M.D., Ph.D.,

Yoshiteru Mori, M.D.,
Masaaki Asamoto, M.D, PhD.

Associate
Yosuke Imai, M.D., Ph.D.,
Ayako Hirai, M.D.,

Ken Kuwajima, M.D., Ph.D.,

Michiko Ushio, M.D.,

Kazuhito Mietani, M.D., Ph.D.,

Yoko Hoshino, M.D.,

Yuko Araki, M.D.,

Takuma Hiraiwa, M.D.,

Reo Inoue, M.D., Ph.D.,

Emi Morinushi, M.D.,

Inhee Jeong, M.D.,

Miyako Nagaya, M.D.,

Kanae Tsutsumi, M.D.,

Yoshika Sudo, M.D.,

Ryosuke Doi, M.D.,

Yuho Tamai, M.D.,

Atsuko Kato, M.D.,
Masaki Iwakiri, M.D.,

Hayato Narita, M.D.,

Yuji Ueda, M.D.,

Tomoaki Nakamura, M.D.,

Kento Omi, M.D.,

Junko Tsukamoto, M.D.,

Rikuhei Tsuchida, M.D.

Homepage https://www.ut-anes.org/
Introduction and Organization
The Department of Anesthesiology was establishedin 1952 and is the oldest department of anesthesiology
in Japan. As of March 1, 2022, the Department ofAnesthesiology consists of Professor Kanji Uchida;
Associate Professor Masahiko Sumitani; Project
Associate Professor Maiko Hasegawa; Lecturers
Nobuko Ito, Masahiko Bougaki, Yoshiteru Mori, Gaku
Kawamura, Taro Kariya, Masaaki Asamoto; 24
Associates, 14 anesthesiology residents, and 6
graduate students. The outpatient clinic is located on
the 2nd floor of Outpatient Clinic Building and the 3rd
floor of Central Clinical Service Building 2, theinpatient units are located on the 9th floor south of

Inpatient Building A, and the offices and laboratories
are located on Clinical Research Building East,
Central Building South, and the 4th floor of ClinicalResearch Building A. The current activities of ourdepartment in clinic, education, and research aredescribed below.

Clinical activities
Department of Anesthesiology is in charge ofanesthesia and perioperative management for patients
undergoing surgery, acute and chronic pain treatment,
and palliative care for cancer patients, of the
University of Tokyo Hospital. The number ofsurgeries at the University of Tokyo Hospital

280

increased as a result of the doubling of the number ofoperating rooms to 23 when the Central Clinical
Service Building 2 became operational in January
2007, and the annual number of surgical cases reached11,323 (8,831 managed by the anesthesiologists) in
FY2019. After a decrease in FY2020 due to
COVID-19 pandemic, the total number of surgeries in
FY2021 (Apr 2021 – Mar 2022) was 11,047, of which
the anesthesiologists managed 8,289 cases. The
number of surgeries for patients with many
complications and elderly patients has been increasing
every year, and in addition, heart, liver, and lungtransplants from brain-dead donors have been
performed.
Because many patients with severe and complicatedconditions, both surgically and medically, are treatedat the University of Tokyo Hospital, we routinely
provide anesthesia for patients with many
preoperative comorbidities, including transplant
recipients with end-stage organ failure. We contributeto a good postoperative recovery by performing a
careful preoperative assessment, optimizing thepatient's condition preoperatively, and performing
appropriate intraoperative anesthetic management. In
the operating rooms, we are also well-prepared torespond quickly to medical or surgical emergencies
that may occur during surgery.
For preoperative patients, we provide outpatient andinpatient preoperative consultation service every
weekday for more detailed preoperative evaluation forcomplicated cases, and took care of 1,736
preoperative patients in FY2021. We have participatedin the Perioperative Management Center Program andare designing and implementing a system for more
efficient and appropriate perioperative patientmanagement. As for postoperative care, we are in
charge of postoperative intensive patient care in the
ICU2 in cooperation with the Department of Acute
Medicine, contributing to safe postoperative management and recovery. The number of postoperative
intensive care patients taken care of by the staff
members of our department was 1,202 (1,110 in
FY2020) in FY2021.
We have also established an obstetric anesthesia
team to improve the safety and comfort of perinatalcare. The obstetric anesthesia outpatient clinic is
opened once or twice a week to evaluate the anesthetic

risk of pregnant women, and the number of visitors in
FY2021 was 307 (308 in FY2020). The number ofneuraxial labor analgesia was 363 (365 in FY2020) in
FY2021.
As an outpatient clinic, the Pain Relief Center (Pain
Clinic) is open every weekday. For patients withvarious pain disorders (including those hospitalized inother departments), we focus on not only the sensory
factors of pain but also the biopsychosocial factors,
and conduct multidisciplinary pain evaluation andtreatment, including neurological, neuropsychiatricand psychiatric evaluations, in cooperation withmultiple departments. The number of outpatients in
FY2021 was 5,112 (6,090 in FY2020), of which 296
were first-time patients (215 in FY2020). The numberof active beds was 1, and the number of inpatients was
15. There were 125 requests for pain consultation for
inpatients in FY2021.
In close collaboration with our department, theDepartment of Pain and Palliative Medicine provides
multidisciplinary palliative care by the palliative careteam, and is also in charge of the outpatient cancer
treatment pain clinic for chronic pain associated withcancer treatment and the second opinion clinic for
cancer pain in the supportive care phase to theadvanced stage, in accordance with the characteristicsof the University of Tokyo Hospital as a cancer
treatment institution.

Education
We give lectures for fourth-year medical students
and provide clinical education (Clinical Clerkship) for
fifth and sixth-year medical students on a
person-to-person basis with our faculty staff members.
The lectures of the FY2021 were: History andmechanisms of anesthesia, Inhalational anesthesia,
Intravenous anesthesia, Regional and local anesthesia,
Preoperative evaluation, Management of the
cardiovascular system in anesthesia, Intraoperative
monitoring, Airway management in anesthesia,
Postoperative management, and Pain clinic.
The major content of the Clinical Clerkship consistsof (1) surgical anesthesia clerkship, (2) pain clinic
clerkship, and (3) short lectures. In the surgicalanesthesia clerkship, students participate inpreoperative examinations, planning of anesthesia

281

management, and onsite anesthesia management tolearn the basic knowledge of examination and testing
techniques as well as physiology and pharmacology
necessary for perioperative management in a clinicalsetting. Pain clinic clerkship aims to deepen
understanding of the causes of various intractablepains and therapeutic methods focusing onpharmacotherapy, nerve block therapy, exercise
therapy, and cognitive-behavioral therapy. The shortlectures cover seven topics: General anesthesiology,
Airway maintenance and intubation, Central venous
access placement, Subarachnoid spinal anesthesia,
Peripheral
nerve
block,
Postoperative
ICU
management, and Pain clinic. Practical training using
a simulator is also provided for tracheal intubation,
central venous puncture, and subarachnoid spinal
anesthesia. As a summary of the Clinical Clerkshipeducation, we ask the students to submit reports onanesthesia cases and reports on anesthetics andcardiovascular drugs, with presentations anddiscussions on the contents. In accordance with thepolicy of the School of Medicine in response to theoutbreak of COVID-19, the Clinical Clerkship for theperiod from January to March 2021 was conducted
online.
For post-graduate education, we accepted a total of
104 junior residents of PGY1 and 2 from the General
Education Center as rotators (1-2 months for eachrotator) in FY2020. The training includes anesthesia
management,
preoperative
andintraoperative
management, and basic skills and knowledge inemergency and resuscitation settings. For the 14
anesthesiology residents of PGY3+, faculty staffs
teach and supervise daily clinical anesthesia,
postoperative ICU care, obstetric anesthesia, and pain
clinic. The anesthesiology residents are encouraged togive presentations at scientific meetings, including theJapanese Society of Anesthesiologists (JSA) annual
meetings, and publish papers. Anesthesiology
residents achieve JSA board certification by the end of
the training. In addition, journal clubs and case studies
are organized to cultivate a professional attitude in
residents and develop their competency to perform
care and research as independent anesthesiologists.

Research
Our department has seven research groups. The
research fields include respiratory, cardiovascular,
pain, nervous, and immune systems.
Our ongoing and recent major research subjects are:
 A role of cytokine signaling in acute lunginjury; Transpulmonary pressure during mechanicalventilation;
 Exploring risk factors of perioperative
exacerbation of interstitial lung disease; Modification of immune system byanesthesia;
 Apoptotic signal transduction induced bysepsis or ischemia-reperfusion injury; A role of lipid mediators in the formation of
hyperalgesia; A role of spinal microglial cells in thedevelopmentof
inflammation-mediatedneuropathic pain; Cognitive-behavioral therapy on chronic pain; Analysis of electroencephalography during
general anesthesia;
 Exploring relationship between postoperativedelirium and blood-brain barrier dysfunction;
 Clinical significance of fatty acid metabolites
in general anesthesia;
 Retrospective analyses on perioperative
management of left ventricular assisting
device implantation or heart transplantation;
 Physiology and molecular biology ofleft/right heart failure of animal models; Invention and validation of new anesthetic
procedures with emerging technologies;
 Epidemiological survey and outcome study
with large administrative database.

Publications
1.

2.

Aoyama H, Uchida K. Respiratory characteristics
andrelatedintraoperative
ventilatory
management for patients with COVID-19
pneumonia. J Anesth. 2021;35:356-360.
Ikeda T, Orii R, Iwakiri M, Uchida K, Yamada Y.
Unexpected deposits in the anesthetic circuit: A
possible cause of PEEP/Pmax valve malfunction.
J Clin Monit Comput. 2021;35:943-948.

282

3.

4.

Inoue R, Abe H, Konishi M, Tsuchida R,
Edamura T, Sumitani M. Capecitabine induced
hand foot syndrome does not emerge in thecomplex regional pain syndrome affected limb: acase report. Mol Clin Oncol. 2021;15.
Kasahara S, Niwa SI, Matsudaira K, Sato N, Oka
H, Fujii T, Konno SI, Kikuchi SI, Yamada Y.
High attention-deficit/hyperactivity disorderscale scores among patients with persistentchronic nonspecific low back pain. Pain
Physician. 2021; 24:e299-e307.

5. Kasahara S, Takahashi N, Matsudaira K, Oka H,
Takatsuki K, Yabuki S. Psychometric properties ofthe multidimensional pain inventory: Japanese
languageversion(MPI-J).

Pain

Physician.

2021;25:E105-E112.
6. Kasahara S, Matsudaira K, Sato N, Niwa S-I. Painand attention-deficit/hyperactivity disorder: Thecase of Margaret Mitchell. Psychosom Med.
2021;83:492-493.
7. Mietani K, Hasegawa-Moriyama M, Inoue R,
Ogata T, Shimojo N, Kurano M, Sumitani M,
Uchida K. Elevated neuron-specific enolase levelis associated with postoperative delirium anddetection of phosphorylated neurofilament heavy
subunit: a prospective observational study. PLoS
ONE. 2021;16:e0259217.
8. Morita Y, Kariya T, El-Bashir J, Galusca D,
Guruswamy J, Tanaka K. TEE image quality
improvement with our devised probe cover.
Echocardiography. 2021;38:1496-1502.
9. Saita K, Sumitani M, Nikaido T, Sekiguchi M,
Inoue R, Abe H, Konno S, Uchida K. Exponential
correlations among neuropathic components, pain
intensity, and catastrophic thoughts in patientswith musculoskeletal pain disorder. Curr Med
Res Opin. 2021;37:1341-1348.
10. Tsuchida R, Tanabe Y, Nishizawa D, Ikeda K,
Abe H, Inoue R, Kurano M, Yatomi Y, Tamura K,
Takano T, Shimizu C, Uchida K, Sumitani M.
Genetic polymorphisms of lysophosphatidic acidreceptor 1 are associated with the onset of
taxane-induced peripheral neuropathy. Br J
Anaesth. 2021;127:e43-e46.
11. Uranbileg B, Ito N, Kurano M, Kano K, UchidaK, Sumitani M, Aoki J, Yatomi Y. Inhibition of

autotaxin activity ameliorates neuropathic pain
derived from lumbar spinal canal stenosis. Sci
Rep. 2021;11,3984.
12. Yoshimoto T, Fujii T, Oka H, Kasahara S,
Kawamata K, Matsudaira K. Pain status and its
association with physical activity, psychologicalstress, and telework among Japanese workers
with pain during the COVID-19 pandemic. Int J
Environ Res Public Health. 2021;18:5595.

283

Department of Acute Medicine
Professor
Kent Doi, M.D.

Lecturer
Takehiro Matsubara, M.D.

Project Lecturer
Yoshihiro Ueda, M.D.

Miyuki Yamamoto, M.D.

Research Associate
Shunsuke Tagami, M.D.

Takuya Sato, M.D.

Hitomi Nakamura, M.D.

Takashi Gondo, M.D.

Mitsuhiro Tokuda, M.D.

Yuko Sato, M.D.

Keiko Gyoten, M.D.

Yohei Ohsiro, M.D.

Tomoaki Kurashige, M.D.

Project Research Associate
Mio Kurimoto, M.D.

Homepagehttps://www.tokyodam.com/

Introduction and Organization
Department of Emergency and Critical Care
Medicine was established in 1965, as the emergency
service within the Central Clinical Service Facilitiesof the University of Tokyo Hospital and at the sametime as the intensive care service for in-hospitalpatients, it became a tertiary emergency care andcritical care center in the metropolitan Tokyo and also
became the principal teaching facility of the
University of Tokyo. It is a designated Level I Trauma
Center, and also the home of one of the newest Life
Flight aeromedical services in the country.
The Emergency Center sees approximately 17,000
patients per year. It contains major trauma and cardiac
resuscitation rooms complete with STAT X-ray andfull monitoring and resuscitation equipment. There are
9 treatment spaces including space for orthopedics,
gynecology, and Ophthalmology-ENT evaluations.
10 overnight-stay monitored beds, X-ray, rapid spiralCT, ultrasound, angiography and STAT Lab arelocated adjacent to the Emergency Center.
In September, 2001, the University of Tokyo

Hospital opened the In-patient Ward A and ourdepartment has necessarily extended services for
management of critical patients, in the new Critical
Care Center now containing adult ICU/CCU of 16
beds in ICU1, 18 beds in ICU2 and 6 beds in
Emergency ICU.
The Emergency Care Center and the Critical Care
Center see an excellent mix of multiple trauma,
high-acuity medical, surgical, pediatric, and gynecologic patients. The Life Flight service provides anotheropportunity for exposure to critically ill patients.
Consult services are available from all of the clinicaldepartments of the Medical School. The university ofTokyo hospital was officially designated as emergency
medical care center in December 2010.

Clinical activities
Our clinical activities are divided into four
categories as follows:
1) Emergency medicine
Our department is responsible for not only

284

tertiary emergency but also primary and secondary
emergency care on 24-hour-a-day basis.
The new ER, four times the size of the previous
ER was built in November, 2006. The facility has 5
consultation rooms, 4 specialized consultation
rooms for dentistry, ophthalmology, otorhinolaryngology and gynecology, 3 resuscitation bays,
and 4 observation beds.
2) Intensive care
Staff members specialized in internal medicine,cardiovascular medicine, orthopedic surgery,
surgery, neurosurgery or anesthesiology create “thesemi-closed ICU” model. We are responsible for theentire care of the critically ill patients (i.e. patientswith respiratory insufficiency such as ARDS, withsepsis, with MOF, with shock), post-operative
patients, and tertiary emergency patients, placing anemphasis on evidence-based medical therapy.
3) Bed management
The objective of bed management services is toprovide a timely and appropriate bed allocation for
all the patients. In our hospital, patients areallocated to three types of wards, that is, generalward, ICU2 and ICU/CCU in accordance with theircritical condition. The ICU2 undertakes the leading
bed management in the hospital to ensure maximum
performance as an acute hospital.
4) Risk management
It is split into two categories – in-hospital and outof hospital disasters. In regard to in-hospital risk
management, including “code blue emergency”, weare responsible for patient safety on 24-hour/365day basis. And in regard to out of hospital risk
management, our hospital has been authorized by
the Tokyo Metropolitan Government as a disasterbase hospital, and also the Government hasrequested the formation of Disaster Medical
Assistant Team (DMAT). We have oxygen andmedical suction equipment on the passageways in
the ER in case of treating the large number ofdisaster patients.

Teaching activities
The topics of lectures for the 2nd year medical
student include the prehospital emergency care, theinitial evaluation of emergency patients, disastermedicine, serious infections disease, and trauma.
Basic Life Support. exercise is also mandatory for the
2nd year medical student.
One month of elective clinical clerkship for the 3rdyear. Immediate Cardiac Life Support (ICLS) course
is held for the participants in the clinical clerkshipprogram, and successful completion of each course
will enable students to be certified as providers.
Clinical integrated lecture for the 4th year students
includes diagnosis and treatment of serious patientsusing case studies of shock, conscious disorder,
trauma, intoxication, infections disease, burns,
hypothermia, and convulsion. Moreover, after exercise
of Advanced Life Support, students experience a realpractice of emergency medicine as fellow passengers
in the ambulances and as one day trainees in theemergency centers of the affiliated hospitals.
In conformity with the guideline by Ministry of
Health, Labor and Welfare, all residents learn andpractice emergency medicine and primary care at
every level, primary, secondary and tertiary. The
residents attend the ICLS course during resident year
to obtain the knowledge and skills in CPR.
Junior residents are also assigned to ICU services togain the knowledge of intensive care from
pathophysiological and internal medicine’s point ofview.
According to the senior resident program in 2006,
we train the senior residents to be skilled in advanced
critical care medicine including primary care trauma,
MOF, shock, and equipment support.

Research activities
Basic research by using the histone injection-induced
ARDS model and the ischemia reperfusion injury
models on several different organs including intestineand kidney has been conducted to clarify themechanisms of remote organ injury in multiple organ
dysfunction syndrome. Our clinical studies revealed
that organ network disruption could be observed by
network analysis with clinical parameters and new
biomarkers of ICU patients.

References1.

Hirayama I, Asada T, Yamamoto M, Hayase N,
Hiruma T, Doi K. Changes in carbon dioxide

285

2.

3.

4.

production and oxygen uptake evaluated using
indirect calorimetry in mechanically ventilated
patients with sepsis. Crit Care. 2021 Dec 4;25(1):416.
Horie R, Endo Y, Doi K. Estimated glomerular
filtration rate may be an independent predictor
for clinical outcomes regardless of acute kidney
injury complication in the emergency department.
PLoS One. 2021 Oct 14;16(10):e0258665.
Evans L, Rhodes A, Alhazzani W, Antonelli M,
Coopersmith CM, French C,Machado FR,
Mcintyre L, Ostermann M, Prescott HC, Schorr C,
Simpson S, Joost Wiersinga W, Alshamsi F,
Angus DC, Arabi Y, Azevedo L, Beale R,
Beilman G, Belley-Cote E, Burry L, Cecconi M,
Centofanti J, Yataco AC, De Waele J, Dellinger
RP, Doi K, Du B, Estenssoro E, Ferrer R,
Gomersall C, Hodgson C, Møller MH, Iwashyna
T, Jacob S, Kleinpell R, Klompas M, Koh Y,
Kumar A, Kwizera A, Lobo S, Masur H,
McGloughlin S, Mehta S, Mehta Y, Mer M,
Nunnally M, Oczkowski S, Osborn T,
Papathanassoglou E, Perner A, Puskarich M,
Roberts J, Schweickert W, Seckel M, Sevransky J,
Sprung CL, Welte T, Zimmerman J, Levy M.
Executive
Summary:
Surviving
SepsisCampaign: International Guidelines for theManagement of Sepsis and Septic Shock 2021.
Crit Care Med. 2021 Nov 1;49(11):1974-1982.
4: Evans L, Rhodes A, Alhazzani W, Antonelli M,
Coopersmith CM, French C, Machado FR,
Mcintyre L, Ostermann M, Prescott HC, Schorr C,
Simpson S, Wiersinga WJ, Alshamsi F, Angus
DC, Arabi Y, Azevedo L, Beale R, Beilman G,
Belley-Cote E, Burry L, Cecconi M, Centofanti J,
Coz Yataco A, De Waele J, Dellinger RP, Doi K,
Du B, Estenssoro E, Ferrer R, Gomersall C,
Hodgson C, Møller MH, Iwashyna T, Jacob S,
Kleinpell R, Klompas M, Koh Y, Kumar A,
Kwizera A, Lobo S, Masur H, McGloughlin S,
Mehta S, Mehta Y, Mer M, Nunnally M,
Oczkowski S, Osborn T, Papathanassoglou E,
Perner A, Puskarich M, Roberts J, Schweickert
W, Seckel M, Sevransky J, Sprung CL, Welte T,
Zimmerman J, Levy M. Surviving sepsis
campaign:
internationalguidelinesformanagement of sepsis and septic shock 2021.

Intensive Care Med. 2021 Nov;47(11):11811247.
5. Yamamoto M, Hiruma T, Ueda Y, Doi K.
Bilateral mandibular head fractures associatedwith convulsion. BMJ Case Rep. 2021 Sep
20;14(9):e245713.
6. Ghannoum M, Berling I, Lavergne V, Roberts
DM, Galvao T, Hoffman RS, Nolin TD,
Lewington A, Doi K, Gosselin S; EXTRIP
workgroup. Recommendations from the EXTRIP
workgroup on extracorporeal treatment forbaclofenpoisoning.
KidneyInt.
2021
Oct;100(4):720-736.
7. Matsuura R, Yamashita T, Hayase N, Hamasaki
Y, Noiri E, Numata G, Takimoto E, Nangaku M,
Doi K. Preexisting heart failure with reduced
ejection fraction attenuates renal fibrosis after
ischemia reperfusion via sympathetic activation.
Sci Rep. 2021 Jul 23;11(1):15091.
8. Hirayama I, Doi K, Yamamoto M, Toida C,
Morimura N. Evaluation of Autonomous Actions
on Bystander-Initiated Cardiopulmonary Resuscitation and Public Access Defibrillation inTokyo. Int Heart J. 2021 Jul 30;62(4):879-884.
9. Nakamura H, Hirayama I, Hiruma T, Doi K.
Subcutaneous injection of organophosphate(Fenitrothion)-Management of preventing theappearance of toxic symptoms: A case report.
Clin Case Rep. 2021 Jul ;9(7):e04424.
10. Hirayama I, Inokuchi R, Fukue M, Doi K. Gianthepatic cyst causing lower extremity edema andscoliosis. Clin Case Rep. 2021 Feb
22;9(4):2483-2484.
11. Fukushima K, Inokuchi R, Hirayama I, Hiruma T,
Doi K. Early diagnosis and antibiotic treatment
for fulminant Clostridium difficile infection. Clin
Case Rep. 2020 Dec 7;9(2):729-731.

Health Sciences and Nursing
1. Health Sciences

287

Department of Mental HealthProfessor
Norito Kawakami, M.D., Ph.D.

Associate Professor
Daisuke Nishi, M.D., Ph.D.

Project Lecturer
Kotaro Imamura, Ph.D.

Research Associate
Erika Obikane, M.D., Ph.D.

Homepage

http://plaza.umin.ac.jp/heart/

Introduction and Organization
The department was firstly established as
Department of Fourth Clinical Medical Nursing in
School of Health Care and Nursing in 1957. When the
School of Health Care and Nursing was reorganized as
the School of Health Sciences in 1965, the department
was renamed Department of Mental Health. In 1992,
as School of Health Sciences became The School of
Health Science and Nursing, Department of Mental
Health became Department of Mental Health andPsychiatric Nursing. As the result of the shift to thechair system of the Graduate School of Medicine in
1996, two departments were established, Departmentof Mental Health and Department of PsychiatricNursing. Faculty, staff, and students of two
departments have been working cooperatively eversince. Since 2007, Department of Mental Healthbecame a part of School of Public Health, with aperspective of “public mental health.”
The department currently has faculty members
introduced above, an associate professor, a project
lecturer, a research associate, part-time lecturers, atechnical specialist, visiting research fellows, 5
doctoral course students, 6 master course students, andsecretaries.
The department has two major objectives: one is toteach mental health to undergraduate and graduate

students in order to produce global leaders in researchand practice in this field. The other is to conductcutting-edge research in the fields of mental health.
All of the activities of the department are conductedin collaboration with staff members in the departments,
other departments within the University of Tokyo, andinstitutions within and outside Japan.

Teaching activities
The department is responsible for giving lectures onmental health; mental disorders; clinical and healthpsychology; and psychometry and behavior evaluation
to undergraduate students. Other than lectures, thedepartment provides students opportunities toexperience mental health activities in relevant mental
health settings.
The department provides graduate courses onmental health I and II, featuring epidemiology andpractice in mental health and occupational mental
health, respectively. The department also provided a
1.5 hour seminar every Wednesday evening for 20
weeks in each semester (40 weeks per year) for
graduate students and research students, withpresentations of research plans and progress, andliterature review by graduate students, as well as
presentation of and lectures by guest speakers.

288

Research activities
The department conducts research on mental healthand psychosocial support and provides education/
training of professionals in related fields from global
perspectives. The World Mental Health Japan survey,
which is part of a WHO international collaboration, isa largest epidemiologic study of common mental
disorders in the community in Japan. Assessment ofhealth effects of job stressors and effectiveness ofinterventions to reduce job stress are also coreresearch activities of the department. Current issues
around occupational mental health (e.g., intervention
program using Internet-based cognitive behavioral
therapy) are also actively investigated. Furthermore,
research in the department includes various othertopics, such as perinatal mental health, traumaticstress and resilience, supporting rehabilitation andrecovery of people with chronic mental illness, suicide
prevention, social disparity in mental health, disastermental health, and global mental health. Most of theresearch has been conducted in a close collaboration
with researchers in other domestic and foreign
institutions/universities.

References
1.

2.

3.

4.

Iida, M, Watanabe, K, Imamura, K, Sakuraya, A,
Asaoka, H, Sato, N, Nozawa, K, & Kawakami, N.
Development and validation of the Japaneseversion of the team job crafting scale for nurses.
Research in Nursing & Health 44.2, 2021: 329343.
Iida, M, Sasaki, N, Kuroda, R, Tsuno, K, &Kawakami, N. Increased COVID-19-related
workplace bullying during its outbreak: a2-month prospective cohort study of full-time
employees in Japan. Environmental andOccupational Health Practice, 2021.
Asaoka H, Sasaki N, Kuroda R, Tsuno K,
Kawakami N. Workplace Bullying and Patient
Aggression Related to COVID-19 and its
Association with Psychological Distress among
Health Care Professionals during the COVID-19
Pandemic in Japan. Tohoku J Exp Med. 2021;
255(4):283-289.
Asaoka H, Sasaki N, Imamura K, Kuroda R,
Tsuno K, Kawakami N. Changes in COVID-19

measures in the workplace: 8-month follow-up ina cohort study of full-time employees in Japan. J
Occup Health. 2021 Jan;63(1):e12273.
5. Imamura K, Tran TTT, Nguyen HT, Sasaki N,
Kuribayashi K, Sakuraya A, Bui TM, Nguyen AQ,
Nguyen QT, Nguyen NT, Nguyen KT, Nguyen
GTH, Tran XTN, Truong TQ, Zhang MW, Minas
H, Sekiya Y, Watanabe K, Tsutsumi A, Kawakami
N. Effect of smartphone-based stress management programs on depression and anxiety of
hospital nurses in Vietnam: a three-arm
randomized controlled trial. Sci Rep. 2021 May
31;11(1):11353.
6. Yang CC, Watanabe K, Kawakami N. The
Associations between Job Strain, Workplace
PERMA Profiler, and Work Engagement. J Occup
Environ Med. 2021 Dec 6.
7. Watanabe K, Kawakami N. Association between
sitting time at work and the onset of major
depressive episode: a 1-year prospective cohort
study using the Bayesian regression. BMC Public
Health. 2021 Oct 29;21(1):1960.
8. Kawakami N, Imamura K, Watanabe K, Sekiya Y,
Sasaki N, Sato N; SMART-CBT Project Team.
Effectiveness of an Internet-Based MachineGuided Stress Management Program Based on
Cognitive Behavioral Therapy for Improving
Depression Among Workers: Protocol for a
Randomized Controlled Trial. JMIR Res Protoc.
2021 Sep 29;10(9):e30305.
9. Sato N, Watanabe K, Kawakami N. Mediating
Effects of Work Eudemonic Well-being for the
Association Between Psychosocial Work
Environment and Overall Eudemonic Well-being
Among Japanese Workers: A Cross-sectional
Study. J Occup Environ Med. 2021 Aug 1;63(8):e542-e548.
10. Sato N, Watanabe K, Nishi D, Kawakami N.
Associations Between Personal Values and WorkEngagement: A Cross-Sectional Study Using A
Representative Community Sample. J Occup
Environ Med. 2021 Jun 1;63(6):e335-e340.
11. de Vries YA, Harris MG, Vigo D, Chiu WT,Sampson NA, Al-Hamzawi A, Alonso J, Andrade
LH, Benjet C, Bruffaerts R, Bunting B, Caldas deAlmeida JM, de Girolamo G, Florescu S, Gureje
O, Haro JM, Hu C, Karam EG, Kawakami N,

289

12.

13.

14.

15.

16.

17.

Kovess-Masfety V, Lee S, Moskalewicz J,
Navarro-Mateu F, Ojagbemi A, Posada-Villa J,
Scott K, Torres Y, Zarkov Z, Nierenberg A,
Kessler RC, de Jonge P; WHO World Mental
Health Survey collaborators. Perceived helpfulness of treatment for specific phobia: Findings
from the World Mental Health Surveys. J Affect
Disord. 2021 Jun 1;288:199-209.
Yang CC, Lee KW, Watanabe K, Kawakami N.
The association between shift work and possible
obstructive sleep apnea: a systematic review andmeta-analysis. Int Arch Occup Environ Health.
2021 Nov;94(8):1763-1772.
Kawakami N, Sasaki N, Kuroda R, Tsuno K,
Imamura K. The Effects of Downloading a
Government-Issued COVID-19 Contact Tracing
App on Psychological Distress During thePandemic Among Employed Adults: Prospective
Study. JMIR Ment Health. 2021 Jan 12;8(1):e23699.
Sasaki N, Yasuma N, Obikane E, Narita Z,
Sekiya J, Inagawa T, Nakajima A, Yamada Y,
Yamazaki R, Matsunaga A, Saito T, Imamura K,
Watanabe K, Kawakami N, Nishi D. Psychoeducational interventions focused on maternal or
infant sleep for pregnant women to prevent theonset of antenatal and postnatal depression: A
systematic review. Neuropsychopharmacol Rep.
41(1):2-13, 2021
Wu Y, Levis B, Ioannidis JPA, Benedetti A,
Thombs BD; DEPRESsion Screening Data
(DEPRESSD) Collaboration (Nishi D, 156/232).
Probability of Major Depression Classification
Based on the SCID, CIDI, and MINI Diagnostic
Interviews: A Synthesis of Three Individual
Participant Data Meta-Analyses. Psychother
Psychosom. 90(1):28-40, 2021
Yasuma N, Imamura K, Watanabe K, Nishi D,
Kawakami N, Takano A. Association between
energy drink consumption and substance use inadolescence: A systematic review of prospective
cohort studies. Drug Alcohol Depend. 219:
108470, 2021
Sasaki N, Imamura K, Nishi D, Watanabe K,
Sekiya Y, Tsuno K, Kobayashi Y, Kawakami N.
Internet-based acceptance and commitment
therapy programme 'Happiness Mom' for well-

18.

19.

20.

21.

22.

23.

being: a protocol for a randomised controlled trial.
BMJ Open. 26;11(2): e042167, 2021
Yasuma, N, Yamaguchi, S, Ogawa, M, Shiozawa
T, Abe M, Igarashi M, Kwaguchi T, Sato S, Nishi
D, Kawakami N, Fujii C. Care difficulties andburden during COVID‐19 pandemic lockdowns
among caregivers of people with schizophrenia:
A cross‐sectional study. Neuropsychopharmacol
Rep. 41(2):242-247, 2021
Kataoka M, Nishi D. Association between WorkRelated Trauma Exposure and PosttraumaticStress Symptoms among Child Welfare Workers
in Japan: A Cross-Sectional Study. International
Journal of Environmental Research and Public
Health. 18(7):3541, 2021
Bhandari PM, Levis B, Neupane D, Patten SB,
Shrier I, Thombs BD, Benedetti A, and the
DEPRESsion Screening Data (DEPRESSD)EPDS Group (Nishi D, 57/82). Data-driven
methods distort optimal cutoffs and accuracy
estimates of depression screening tools: asimulation study using individual participant data.
Journal of Clinical Epidemiology. 137:137-147,
2021
Obikane E, Baba T, Shinozaki T, Obata S,
Nakanishi S, Murata C, Ushio E, Suzuki Y,
Shirakawa N, Honda M, Sasaki N, Nishi D,
O’Mahen H, Kawakami N. Internet-based
behavioural activation to improve depressive
symptoms and prevent child abuse in postnatal
women (SmartMama): a protocol for a pragmatic
randomized controlled trial. BMC Pregnancy
Childbirth 21:314, 2021
Nangaku M, Kadowaki T, Yotsuyanagi H,
Ohmagari N, Egi M, Sasaki J, Sakamoto T,
Hasegawa Y, Ogura T, Chiba S, Node K, Suzuki
R, Yamaguchi Y, Murashima A, Ikeda N,
Morishita E, Yuzawa K, Moriuchi H, Hayakawa
S, Nishi D, Irisawa A, Miyamoto T, Suzuki H,
Sone H, Fujino Y. The Japanese Medical Science
Federation COVID-19 Expert Opinion English
Version. JMA J. 15;4(2):148-162, 2021
Nakao T, Murayama K, Takahashi S, Kayama M,
Nishi D, Horinouchi T, Oya N, Kuga H. Mental
Health Difficulties and Countermeasures during
the Coronavirus Disease Pandemic in Japan: A
Nationwide Questionnaire Survey of Mental

290

24.

25.

26.

27.

28.

Health and Psychiatric Institutions. Int J Environ
Res Public Health. 8;18(14):7318, 2021
Stein DJ, Kazdin AE, Ruscio AM, Chiu WT,Sampson NA, Ziobrowski HN, Aguilar-Gaxiola S,
Al-Hamzawi A, Alonso J, Altwaijri Y, Bruffaerts
R, Bunting B, de Girolamo G, de Jonge P,
Degenhardt L, Gureje O, Haro JM, Harris MG,
Karam A, Karam EG, Kovess-Masfety V, Lee S,
Medina-Mora ME, Moskalewicz J, NavarroMateu F, Nishi D, Posada-Villa J, Scott KM,
Viana MC, Vigo DV, Xavier M, Zarkov Z,
Kessler RC; WHO World Mental Health Survey
collaborators. Perceived helpfulness of treatment
for generalized anxiety disorder: a World Mental
Health Surveys report. BMC Psychiatry. 21(1):392, 2021
Sasaki N, Carrozzino D, Nishi D. Sensitivity andconcurrent validity of the Japanese version of the
Euthymia scale: a clinimetric analysis. BMC
Psychiatry. 4;21(1):482, 2021.
Sasaki N, Obikane E, Vedanthan R, Imamura K,
Cuijpers P, Shimazu T, Kamada M, Kawakami N,
Nishi D. Development and Validation of
Implementation Outcome Scales for Digital
Mental Health (iOSDMH). JMIR Formative
Research 23;5(11):e24332, 2021
Roest AM, de Vries YA, Al-Hamzawi A, Alonso J,
Ayinde O, Bruffaerts R, Bunting B, Caldas-deAlmeida, JM, de Girolamo G, Degenhardt L,
Florescu S, Gureje O, Haro JM, Hu CY, Karam
EG, Kiejna A, Kovess-Masfety V, Lee S,
McGrath JJ, Medina-Mora ME, Navarro-Mateu F,
Nishi D, Piazza M, Posada-Villa J, Scott KM,
Stagnaro JC, Stein DJ, Torres Y, Viana MC,
Zarkov Z, Kessler RC, de Jonge P, on behalf of
the WHO World Mental Health Survey
collaborators. Previous disorders and current
impairment and suicidality in individuals with
12-month major depressive disorder in the World
Mental Health surveys. Epidemiology andPsychiatric Sciences 11;30:e70, 2021
Asaoka H, Koido Y, Kawashima Y, Ikeda M,
Miyamoto Y, Nishi D. Longitudinal change indepressive symptoms among healthcare professionals with and without COVID-19 vaccine
hesitancy from October 2020 to June 2021 inJapan. Industrial Health (Epub ahead of print)

29. Sasaki N, Akiyama H, Kawakami N, Nishi D.
Preconception menstrual cycle disorder andantenatal depression: A cross-sectional study withpre-recorded information. J Psychosom Obstet
Gynaecol. (Epub ahead of print)
30. Asaoka H, Koido Y, Kawashima Y, Ikeda M,
Miyamoto Y, Nishi D. Longitudinal Change of
Psychological Distress among Healthcare
Professionals with and without PsychologicalFirst Aid Training Experience during the
COVID-19 Pandemic. International Journal ofEnvironmental Research and Public Health.
18(23):12474, 2021
31. Mascayano F, van der Ven E, Moro MF, Schilling
S, Alarcón S, Barathie JA, Alnasser L, Asaoka H,
Ayinde O, Balalian AA, Basagoitia A, Brittain K,
Dohrenwend B, Durand–Arias S, Eskin M,
Fernández–Jiménez E, Freytes M, Giménez L,
Gisle L, Hoek HW, Jaldo R, Lindert J,
Maldonado H, Martínez -Alés G, Martínez-Viciana C, Mediavilla R, McCormack C, Myer L,
Narvaez J, Nishi D, Ouali U, Puac-Polanco V,
Ramírez J, Restrepo-Henao A, Rivera -Segarra E,
Rodríguez AM, Saab D, Seblova D, Tenorio A,
Valeri L, Alvarado R, Susser E, On behalf of the
HEROES group. The impact of the COVID-19
pandemic on the mental health of healthcare
workers: study protocol for the COVID-19
HEalth caRe wOrkErS (HEROES) study. Social
Psychiatry and Psychiatric Epidemiology (inpress)
32. Hidaka Y, Imamura K, Watanabe K, Tsutsumi A,
Shimazu A, Inoue A, Hiro H, Odagiri Y, Asai Y,
Yoshikawa T, Yoshikawa E. Associations
between work-related stressors and QALY in a
general working population in Japan: a crosssectional study. International Archives ofOccupational and Environmental Health. 2021
May 30:1-9.
33. Hidaka Y, Sasaki N, Imamura K, Tsuno K,
Kuroda R, Kawakami N. Changes in fears andworries related to COVID-19 during the
pandemic among current employees in Japan: a
5-month longitudinal study. Public health. 2021
Sep 1;198:69-74.
34. Hidaka Y, Watanabe K, Imamura K, Tatha O,
Kawakami N. Reliability and validity of the

291

35.

36.

37.

38.

39.

40.

Chinese version of the New Brief Job Stress
Questionnaire (New BJSQ) among workers in
China. Industrial health. 2021 Nov 1.
Komase Y, Watanabe K, Hori D, Nozawa K,
Hidaka Y, Iida M, Imamura K, Kawakami N.
Effects of gratitude intervention on mental healthand well-being among workers: A systematic
review. Journal of Occupational Health, 2021;63:
e12290.
Yasuma, N., Nishi, D., Watanabe, K., Ishikawa,
H., Tachimori, H., Takeshima, T., . . . Kawakami,
N. (2021). Association between Urban
Upbringing and Compulsive Internet Use inJapan: A Cross-Sectional, Multilevel Study with
Retrospective Recall. Int J Environ Res Public
Health, 18(18), 9890.
Komase Y, Watanabe K, Natsu S, Kawakami N.
The effect of perceived gratitude from others on
work engagement: a cross-sectional study.
Journal of Occupational and Environmental
Medicine. 2021;63:e592-e595.
Yasuma N, Yamaguchi S, Ogawa M, et al. Caredifficulties and burden during COVID ‐ 19
pandemic lockdowns among caregivers of people
with schizophrenia: A cross ‐ sectional study.
Neuropsychopharmacol Rep. 2021; 00: 1– 7.
Komase Y, Watanabe K & Kawakami N. Effects
of a gratitude intervention program on work
engagement among Japanese workers: a protocol
for a cluster randomized controlled trial. BMC
Psychol 9, 35 (2021).
Yasuma N, Watanabe K, Nishi D, Ishikawa H,
Tachimori H, Takeshima T, Umeda M and
Kawakami N (2021) Psychotic Experiences and
Hikikomori in a Nationally Representative
Sample of Adult Community Residents in Japan:
A Cross-Sectional Study. Front. Psychiatry 11:602678.

292

Department of Biostatistics/
Epidemiology and Preventive
Health Sciences
Professor
Yutaka Matsuyama, Ph.D.

Associate Professor
Koji Oba, Ph.D.

Assistant Professor
Yasuhiro Hagiwara, Ph.D., M.P.H.

Homepage

http://www.epistat.m.u-tokyo.ac.jp/en/

Introduction and Organization
The Department of Epidemiology andBiostatistics evolved from the Department of
Epidemiology in 1992. Since then, we have been
responsible for providing educational courses on
methodology of epidemiologic research and biostatistics to undergraduate students. We belong to
Graduate School of Medicine as Departments ofBiostatistics/ Epidemiology and Preventive Health
Sciences, providing education for undergraduate aswell as graduate-school students and consultation toclinical researchers.
Unfortunately, education programs for biostatistics and epidemiological methodology are notsufficient in Japanese universities and graduate
schools compared to the situation in the US andEuropean countries. Nevertheless, the necessity forcollaboration among biostatisticians and clinicalresearchers/ epidemiologists has been claimed inrecent years. Hence, the central missions of oureducational courses are devoted to provide students
expert knowledge and extensive experience inbiostatistics and epidemiology to take part in clinical/
epidemiological research as biostatisticians or
methodologists. We do not only focus on practicalaspects on statistical analysis in medical research but
also place emphasis on the methodological principles
of biostatistics/epidemiology.
Our main research area is the development ofmethodology for clinical/epidemiological research. Of
course, it requires keeping in touch with real clinical/
epidemiological problems. So, another indispensable
research area is a support for real-world clinical andepidemiological studies including clinical trials. To
achieve these requirements simultaneously, a nonprofit organization the Japan Clinical Research
Support Unit (current EP-CRSU, Co., Ltd.) wasestablished in 2001 by the former faculty members inour department. This organization J-CRSU hadprovided research support and coordination in design,
data management, and statistical analysis in many
projects inside/outside the university. Our experiencein J-CRSU is the basis of our supportive activities forclinical research that we work through today.

Teaching activities
 Undergraduate Courses
1) Epidemiology (2 credits)
2) Biostatistics (2 credits; named “Statistics” inmedical doctor course)2933) Applied Mathematics (2 credits)
4) Biostatistics Practice (1 credit)
5) Practical Examples in Clinical andEpidemiologic Research (1 credit)
6) Medical Data Analysis, and its Practice (1 credit
each)7) Theoretical Epidemiology (2 credits) School of Public Health (Graduate School)
1) Statistical Analysis of Medical Research(2 credits)
2) Practice of Biostatistics (2 credits)3) Design of Medical Research (2 credits) Doctoral Courses (Graduate School)
1) Biostatistics (4 credits)
2) Epidemiology and Preventive Health Sciences(4 credits)
3) Introduction to Medical Statistics(2 credits; for the School of Medicine)
The faculty of the department had provided
lectures in a series of educational courses organizedby “The Clinical Bioinformatics Research Unit” in
2002-2007.

Research activities
1. Methodology for designing and analyzing clinical
trials: Interim analysis
 Adaptive designs
 Multiplicity
 Data management of large-scale multicenter
clinical trials
2. Methodology of Biostatistics and theoreticalepidemiology:
 Analysis of longitudinal (time-to-event and/or
repeated measures) data
 Analysis of missing/incomplete data Causal inference Semiparametric modeling
3. International collaboration of individual-levelmeta-analysis on gastric cancer
4. Coordination and data analysis of collaborative
epidemiological/clinical research:
 Japan Arteriosclerosis Longitudinal Study Japan Diabetes Collaborative Study Chronic Kidney Disease Japan Cohort
5. Validity/reliability studies of QOL questionnaires
and other rating scales
6. Pharmacoeconomic assessment of medical technology
We had been supporting some of the above
collaborative clinical/epidemiologic studies throughthe aforementioned J-CRSU (a non-profit organization), which aims to support investigator- initiatedstudies and to provide education to researchers andsupport staffs. Currently, we are officially conducting
a consultation for design and analysis of clinical trials
assisted by the Clinical Research Promotion Center of
the University of Tokyo Hospital.
The University of Tokyo participated in "Support
Programfor
Biostatisticians,"
anindustry-government-academia collaborative project
launched by the Japan Agency for Medical Researchand Development (AMED) in FY2016, and has been
participating in its successor, "Promotion Program for
Biostatisticians,"
since
FY2021(principal
investigator: Professor Matsuyama). Both projects are
aimed at fostering biostatisticians at clinical research
institutes and research centers in Japan, and aredesigned and implemented for master course andone-year post-graduate education/training programs.
Our department is also officially participating in these
programs, and will provide more and moreeducational/practical supports to future biostatisticianson the basis of our rich experience in biostatisticaleducation and support in variety of research.

References
1.

2.

Ebata S, Yoshizaki A, Oba K, Kashiwabara K,
Ueda K, Uemura Y, Watadani T, Fukasawa T,
Miura S, Yoshizaki-Ogawa A, Asano Y, Okiyama
N, Kodera M, Hasegawa M, Sato S. Safety andefficacy of rituximab in systemic sclerosis:
a double-blind, parallel-group comparison,
investigators initiated confirmatory clinical trial(DESIRES). Lancet Rheumatol. 2021;3:E489–
E497.
Kuwabara M, Oba K, Takano N, Nagamine N,
Maruyama Y, Ito N, Watanabe I, Ikeda C,

294

3.

4.

5.

6.

7.

8.

9.

Sakamoto J. An exploratory questionnaire survey
about overwork on mental health of Japaneseelementary and junior high school teachers. J
Ment Health Train Educ Pract 2021;16:181–186.
Ota K, Oba K, Fukui K, Ito Y, Hamada E, Mori N,
Oka M, Ota K, Shibata Y, Takasu A. Sites ofblood collection and topical antiseptics associated with contaminated cultures: prospective
observational study. Sci Rep. 2021;11:6211.
Takeuchi Y, Kumamaru H, Hagiwara Y, Matsui H,
Yasunaga H, Miyata H, Matsuyama Y.
Sodium-glucose cotransporter-2 inhibitors andthe risk of urinary tract infection among diabetic
patients in Japan: Target trial emulation using anationwide administrative claims database.
Diabetes Obes Metab. 2021;23:1379–1388.
Yamada G, Hagiwara Y, Kimura T, Takeuchi Y,
Oba K, Masuda K, Matsuyama Y. Impact of bodyweight gain on the incidence of non-alcoholic
fatty liver disease in non-obese Japaneseindividuals. Am J Gastroenterol. 2021;116:733–
740.
Sasaki S, Nagasaki T, Oba K, Akiyoshi T, Mukai
T, Yamaguchi T, Fukunaga Y, Fujimoto Y. Risk
factors for outlet obstruction after laparoscopic
surgery and diverting ileostomy for rectal cancer.
Surg Today. 2021;51:366–373.
Hagiwara Y, Shinozaki T, Mukai H, Matsuyama
Y. Sensitivity analysis for subsequent treatments
in confirmatory oncology clinical trials: a
two-stage stochastic dynamic treatment regime
approach. Biometrics. 2021;77:702–714.
Kozuma K, Kozuma K, Shinozaki T,
Kashiwabara K, Oba K; Xience P. M. S. Group;
PROMUS Element/Element Plus P. M. S. Group,
Matsuyama Y. Multivariable Prediction Model to
Estimate the Probability of Restenosis at
Proximal Edge After 2nd-generation DrugEluting-Stent Implantation: Development andInternal Validation Using a Quantitative
Coronary Angiography From the Post-Marketing
Surveillance Studies of Everolimus-Eluting Stent
in Japan. Cardiovasc Interv Ther. 2021;36:190–
197.
Fuyama K, Hagiwara Y, Matsuyama Y. A
simulation study of regression approaches for
estimating risk ratios in the presence of multiple

confounders. Emerg Themes Epidemiol. 2021;18:18.
10. Ito C, Hashimoto A, Uemura K, Oba K.
Misleading Reporting (Spin) in Noninferiority
Randomized Clinical Trials in Oncology With
Statistically Not Significant Results: A
Systematic Review. JAMA Netw Open. 2021;4:
e2135765.
11. Ota K, Oba K, Ito Y, Cheng J, Ota K, Takasu A.
Focused Assessment with Sonography forTrauma (FAST) training for first-year resident
physicians at a university hospital in Japan: Alongitudinal, observational study. SAGE Open
Medicine. 2021;9:20503121211044367.
12. Takeuchi Y, Ogawa M, Hagiwara Y, Matsuyama
Y. Non-parametric approach for frequentist
multiple imputation in survival analysis withmissing covariates. Stat Methods Med Res. 2021;
30:1691–1707.
13. Hagiwara Y, Sawaki M, Uemura Y, Kawahara T,
Shimozuma K, Ohashi Y, Takahashi M, Saito T,
Baba S, Kobayashi K, Mukai H, Taira N. Impact
of chemotherapy on cognitive functioning inolder patients with HER2-positive breast cancer:
a sub-study in the RESPECT trial. Breast Cancer
Res Treat. 2021;188:675–683.
14. Chamseddine AN, Oba K, Buyse M, Boku N,
Bouché O, Satar T, Auperin A, Paoletti X. Impactof follow-up on generalized pairwise comparisons for estimating the irinotecan benefit inadvanced/metastatic gastric cancer. Contemp Clin
Trials. 2021;105:106400.
15. Kawaguchi Y, Hasegawa K, Hagiwara Y, De
Bellis M, Famularo S, Panettieri E, Matsuyama Y,
Tateishi R, Ichikawa T, Kokudo T, Izumi N,
Kubo S, Sakamoto M, Shiina S, Takayama T,
Nakashima O, Murakami T, Vauthey JN,
Giuliante F, De Carlis L, Romano F, Ruzzenente
A, Guglielmi A, Kudo M, Kokudo N. Effect ofdiameter and number of hepatocellular
carcinomas on survival after resection, transarterial chemoembolization, and ablation. Am J
Gastroenterol. 2021:116;1698–1708.
(Only main publications)295

Department of Biomedical Ethics &Department of Health Promotion
Sciences
Professor
Akira Akabayashi, M.D., Ph.D.

Associate Professor
Yoshiyuki Takimoto, M.D., Ph.D.

Lecturer
Eisuke Nakazawa, Ph.D.

Research Associate
Makoto Udagawa, MA

Homepage

http://www.ethps.m.u-tokyo.ac.jp/

Introduction and Organization
The former Department of Health Administration wasestablished in 1967 and Dr. Tsuneo Tanaka became its
first professor in 1974. He devoted himself to thedevelopment of the community health care system inJapan and published numerous papers concerning thesocial theory of health administration and data
management systems for community health care. He
also contributed to the establishment of the School of
Health Sciences. In 1985, Dr. Atsuaki Gunji became
the second professor of the department. During Dr.
Gunji’s tenure, two major research projects were
undertaken. One was “The effects of physical activity
and inactivity on health.” From 1990, a 20-day bed
rest human experimental study was conducted every
year in the context of an international cooperative
research project that was supported by government
grants. The other project concerned health caresystems, especially health care economics and thequality of hospital care.
In 1996, the Department of Health Administration developed into two departments: the Department
of Health Economics and the Department of Health

Promotion Sciences. Both were established as
departments of the Graduate School of Medicine. In
1998, Dr. Yasuki Kobayashi became the professor of
the Department of Health Economics. He conducted
research into health care delivery systems in Japan. In
2001, he moved to the Department of Public Health.
From 1996 to 2002, Dr. Kiyoshi Kawakubo tookcharge of the Department of Health Promotion
Sciences as the associate professor.
In June 2002, Dr. Akira Akabayashi became
professor of the Department of Health Economics.
Professor Akabayashi’s area of research is biomedical
ethics. In April 2003, the Department of Health
Economics was restructured and named the Department of Biomedical Ethics. From 2007, Dr. Jung Su
Lee became the associate professor and took charge of
the Department of Health Promotion Sciences. In
2017, Dr. Yoshiyuki Takimoto acceded to the chair of
the Department of Health Promotion Sciences. In
2019, the Department of Health Promotion Sciences
was consolidated into the Department of Biomedical
Ethics.
Staff members of the department include a296

professor, an associate professor, a lecturer, anassociate, and a technical specialist. All five members,
twoproject researchers, eleven lecturers from otherorganizations, and seven visiting researchers
contribute to department teaching and research
activities.
We have eight department graduate students. Fiveof them are doctoral program students.
In this annual report, the organization andteaching activities are reviewed followed by an
explanation of research activities.

Graduate Courses
1) Biomedical Ethics I
2) Biomedical Ethics II

Teaching activities

Research activities

Our departments highly prioritize the teaching andguidance of graduate students and their research
activities. Eighteen bachelor theses, twenty-two
master theses, and eleven doctoral dissertations werecompleted between April 2004 and March 2020. Our
department’s staff members are also responsible forthe following undergraduate and graduate courses.

The Department of Biomedical Ethics is interested in
the current topics of health care ethics. We are
currently conducting studies in the fields ofbiomedical ethics, research ethics and clinical ethics.
Methodology is two-folded―theoretical and empirical.
While conducting theoretical research on ethics andphilosophy of health care, we also have adopted a
descriptive approach.
We have recently established The University ofTokyo Center for Biomedical Ethics and Law (CBEL)―a new interdisciplinary and international education
research center aimed to address bioethical issues
relevant to Japan and the international community.
Our center will form an international network by
establishing partnerships with research centersoverseas (GABEX: Global Alliance of Biomedical
Ethics Centers Project). Through these efforts, we will
foster the next generation of bioethics experts inpolicy-making, research, and clinical medicine whoare capable of providing international leadership in the
future (http://www.cbel.jp/).

Undergraduate Courses
Required courses
1) Introduction to Biomedical Ethics (Lecture)2) Biomedical Ethics I (2 credits, lecture)3) Theory and Science of Health Behavior (2credits, lecture)4) Seminar in Public Health Science II (2 credits,seminar)5) First-Year Seminar for Natural Science Students(2 credits, seminar)
Elective courses
6) Integrated Lecture of Clinical Medicine(Lecture)
7) Integrated Lecture of Clinical Medicine,
Biomedical ethics (Lecture)8) Integrated Lecture of Clinical Medicine,
Biomedical ethics and Geriatric Medicine(Lecture)9) Social Medicine (Lecture)10) Biomedical Ethics II (2 credits, lecture)11) Clinical Ethics (2 credits, lecture)12) Public Health Ethics (2 credits, lecture)13) Global Bioethics (2 credits, lecture)

In addition to these courses, the department operates
lectures, practical training, and joint seminars forresearch guidance on a regular basis.
Graduate level courses in Biomedical Ethics
focus on the analytical study of ethical theories and on
the review of several empirical studies within the field
and its related areas.

Specific research topics include:
1) Study of methods for promoting social consensus
on topics related to advanced medical technology
2) Study of the function and responsibilities of
ethics committees in Japan
3) Acceptability of advance directives in Japanesesociety4) Development of evaluative methods forbio-medical ethics education
5) Ethical and psychosocial aspects of living relatedorgan transplantation

2976) Publication of a medical ethics case book forJapan7) Comparative study of clinical ethics in the Asian
region8) Historical analyses for the term “bioethics” in theJapanese context

References
1.

2.

3.

4.

5.

6.

7.

8.

Ino H, Nakazawa E, Akabayashi A. Drug
repurposing for COVID-19: Ethical considerations and roadmaps. Camb Q Healthc Ethics.
2021;30:51-58. doi:10.1017/S0963180120000481.
Kubota S, Nakazawa E. Concept and implicationsof sexual consent for education: A systematic
review of empirical studies. Sex Relation Ther.
Published online first on February 15, 2022.
doi:10.1080/14681994.2022.2039617.
Kurisu K, Yamanaka Y, Yamazaki T, Yoneda R,
Otani M, Takimoto Y, Yoshiuchi K. A clinicalcourse of a patient with anorexia nervosa
receiving surgery for superior mesenteric artery
syndrome. J Eat Disord. 2021 Jun 30;9(1):79.
doi:10.1186/s40337-021-00436-2.
Nakazawa E, Akabayashi A. Citizen and patientparticipation in precision medicine: Epilepsy
treatment using brain organoids derived from iPS
cells. AJOB Neurosci 2022;13(2):138-140. doi:
10.1080/21507740.2022.2048737.
Nakazawa E, Akabayashi A. Covid-19, global
ethics, and Jihi: A voice from East Asian
philosophy. Indian J Med Ethics. 2021;6(2):138139. doi:10.20529/IJME.2020.126.
Nakazawa E, Akabayashi A. Unauthorized
Immigrants in Japan Facing the COVID-19
Pandemic. Journal of Seizon and Life Sciences.
2021;32(1):75-88.
Nakazawa E, Yamamoto K, London AJ,
Akabayashi A. Solitary death and new lifestyles
during and after COVID-19: wearable devices
and public health ethics. BMC Med Ethics. 2021;
22:89. doi:10.1186/s12910-021-00657-9.
Ohsawa M, Makino T, Takimoto Y, Inui A.
Application of Kampo medicines for thepalliation of cancer cachexia. Neuropeptides.
2021 Dec;90:102188. doi: 10.1016/j.npep.2021.
102188.

9.

Takimoto Y. Should suicide be prevented amongcancer patients? Palliat Support Care. 2021 Mar
10;1-2. doi:10.1017/S1478951521000249.

Health Sciences and Nursing
2. Preventive and Administrative Nursing

299

Department of
Nursing Administration /Advanced Clinical Nursing
Associate Professor
Yukie Takemura, Ph.D., R.N., C.N.A.

Assistant Professor
Naoko Ichikawa, Ph.D., R.N.
Ryohei Kida, Ph.D., R.N.
Tamaki Isobe, Ph.D., R.N

Project Assistant Professor
Satoko Nagai, MSN, R.N. (2021.9~)

Homepage http://nurs-adm.umin.jp/
Introduction and Organization

Teaching activities

The Department of Nursing Administration /Advanced Clinical Nursing has 60 years of history andtradition. It was first established in 1954 as the
Department of Fundamental Nursing at the School of
Health Care and Nursing. The School of Health Careand Nursing was composed of two basic medical
departments and six nursing departments. When it was
reorganized as the School of Health Sciences in 1965,
only one nursing department remained. Renamed theDepartment of Nursing, it was responsible for nursing
education. In 1992, the School of Health Sciences
became the School of Health Sciences and Nursing, andtwo new departments of nursing were established; theDepartment of Nursing then became the Department ofFundamental Nursing. As a result of the shift to the chairof the Graduate School of Medicine in 1996, two
departments were established: the Department of
Nursing Administration and the Department ofAdvanced Clinical Nursing. Our department is
responsible for undergraduate fundamental nursing
education.

Undergraduate Courses
In the undergraduate program, our department
oversees lectures and clinical practicums for
Introduction to Nursing Science, Fundamental Nursing I,
Fundamental Nursing II, Basic Nursing Skills, andNursing Administration.
Introduction to Nursing Science (1 credit, lecture)
In this course, students learn nursing concepts,
functions, theories, targets, and the practical side ofnursing
throughlectures,discussions,andinter-professional education.
Theory and Methodology of Nursing I (2 credits,
lecture)This course provides knowledge and nursing skills forunderstanding patients and providing care. Students
learn about the nursing process and skills necessary forknowing and caring for patients, which are essential for
providing appropriate nursing care.
Theory and Methodology of Nursing II (2 credits,elective course, lecture)
This course offers perspectives on the nursing

300

profession through a series of lectures from various
experts and discussions.
Basic Nursing Skills (2 credits, lecture)
This course covers the basics of assessing clients’
health, including physical examination skills andpractices in fundamental nursing skills, which areessential for providing nursing care with physiologicaland psychosocial integrity. Students learn about thenursing process through case discussions.
Practicum: Basic Nursing Skills(2 credits, practicum)
Under instructors’ supervision, students have theopportunity to apply their fundamental knowledge andnursing skills in a variety of settings. Students willassess clients’ health and needs by applying the nursing
process.
Nursing Administration (1 credit, lecture)
This course introduces students to the roles of nurse
administrators/managers in all types of healthcare
settings, such as institutions, organizations, andcommunities as well as political settings. Students willlearn the fundamental theories and practices of nursing
administration/management by analyzing current issues
in healthcare and nursing.
Practicum: Nursing Administration(1 credit, practicum)
Students participate in a nursing administrative
practicum in units or divisions in hospitals. They willlearn about care delivery systems, such as staffing andpatient classification systems, nursing informatics, andbudgetary issues (e.g., cost effectiveness and quality
improvement).

Graduate Courses
In the graduate program, our department oversees
lectures and seminars for Nursing Administration andAdvanced Clinical Nursing.
Nursing Administration I (2 credits)
During this course, students acquire the necessary
knowledge and perspectives to become actively
involved in an organization and to conduct research that
focuses on organizational phenomena through lectureson and a critical analysis of relevant organizational andhuman resource management theories, the environment
surrounding nursing science and nursing practice, andpolitical decision making.
SeminarWe have an accredited departmental seminar where
members discuss their own research project plans.

Research activities
We aim to clarify the systems and methodologies
that fulfil the organizational and human resource
potential to contribute to the wellbeing of patients,
nurses, and other healthcare professionals as well associety in general.
Development of Research Methods for Depicting
Organizational Phenomena
Careful extraction and accumulation of knowledge
from organizational case studies is necessary todevelop nursing administrators and contribute toclinical practice. For this reason, when analyzing suchcases, we clarify phenomena shared acrossindividuals and facilities in multiple cases anddevelop research methods to vividly describe
dynamic and complex workplace-related andorganizational processes. For instance, we examine
workplace experiences based on studies of multiple
organizations
anddescribe
organizational
management processes based on the experiences of
those providing and receiving support.
Discovering Knowledge Required for Effective
Organizational Management and Development
It is important that workers, including nursing
administrators, use their abilities to the fullest andfunction effectively to provide quality care to patients,
families, and society in general. We engage in
research that clarifies the key elements and processes
involved. Concrete examples include investigating
nursing organizational operation models during timesof crisis, based on case studies following the 2011
earthquake and tsunami in Fukushima, case study of
medical facilities that systematically work to improve
the workplace environment for nurses, as well as
exploring connections between nursing managers’
competencies and leadership and staff development,
professional commitment, on-the-job behavior, job
satisfaction, workplace culture, and employee
turnover rates.

301

Creating Workplaces Where Staff and Teams Can
Demonstrate Their Abilities
We engage in research that contributes to thecreation of workplaces where staff and teams candemonstrate their latent abilities to the fullest. This
includes supporting individuals and teams,
organizational development, and the improvement of
individuals and team environments. Concrete
examplesincludeorganizational
learning,
intra-organizational communication and roles,
diversity climate in nursing organizations, andperson-environment fit in nurses.
Creating Mechanisms that Sustainably Provide
High-Quality Medical Care and Nursing
We engage in research that contributes to thecreation of sustainable organizations and careenvironments, including securing nursing humanresources, maintaining the quality of such resources,
and creating systems in organizational environments.
Examples include research investigating thedevelopment of nursing careers and professional
expertise, returning to work in the nursing profession,
the nursing labor market, and impact of nursing
turnover on the organization.

References
1.

2.

3.

4.

Ishii K, Takemura Y, & Ichikawa, N. Relationships
between the components of nurse managers'
transformational leadership and organizational
learning subprocesses in a hospital ward: A
cross-sectional study. Journal of Nursing
Management. 2021; 29(4); 672-680.
Inoue M, Kunie K, Takemura Y, Ichikawa N, &Kida R. The influence of learning circumstancesand on-the-job opportunities for professional
growth on perceived person-environment fit amonghospital nurses: A longitudinal study. Journal of
Nursing Management. 2021; 29(4); 776-784
Saiki M, Kunie K, & Takemura Y. Nursing
assistants’ desired roles, perceptions of nurses’
expectations, and effect on team participation: A
cross-sectional study. Journal of Nursing
Management. 2021; 29(5); 1046-1053.
Kida R & Takemura Y. Strategies at health carefacilities to improve working environment forJapanese nursing staff: Multiple case study. The

Journal of the Japan Academy of Nursing
Administration and Policies. 2021; 25(1); 20-33.
[in Japanese]
5. Komagata M, Takemura Y, Ichikawa N, Takehara
K, & Kunie K. Reliability and validity of theJapanese version of the job characteristics scale
among nurses. The Journal of the Japan Academyof Nursing Administration and Policies. 2021;
25(1); 12-19. [in Japanese]
6. Piao X, Tsugawa S, Takemura Y, Ichikawa N, Kida
R, Kunie K, Managi S. Disability Weights
Measurement for 17 Diseases in Japan: A Survey
Based on Medical Professionals. Economic
Analysis and Policy. 2021; 70; 238-248
7. Takahashi Y, Kunie K, & Takemura Y. The lasting
impacts of work-attendance decisions of healthcare employees under uncertainty: Japanesehospital nurses’ experiences outside the evacuation
zone after the nuclear accident. Journal of
Organization and Discourse. 2021; 2(1); 9-19.
8. Tanaka S, Kunie K, Takemura Y, Ichikawa N, &Kida R. Exploring nurses’ clinical reasons for bed
transfers in acute care wards: An observational
study. Journal of Nursing Management, 2021;
29(7); 2297-2306.
9. Kawaguchi S, Takemura Y, Takehara K, Kunie K,
Ichikawa N, Komagata K, Kobayashi K, Soma M,& Komiyama C. Relationship between teams’
Leader–Member Exchange characteristics andpsychological outcomes for nurses and nurse
managers: A cross-sectional study in Japan. Sage
Open Nursing, 2021; 7: 1-11.
10. Tanaka S, Kunie K, Takemura Y, Ichikawa N, &Kida R. The patterns and reasons for changing bed
placement in multi-bed rooms in acute care settings.
Journal of Society of Nursing Practice 2021; 33(3):11-23.
11. Ishii K, Takemura Y, Ichikawa N, Kunie K, Kida R.
The relationship between nursing groups’
organizational socialization and nurses’ perceptionof organizational learning subprocesses: across-sectional study in hospital wards. Team
Performance Management: An International
Journal. 2021 Aug 16.
12. Inoue M, Kunie K, Takemura Y, Ichikawa N, &Kida R. Development of a Japanese version ofperceived fit scale to measure perceived

302

multidimensional person-environment fit: Validity
and reliability tests among nurses. Journal of Japan
Academy of Nursing Science. 2021;41:692-700.
[in Japanese]
13. Saiki M, Takemura Y, & Kunie K. Development
and evaluation of an intervention program fornurses and nursing assistants to recognize the rolesof nursing assistants. Journal of Japan Academy of
Nursing Science. 2021;41:638-46. [in Japanese]

303

Department of Family Nursing
Professor
Mari Ikeda, Ph.D., R.N., R.C.P.

Lecturer
Iori Sato, Ph.D., R.N., P.H.N.

Assistant Professors
Mayumi Morisaki, Ph.D., R.N., P.H.N.

Homepage

http://www.fn.m.u-tokyo.ac.jp/

Introduction and Organization
This department was established in 1992. Three
faculty members currently serve the department: aprofessor, a lecturer, and an assistant professor.
Enrolled at present is 1 doctoral student, and 1
administrative staff.

Education
1. Graduate Courses, School of Health Sciences andNursing (credit hours)
Advanced Family Nursing I (2)Advanced Family Nursing II (2)Laboratory and/or Field Work on Family Nursing(16)
Practicum in Translational Research Nursing (2)2. Undergraduate Courses for Students in the Schoolof Integrated Health Sciences (credit hours)
Family Health (2)Health Communication (1)3. Undergraduate Courses for Nursing Students in the
School of Integrated Health Sciences (credit hours)
Pediatric and Child Health Nursing (4)Clinical Practicum in Pediatric and Child HealthNursing (2)Integrated Clinical Practinum in Nursing (1)Research
Our department research family with healthproblems, developmental task or encounter withchanges in the community to which the family belongs.
We aim to reveal the fluctuation that have occurred in
the family system and create family support. Our
on-going, specific research theme include thefollowing:
1. Mental health and childcare Support during
family formation;
2. Development and dissemination of nursing carefocusing on attachment styles;
3. QOL for cancer patients and their families;
4. Development of a Pediatric Quality of Life (QOL)
Inventory for children with chronic illness andtheir parents;
5. Lifetime support for survivors of childhood
cancer and their families: treatment and care in
their late effects, special needs education, andworking;
6. Transitional care for children, adolescent andyoung adult with childhood-onset chronic
diseases;
7. Research about prevention of deterioration of
postpartum depression, child abuse and neglect;
8. Support for bereavement from family members.
Regarding the "Development and dissemination ofnursing care focusing on attachment style," we havebeen disseminating the Attachment Style Interview(ASI) developed by Professor Bifilco in the UK which
is translated into Japanese version as ASI-J. We also
completed a translated version of the ASI-J for304

children between 2019 and 2021, and conducting its
reliability and validity studies. Currently, we areconducting online training of the ASI-J for researchers,
clinical practitioners, and graduate students.
Studies on “Development of a Pediatric Quality ofLife (QOL) Inventory for children with chronic illness
and their parents” and “Lifetime support for survivorsof childhood cancer and their families: treatment andcare in their late effects, special needs education, andworking” have been ongoing, in collaboration withpediatric cancer researchers and a variety of family
support organizations across the country. Funding forthese research projects was granted through a
2004-2006 Ministry of Education, Culture, Sports,
Science and Technology Grant-in-Aid for Scientific
Research, and currently through a Practical Research
for Innovative Cancer Control (AMED) and a
2014-2016 Ministry of Education, Culture, Sports,
Science and Technology Grant-in-Aid for Scientific
Research. Based on the department’s rich collective
research experiences, we founded the Center for
Quality-of-Life Research in April 2012 to study QOL
across wide developmental stages and healthconditions. Using this platform, we aim to accumulate,integrate, and disseminate scientific research andknowledge on QOL in a more systematic manner.
Studies focusing on transition such as “Transitionalcare for children, adolescent and young adult withchildhood-onset chronic diseases” in patients withchild chronic diseases has been conducted since 2016.
We established a transition outpatient clinic in the
University of Tokyo Hospital in June 2016 and havebeen providing transitional cares for patients withcongenital heart disease, epilepsy, chromosomal
abnormality, hematologic disease, and endocrine
disease in the clinic. We also developed the tool “My
Health Passport” in order for patients to summarize
the information about their disease and share theirexperiences with others (e.g., friends and coworkers)
and established evidence of its effectiveness. We
collaborate with the evidence-based clinic, with regard
to research, practice and graduate education.
In addition, we hold bimonthly family nursing
research seminar, whereby deeper understanding offamily nursing practice and research are promoted. In
this we aim to enhance the quality of clinical practiceand research in family nursing and contribute to theestablishment of the science of family nursing.

Publications
1.

2.

3.

4.

5.

Nakahachi T, Ishii R, Canuet L, Sato I,
Kamibeppu K, Ueda M, Ueno K, Iwase M.
Influence of mood states on the correlation
between changes in oxygenated hemoglobin
concentration and behavioral performance during
Tetris gameplay in the frontal cortex. Cognition& Rehabilitation. 2021; 2(1): 128-30.
Kita S, Sato I, Sakka M, Soejima T, Kamibeppu
K. Does the use of childcare services reduce theimpact of intimate partner violence on the qualityof life of children?: Multiple-group structural
equation modeling. Applied Research in Qualityof Life. 2021; 16: 1825-45.
Morisaki-Nakamura M, Suzuki S, Kobayashi A,
Kita S, Sato I, Iwasaki M, Hirata Y, Sato A, Oka
A, Kamibeppu K. Development and validation ofa Japanese version of the Transition-Q. Pediatrics
International. 2021; 63, 270-8.
Sakka M, Kita S, Sato I, Soejima T, Eguchi H,
Tokita M, Yamamoto-Mitani N, Shimazu A,
Kamibeppu K. Reliability and validity of theJapanese version of the Caregiving Interface
Work Scale in employed Japanese family caregivers. Geriatrics & Gerontology International.
2021; 21: 254-61.
Sakai S, Nagae H, Miyashita M, Harasawa N,
Iwasaki T, Katayama Y, Takenouchi S, Ikeda M,
Ito M, Tamura K. Developing an instrument toassess the readiness for advance care planning.
Journal of Pain and Symptom Management.
2021:, 63(3): 374-386

305

Department ofCommunity Health Nursing /Public Health Nursing
Professor (concurrent)
Noriko Yamamoto-Mitani, Ph.D., R.N., P.H.N.

Lecturer (~May, 2021)
Takashi Naruse, Ph.D., R.N., P.H.N.

Assistant Professor
Riho Iwasaki, Ph.D., R.N., P.H.N.
Chikako Honda, Ph.D., R.N., P.H.N.
Yuka Sumikawa, Ph. Ph.D., R.N., P.H.N.

Homepagehttps://chiikikango.m.u-tokyo.ac.jp/

Introduction and Organization
Department of Community Health Nursing wasestablished in June 1992. Department of Public HealthNursing was established related to opening of mastercourse for public health nurses in 2006. In addition,
program for public health nurse license was started in2014, and our department is in charge of it.

Teaching activities
In the undergraduate program, we lecture about
fundamental methodologies and theories of healthpromotion for individuals, families, and specificpopulations living in the community. The titles are
below; Home Health Nursing, Community HealthNursing, Home Health Nursing Practice. There is a
total of four credits of lectures and two credits ofnursing placement training.
In the graduate program, we lecture about theadvanced methodologies and theories in community
health nursing and public health nursing. The titles are
below; Advanced Community Health Nursing I,

Advanced Community Health Nursing II, Advanced
Community Health Nursing Seminar I, II and PracticeI, II. There are a total of 12 credits: 4 credits oflectures and 8 credits of exercises and practicaltraining.
We also provide additional eight kinds of lectures/practical training as a part of the education programfor public health nurse licenses. The titles are below;
Skills for Public Health Nursing I, Skills for Public
Health Nursing II, Public Health Nursing I, Public
Health Nursing II, Public Health Nursing III, Public
Administration for Nurses, Public Health Nursing
Practice I, Public Health Nursing Practice II. There are
12 credits of lectures and five credits of practicaltraining.
And we also assist undergraduate/graduate students
with their thesis.

Research activities
Our research focuses on the development andevaluation of health care programs, establishment of306

community health care systems, and standardizationof skills among public health nurses in response to thehealth care needs of individuals, families, aggregatesand communities. Our research is supported by aGrant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science andTechnology, Health Science research, and otherfoundations.
Ongoing research projects in our department are listed
below.
1. Developing a community care system and fosteringcollaboration between home-care service providers.
Fostering collaboration between home-care service
providers is an international concern in community
care, especially elderly health care. We are conducting
a study to measure the status of collaboration between
care providers in a community setting; it also aims todevelop efficient and feasible strategies to improve
this status.
2. Discharge planning
Discharge planning is an interdisciplinary process that
is ideally available to aid patients and their families indeveloping a feasible plan for the next step of care.
Demand for discharge planning is increasing. We areattempting to standardize discharge planning activities
and develop outcome indicators and an educational
program on discharge planning for ward nurses. We
are also conducting research on the discharge planningsystem, developing guidelines for multi-sectional andinter-agency cooperation among nurses, nurses’
support at outpatient settings.
3. Support for families with infants and children
Recently, custodial parents have faced manydifficulties and challenges. To address this, we areconducting research on children's injury prevention
and social environments for child-rearing parents.
4. Community health care for the elderly
We are conducting research on the health of theelderly to support favorable living conditions for thispopulation. Our research includes (1) identification ofservice needs among frail elderly persons incommunity dwellings, (2) evaluation of community

care services’ impact on the elderly and their family
caregivers, and (3) the development of an approach
aimed at providing care for the terminally ill incommunity settings (e.g., monitoring of resident
transfers).
5. Skills of public health nurses
Public health nurses use high-level support skills;
however, many of these skills have not been identified
through research. We aim to identify and standardize
the skills of public health nurses, focusing inparticular on skills regarding new community
diagnostic method and group dynamics.

References
1.

2.

3.

4.

5.

6.

Yoshioka-Maeda K, Honda C, Iwasaki-Motegi R.
Development of a Family-Friendly System forJapanese Parents Infected With COVID-19.
Asia-Pacific journal of public health. 2021, 33(1)145 - 146. doi: 10.1177/1010539520984361
Matsumoto H, Kageyama M, Yamamoto-Mitani
N, Nagata S. The Use of a Public Space in a
Public Housing Complex by Senior Citizens: A
Qualitative Study. Journal of Aging andEnvironment 2021, 35(2), p.107-124.
Sumikawa Y, Yamamoto-Mitani N. Transitionalcare during COVID-19 pandemic in Japan: Calls
for new strategies to integrate traditional
approaches with information and communication
technologies Bio Science Trends. 2021, 15(1),p.55-57. doi: 10.5582/bst.2021.01056.
Honda C, Naruse T, Yamana H, YamamotoMitani N. Infant Injury Prevention Education forPregnant Women Attending Antenatal Class: A
Quasi-Experimental Study. International Journalof Environmental Reserch and Public Health.
2021, 18(18), 9393. doi.org/10.3390/ijerph18179
393
Honda C, Sumikawa Y, Yoshioka Maeda K,
Iwasaki Motegi R, Yamamoto Mitani N.
Confusions and responses of managerial publichealth nurses during the COVID-19 pandemic in
Japan. Public health nursing. 2021,39,161-169.
doi.org/10.1111/phn.13011
Sumikawa Y, Honda C, Yoshioka-Maeda K,
Yamamoto-Mitani N. Characteristics of COVID-

307

7.

8.

9.

10.

11.

12.

13.

19-related free telephone consultations by publichealth nurses in Japan: A retrospective study.
Healthcare. 2021, 9(1022). doi.org/10.3390/
healthcare9081022
Yoshioka-Maeda K, Sumikawa Y, Tanaka N,
Honda C, Iwasaki-Motegi R, Yamamoto-Mitani
N. Content Analysis of the Free COVID-19
Telephone Consultations Available during theFirst Wave of the Pandemic in Japan. Healthcare.
2021. 9(11), 1593. doi.org/10.3390/healthcare911
1593
Naruse T, Yamamoto-Mitani N. Service Use
Objectives among Older Adult Day Care Clientswith Disability in Japan. Nursing reports. 2021,
11(3), 608-614. doi.org/10.3390/nursrep110300
58.
Yamamoto-Takiguchi N, Naruse T, Fujisaki-SuedaSakai M, Yamamoto-Mitani N. Characteristics ofPatient Safety Incident Occurrences Reported by
Japanese Homecare Nurses: A Prospective
Observational Study. Nurs Rep. 2021;11(4):9971005. doi: 10.3390/nursrep11040090.
Matsumoto H, Maeda A, Igarashi A, Weller C,
Yamamoto-Mitani N. Dementia education andtraining for the general public: a scoping review.
Gerontology & Geriatrics Education. 2021. Nov(18), 1–31. doi.org/10.1080/02701960.2021.1999
938.
Matsumoto H, Kawagoe M, Hotta S. Older
Adults Used Fewer Home Care Services During
The COVID-19 Pandemic: Findings From A
Secondary Analysis Of An Urgent Survey In
Japan. Annals of Geriatric Medicine andResearch. 2021. 25(4), 286–93. doi.org/10.4235/
agmr.21.0108.
Igarashi A, Matsumoto H, Takaoka M, Kugai H,
Suzuki M, Murata S, Miyahara M, YamamotoMitani N. Building Relationships Between
Community Care Professionals and Convenience
Stores in Japan: Community-Based Participatory
Research. Progress in Community HealthPartnerships: Research, Education, and Action.
2021 (in printing).
Sumino K, Iwasaki R, Naruse T, YamamotoMitani N. The Background of Obtaining a Health
Checkup among Middle-aged People in Rural
Areas Who Have national health Insurance: A

Qualitative Research (in Japanese). Jpn Health &Huan Ecology. 2020, 87(4), p161-172.

Health Sciences and Nursing
3. Clinical Nursing

309

Department of GerontologicalHome Care and Long-term Care
Nursing/Palliative Care Nursing
Professor
Noriko Yamamoto-Mitani, Ph.D., R.N.

Associate Professor
Ayumi Igarashi, Ph.D., R.N.

Assistant Professor
Mariko Sakka, Ph.D., R.N.
Chie Fukui, Ph.D., R.N.

Homepage

http://www.adng.m.u-tokyo.ac.jp/

Introduction and Organization
The Department of Adult Health Nursing/ Palliative
Care Nursing has almost 50 years of history andtradition. Originally the department was started as the
Department of Adult Health in 1965 and it underwent
several re-organizations. The current structure with
two sub-divisions of Adult Health Nursing and
Palliative Care Nursing has started in 2006. Further,
Adult Health Nursing was renamed to GerontologicalHome Care and Long-term Care Nursing in 2016.
Noriko Yamamoto-Mitani has been responsible foradministration as a department chair since 2012.

Education
In the undergraduate program, our department is incharge of the lectures and clinical practicums for adult
health nursing. In graduate education, we aim to
educate students into independent researchers andcompetent clinicians who effectively use research. For
this purpose, we respect each student’s researchinterest that they derived from their clinicalexperiences. Each student completes his/her Master’s
thesis or doctoral dissertation from developing

research question from their own scientific interests
regarding nursing practice for older people or adults inchronic stage.
In education, we emphasize critical thinking
process as a researcher who conduct unique andoriginal research: from cultivating perspectives as a
researcher to come up with original research topic,
developing research topic into unique researchquestions/ hypotheses, choosing appropriate researchmethods, and to developing valid research protocols.

Research
In research, we aim to contribute to the development of nursing science and improvement in quality ofnursing practice through collaborative research withclinicians. Especially we aim to develop new nursing
knowledge grounded on Japanese culture, as needed in
tomorrow’s aged society.
Faculty members conduct studies on various topics
in the field of adult and gerontological nursing.
As research methods, along with conventional
statistical methods, we often utilize qualitative
methods to understand experiences of individual
patients and/or nurses and to conceptualize and310

theorize them.
1) Quality assurance and improvement for long-termcare for older people
The goal of long-term care nursing is to allow older
adults live as high-quality lives as possible, even withdiseases/disabilities; the paradigm of long-term care isdifferent from that of acute care that typically aim tohave the patients recover promptly from disease
conditions. There has not been enough attention to
long-term care nursing in today’s healthcare practice;there has been little research on quality assurance andimprovement in long-term care field in Japan. In thisdepartment, we have been conducting multiple studies
on long-term care in facilities and homecare nurse
agencies regarding care quality assurance andimprovement.
First, we attempt to develop intervention models toimprove care quality in close collaboration withclinicians, including nurses and care workers. We aim
to develop sustainable systems to improve their dailycare practice, collaborating with nurses at long-termcare facilities and homecare nurse agencies.
Second, we develop indicators to assess quality oflong-term care, including home care nursing. We havebeen developing them as a part of overall assessment
system needed for long-term care nursing.
Quality assurance and improvement for long-termcare facilities and home-care nurse agencies grow inimportance, given the educational opportunities forhealthcare provider working at long-term carefacilities and homecare nurse agencies are limited
compared to that working at critical hospital.

elderly persons by the community. As one of themeasures to solve the problem, the evaluation of theappropriateness of the public services in thecommunity is necessary. We have been examining
what combination of services the senior adults areusing and what factors are related to that use. We also
examine the outcomes affected by the combination of
the used services.
In addition, in the integrated community care, theutilization of the local resources, including
nongovernmental services, is demanded. We havediscussed the possibility of utilizing convenience
stores, which exist closely in local communities inJapan, as a hub of the elderly support. We haveconducted action research to promote collaboration
with the convenience stores in the elderly support incommunity.
4) End-of-life care decision making in communitydwelling older people
We conduct research about end-of-life carepreference of community dwelling elderly people(including facility for the elderly). In the Asian region,
Japan, Hong Kong, and South Korea, which are aging
societies, need to promote advanced care planning,and has been designed institutional plan. By
conducting collaborate research in the three countries,
we attempt to clarify common issues in the Asian
region and problems inherent to Japan and propose
concrete policies that the administration should do.
Hence, we aim to contribute to promotion ofAdvanced Care Planning considering cultural factor.

2) Establishing a case study method to develop
nursing science from clinical sites
We attempt to develop a new research method thatclinicians could use to conduct effective case studies.
Although case study has been used for long time, it
has not had a standardized method. We aim to develop
a protocol on conducting case study that contributes todevelop nursing science.

5) Supporting employed family caregivers
In the super-aged society, the number of family
members who have two roles, working and providing
care to their own parents, are increasing. Our
department contribute to the development of aprogram for employed family caregivers to prevent
leaving their job because of care giving for theirparents with dementia and enhance their work-lifebalance.

3) Establishment of support system for older people
in the integrated community care
In the Japanese aged society, it is an urgent problem
to establish a local structure supporting the life of the6) Prevention of turnover among homecare nurses
who support community dwelling persons
Homecare nursing is one of the services which areessential to support community-dwelling persons. We

311

have conducted a cohort study to examine the factors
related to actual homecare nurse’s turnover.
Furthermore, we have developed and evaluated thecase-based program to prevent homecare nurse’turnover.
We also conduct studies on a range of topics innursing of chronic conditions, from preventive to
end-of-life phase. We have been conducting studies
which are expected to allow us to understand the stateof individuals who require nursing in those periods
and investigate effective and efficient nursing care forsuch individuals.

6.

7.

8.

Publications
1.

Giannetta N, Dionisi S, Stievano A, Eltaybani S,
Abdelgawad ME, Katigri MR, Azadboni TT,
López Soto PJ, Morales-Cané I, Ali I, Urban J,
Shrestha S, Christensen M, Voutilainen A,
Vaajoki A, Hamdan K, Rubicini G, Rivera Pizarro
JY, Liquori G, Cassar M, Trapani J, Rocco G, Orsi
GB, Di Simone E, Di Muzio M. Comparison
across 12 countries on knowledge, attitude, andbehavior scores about medication errors in
Intensive Care Units: an international study. Eur
Rev Med Pharmacol Sci. 2021;25(23):7223-7230.
2. Eltaybani S, Abdelhalim GE, Abdelgawad ME.
Nursing students' and educators' experience withelearning during a pandemic: An online survey.
Nurs Forum. 2021;56 (4) :878-888.
3. Eltaybani S, Ahmed FR. Family satisfaction in
Egyptian adult intensive care units: A mixedmethod study. Intensive Crit Care Nurs.2021;66:103060.
4. Lepore M, Edvardsson D, Meyer J, Igarashi A.
How long-term care quality assurance measures
address dementia in Australia, England, Japan,
and the United States. Aging and Health Research.
2021; 1(2):100013.
5. Yamamoto-Takiguchi N, Naruse T, FujisakiSueda-Sakai M, Yamamoto-Mitani N.
Characteristics of Patient Safety Incident Occurrences
Reported by Japanese Homecare Nurses: A
Prospective Observational Study. Nurs Rep. 2021
Dec 14;11(4):997-1005.

9.

10.

11.

12.

13.

14.

Bowers BJ, Chu CH, Wu B, Thompson RA,
Lepore MJ, Leung AYM, Brunkert T, Sharew NT,
Yamamoto-Mitani N, Mateos JT, McGilton KS.
What COVID-19 Innovations Can Teach Us
About Improving Quality of Life in Long-Term
Care. J Am Med Dir Assoc. 2021 May;22(5):929-932.
Li CC, Yamamoto-Mitani N. Ward-level nurse
turnover and related workplace factors inlong-term care hospitals: A cross-sectional survey.
J Nurs Manag. 2021 Sep;29(6):1587-1595.
Sumikawa Y, Yamamoto-Mitani N. Transitionalcare during COVID-19 pandemic in Japan: Calls
for new strategies to integrate traditional
approaches with information and communication
technologies. Biosci Trends. 2021 Mar 15;15(1):55-57.
Eltaybani S, Yamamoto-Mitani N, Ninomiya A,
Igarashi A. The association between nurses'
burnout and objective care quality indicators: across-sectional survey in long-term care wards.
BMC Nurs. 2021 Feb23;20(1):34.
Fukui C, Igarashi A, Noguchi-Watanabe M,
Sakka M, Naruse T, Kitamura S, Inagaki A,
Takaoka M, Kobayashi H, Yasaka T, YamamotoMitani N. Development of quality indicators forevaluating the quality of long-term care. Geriatr
Gerontol Int. 2021 Apr;21(4):370-371.
Eltaybani S, Yasaka T, Fukui C, Inagaki A,
Takaoka M, Suzuki H, Maruyama M, YamamotoMitani N. Family-oriented interventions inlong-term care residential settings: a scoping
review protocol. JBI Evid Synth. 2021 Feb 9.
Sari DW, Noguchi-Watanabe M, Sasaki S, Sahar
J, Yamamoto-Mitani N. Estimation of sodium andpotassium intakes assessed by two 24-hour urine
collections in a city of Indonesia. Br J Nutr. 2021
Nov 28;126(10):1537-1548.
Sakka M, Kita S, Sato I, Soejima T, Eguchi H,
Tokita M, Yamamoto-Mitani N, Shimazu A,
Kamibeppu K. Reliability and validity of theJapanese version of the Caregiving Interface
Work Scale in employed Japanese family
caregivers. Geriatr Gerontol Int. 2021 Feb;21(2):254-261.
Eltaybani S, Igarashi A, Yamamoto-Mitani N.
Palliative and end-of-life care education in312

prelicensure nursing curricula: A nationwide
survey in an Arab country. Nurse Educ Today.
2021 Jan;96:104644.
15. Kawakami A, Kwong EW, Lai CK, Song MS,
Boo S, Yamamoto-Mitani N. Advance careplanning and advance directive awareness among
East Asian older adults:Japan, Hong Kong andSouth Korea. Geriatr Gerontol Int. 2021 Jan;
21(1):71-76.
16. Noguchi-Watanabe M, Yamamoto-Mitani N,
Nagami Y, Eltaybani S, Inagaki A, Taniguchi Y.
Homecare nurses' length of conversation andintention to remain at the workplace: A multilevel
analysis. J Nurs Manag. 2021 May;29(4):721730.

313

Department ofMidwifery and Women's HealthProfessor
Megumi Haruna, Ph.D., R.N.M.

Assistant Professor
Emi Sasagawa, Ph.D., R.N.M.

Assistant Professor
Kaori Yonezawa, Ph.D., R.N.M.

Assistant Professor
Yuriko Usui, Ph.D., R.N.M.

Homepage

http://midwifery.m.u-tokyo.ac.jp/

Introduction and Organization
The Department of Midwifery and Women’s Healthwas established in 2002.
It has 4 faculty members introduced above, 23
graduate students (12 in master’s courses, 11 indoctoral courses), and 10 visiting researchers.

Teaching activities
We have graduate and undergraduate courses.
1. Graduate Courses, School of Health Sciences andNursing1) Advanced Midwifery and Women’s Health I(2 credits, lectures)
2) Advanced Midwifery and Women’s Health II(2 credits, lectures)
2. Graduate Courses, School of Health Sciences andNursing for midwifery
1) Midwifery I (2 credits, lectures)
2) Midwifery II (2 credits, lectures)
3) Midwifery III (2 credits, lectures)
4) Midwifery IV (2 credits, lectures)
5) Midwifery V (2 credits, lectures)

6) Midwifery VI (1 credit, lectures)
7) Clinical Practicum of Administration for
Midwifery (1 credit, practices)8) Clinical Practicum in Midwifery I(2 credits, practices)9) Clinical Practicum in Midwifery II(8 credits, practices)
3. Undergraduate Courses of Nursing, School of
Health Sciences and Nursing
1) Maternal-Newborn Nursing (2 credits, lectures)
2) First AID course (1 credit, lecture)3) Clinical Practicum in Maternal-Newborn
Nursing (2 credits, practices)

Research activities
Our research activities encompass the field ofmaternal and child health emphasizing on the
promotion of women’s health and quality of life at
every stage of life.
We aim to conduct the following research projects:
1. Creating evidence of health guidance during
pregnancy
1) Healthy lifestyle: Adequate maternal nutrition,weight management, exercise, physical activity,

314

sleep, and mental health are needed to ensure ahealthy lifestyle among pregnant women.
We aim to conduct the Japan Pregnancy, Eating,
Activity, Cohort Study (J-PEACH study) toprovide evidence for appropriate healthguidance. It investigates maternal body weight,
glucose and lipid metabolite biomarkers,
nutritional intakes, and physical activities tooptimize weight management and a healthy
lifestyle during pregnancy to prevent adverse
perinatal outcomes including low birth weight.
2. Development of a support system for reliablechildbirth1) Midwifery care for positive childbirth experiences
This study evaluates the care provided by
midwife-led system and in-hospital midwifery
clinic with the aim of building a positive andefficient midwifery care for a positive birthexperience for the mother.
2) “Fear of childbirth” and psychosocial factors
among pregnant Japanese womenThis study aims to identify the psychosocial risk
factors of intense fear of childbirth.
3) Development of assessment methods of birthcanal using transperineal ultrasonography
This study aims to develop the objective
assessment methods of birth canal and theassociation of birth canal and delivery modeusing transperineal ultrasonography.
4) Development of the strategy for safe delivery in
El Salvador
To reduce the maternal mortality ratio in El
Salvador, a program for humanized childbirth
based on scientific evidence that leads tomaternal safety and comfort during childbirth isdeveloped.
5) Evaluation of learning efficacy of Virtual
Reality on midwifery education
Collaborative research between the Universityof the Sunshine Coast, Queensland, Australia
and the Waikato Institute of Technology, New
Zealand is conducted to create and evaluate
educational content related to midwifery using
virtual reality technology. Furthermore, a 360°
camera is being used to create teaching materials

and to study its effectiveness in midwifery
education.
6) Development and effectiveness of an online
Japaneseversionofmindfulness-basedchildbirth and parenting programThis study aims to develop a short online
Japanese version of the Mindfulness-BasedChildbirth and Parenting (MBCP) program andto investigate the program’s effectiveness on
women’s prenatal mental health.
3. Development of a support system for postpartum
body management
1) Pelvic floor disorders among postpartum womenThis study evaluates the effect of pelvic floor
muscle training in prevention of postpartum
pelvic floor disorders (e.g., urinary incontinence). Furthermore, this study aims to develop
and implement a pelvic floor muscle training
program.
4. Development of a support system for women’s
health1) Health Support for working mothers and womenThis study investigates the cadences of daily lifeand conditions of sleep such as excessive
daytime sleepiness and other related factors
among working mothers. Furthermore, it also
explores factors associated with work
engagement among working pregnant women.
2) Support for breastfeeding mothers and babies
This study aims to develop the Japanese versionof the Infant Breastfeeding Assessment Tool
(IBFAT), to assess the instinctive feeding
behavioral reflexes of newborns, and explore
factors affecting the IBFAT.
5. Creating evidence of health guidance for neonatalskin care1) Development of an effective skin careintervention to prevent neonatal skin problems.
This study investigates the effect of following amoisturizing skincare routine on improving skinbarrier functions among healthy neonates.
Moreover, we will investigate the relationshipbetween newborns’ skin problems and allergies(i.e., food allergy or atopic dermatitis).

3152) Effect of skincare on skin barrier function andnormal bacterial flora
This study investigates the effect of skin care,including bathing, on infants’ skin. It focuses onskin barrier function and normal bacterial flora
as a skin condition.

Publications
1.

2.

3.

4.

International Committee of the Japan Society of
Midwifery Education (2017 ~ 2018): ThararaSasagawa E, Ota Y, Matsuzaki M, Shimpuku Y,
Oishi T. Visualization of midwifery education in
109 countries on a world map: Secondary
analysis of the data from the International
Confederation of Midwives(ICM). Journal ofJapan Academy of Midwifery. 2021;35(1):48-56.
Kelleher, MM, Cro S, Cornelius V, Lodrup
Carlsen KC, Skjerven HO, Rehbinder EM, Lowe
AJ, Dissanayake E, Shimojo N, Yonezawa K,
Ohya Y, Yamamoto-Hanada K, Morita K, Axon
E, Surber C, Cork M, Cooke A, Tran L, Van
Vogt E, Schmitt J, Weidinger S, McClanahan D,
Simpson E, Duley L, Askie LM, Chalmers JR,
Williams HC, Boyle RJ. Skin care interventionsin infants for preventing eczema and food allergy.
Cochrane Database of Systematic Reviews. 2021;
Issue 2. Art. No.: CD013534. DOI: 10.1002/
14651858.CD013534.pub2.
Kelleher MM, Cro S, Van Vogt E, Cornelius V,
Lodrup Carlsen KC, Ove Skjerven H, Rehbinder
EM, Lowe A, Dissanayake E, Shimojo N,
Yonezawa K, Ohya Y, Yamamoto-Hanada K,
Morita K, Cork M, Cooke A, Simpson EL,
McClanahan D, Weidinger S, Schmitt J, Axon E,
Tran L, Surber C, Askie LM, Duley L, Chalmers
JR, Williams HC, Boyle RJ. Skincare interventions in infants for preventing eczema andfood allergy: A cochrane systematic review andindividual participant data meta-analysis. Clin
Exp Allergy. 2021 doi: 10.1111/cea.13847.
Shimizu S, Yonezawa K, Haruna M, Sasagawa E,
Hikita N, Minematsu T, Sanada H. Relationshipbetween the skin barrier function of 2-week old
infants after bathing and facial skin problems
during the first 6 weeks of life: A prospective
observational cohort study. Japan Journal of

Nursing Science. 2021;28:e12408. doi: 10.1111/
jjns.12408.
5. Sugawara C, Yamana H, Sasagawa E, Yonezawa
K, Hikita N, Morita K, Matsui H, Yasunaga H,
Haruna M. Factors Associated with SurgicalTreatment in Postpartum Women with Mastitis or
Breast Abscess: A Retrospective Cohort Study.
Breastfeeding Medicine. 2021;Dec 21.
6. Murakami M, Yonezawa K, Shimizu S, Haruna
M, Sasagawa E, Usui Y. Newborn-oriented andenvironmental factors for newborns' skin barrier
functions. Japan Journal of Nursing Science.
2021;e12457.
7. Shiraishi M, Matsuzaki M, Tsunematsu R,
Watanabe S, Kobayashi R, Haruna M. Effects ofIndividual Dietary Intervention on Nutrient
Intake in Postpartum Japanese Women: A
Randomized Controlled Trial. Nutrients. 2021;
13(9):3272.
8. Haruna M, Tanaka M, Nakano K, Nishihara N,
Sasagawa E, Yonezawa K, Usui Y, Hikita N,
Fujita M. A Cohort Study from Pregnancy to
Postpartum during the COVID-19 Pandemic:
J-PEACH Study. Developmental origins of healthand disease research. 2021;10(1):46-48. (inJapanese)
9. Sasagawa E, Haruna M, Misago C. Humanizationof childbirth in Latin America ： Laws andregulations of midwifery care. Journal of Japan
Academy of Midwifery, 2021;35(1):57-65. (inJapanese)
10. Sasagawa E, Haruna M, Misago C. Expansion
and adoption of the concept of “humanization ofchildbirth” in the legislation and policies of Latin
American countries. Journal of International
Health. 2021;36(2):73-87. (in Japanese)
11. Yokoyama M, Oie C, Haruna M, Yonezawa K.
The validation of predictive validity of infant ‘sskin assessment tool -Can it predict the onset of
atopic dermatitis?- Study for Nursing Education.
2021;28:112-119. (in Japanese)

316

Department of Psychiatric Nursing
Professor
Norito Kawakami, M.D., Ph.D.

Associate Professor
Yuki Miyamoto, R.N., P.H.N., P.S.W., Ph.D.

Project Research Associate
Utako Sawada, R.N., Ph.D.

Homepage http:// plaza.umin.ac.jp/heart/
Introduction and Organization
Our department was firstly established as Department of Fourth Clinical Medical Nursing in School of
Health Care and Nursing in 1957. When the School of
Health Care and Nursing was reorganized as the
School of Health Sciences in 1965, the department
was renamed Department of Mental Health. In 1992,
as School of Health Sciences became The School of
Health Science and Nursing, Department of Mental
Health became Department of Mental Health andPsychiatric Nursing. As the result of the shift to thechair system of the Graduate School of Medicine in
1996, two departments were established, Departmentof Mental Health and Department of PsychiatricNursing. Faculty, staff, and students of two departments have been working cooperatively ever since.
Our department currently has two faculty
members introduced above, a project research
associate, part-time lecturers, visiting research fellows,
8 doctoral course students, 4 master course students,
and research associates.
Our department’s mission comprises twoelements. One is to provide education and researchtraining in mental health and psychiatric nursing toundergraduate and graduate students in order toprepare students to assume leadership roles in nursing
clinical practice, administration, teaching, andresearch in this field. The other is to conduct clinicalresearch in the fields of psychiatric nursing andadvance knowledge and theory through research.
All activities of our department are conducted incollaboration with staff members in the Department of
Mental Health.

Education
Our department is responsible for giving lectureson psychiatric nursing to undergraduate students.
Other than lectures, our department provides students
opportunities to practice psychiatric nursing activities
in several relevant facilities.
Our department is also obliged to educate
graduate students in master and doctor programs in
psychiatric nursing. To accomplish this objective, ourdepartment has a specialized lecture course on
psychiatric nursing, and seminars on mental healthand psychiatric nursing for graduate students. These
activities are conducted and supervised by the faculty.
In collaboration with the department of mental health,
we also have the department seminar every
Wednesday evening, where members provide theactual plans for their own research and discuss the
topic.
We also have a variety of study clubs. We havepsychiatric nursing study club, study group for
multi-level analysis, qualitative research study group,and so on.

317

Research

Publications

Our research field covers mental health andpsychiatric nursing. Our department has many
research projects across diverse fields as follows:
study of self-management in mental health; recovery
in people with mental health difficulties; community
support system for the people with mental healthneeds; peer support; stigma; social inclusion; mental
health in people with substance use disorder orphysical diseases; mental health in nurses or otherworkers; disaster mental health nursing; traumainformed care, and reducing the use of seclusion andrestraint. We are conducting studies in collaboration
with researchers in other institutions and universities.
One of our research topics is "recovery," aconcept that has proximity and overlap with quality oflife among people who have experienced mental
health difficulties. Recovery is a dynamic concept that
includes restoring life, which means developing theindividuals' aspirations for their life and getting backthe life they want to live. In Japan, mental health careis changing and will increasingly need to emphasize
the quality of life and recovery of those who haveexperienced mental health difficulties.
Some examples of our research work on recovery
include (1) Accumulating the narratives of people whohave experienced mental illness. (2) Developing
patient-reported outcome measures that people withmental disorders feel are relevant to their lives. (3)Developing practices that enhance the well-being ofpeople with and without mental disorders. We are also
involved in a range of other projects.
It is necessary to pursue research involving
people who have experience of mental healthdifficulties. We are co-producing research with people
who have experienced mental health difficulties(patient and public involvement in designing andconducting research). There is a need to share thepremise that any person's thoughts and opinions areimportant and valuable. We aim to improve mental
health and medical welfare and to contribute to therealization of a society in which individuals feel thatthey are respected as they are.

1.

2.

3.

4.

5.

6.

7.

8.

Chiba R, Yamazaki Y, Miyamoto Y, Funakoshi A.
Related changes in personal recovery, benefit
finding, and sense of coherence among people
with chronic mental illness: a two-wave study.
The Journal of Psychology. 2021. DOI: 10.1080/
00223980.2021.1880360.
Kato Y, Chiba R, Yamaguchi S, Goto K, Umeda
M, Miyamoto Y. Association between Work
Environments and Stigma towards People with
Schizophrenia
among
MentalHealthProfessionals in Japan. Healthcare. 2021; 9(2):107. DOI: 10.3390/healthcare9020107.
Funakoshi A, Miyamoto Y. Relationships
between medical incidents, clinical competency,
and clinical experience in child and adolescent
psychiatric in patient nursing: A structural
equation modeling approach. J Child Adolesc
Psychiatr Nurs. 2021. DOI: 10.1111/jcap.12333.
Iida, M, Watanabe, K, Imamura, K, Sakuraya, A,
Asaoka, H, Sato, N, Nozawa, K, & Kawakami, N.
Development and validation of the Japaneseversion of the team job crafting scale for nurses.
Research in Nursing & Health 44.2, 2021: 329343.
Iida, M, Sasaki, N, Kuroda, R, Tsuno, K, &Kawakami, N. Increased COVID-19-related
workplace bullying during its outbreak: a2-month prospective cohort study of full-time
employees in Japan. Environmental andOccupational Health Practice, 2021.
Asaoka H, Sasaki N, Kuroda R, Tsuno K,
Kawakami N. Workplace Bullying and Patient
Aggression Related to COVID-19 and its
Association with Psychological Distress among
Health Care Professionals during the COVID-19
Pandemic in Japan. Tohoku J Exp Med. 2021;
255(4):283-289. DOI: 10.1620/tjem.255.283.
Asaoka H, Sasaki N, Imamura K, Kuroda R,
Tsuno K, Kawakami N. Changes in COVID-19
measures in the workplace: 8-month follow-up ina cohort study of full-time employees in Japan. J
Occup Health. 2021 Jan;63(1):e12273. DOI: 10.
1002/1348-9585.12273.
Imamura K, Tran TTT, Nguyen HT, Sasaki N,
Kuribayashi K, Sakuraya A, Bui TM, Nguyen

318

9.

10.

11.

12.

13.

14.

AQ, Nguyen QT, Nguyen NT, Nguyen KT,
Nguyen GTH, Tran XTN, Truong TQ, Zhang
MW, Minas H, Sekiya Y, Watanabe K, Tsutsumi
A, Kawakami N. Effect of smartphone-based
stress management programs on depression andanxiety of hospital nurses in Vietnam: athree-arm randomized controlled trial. Sci Rep.
2021 May 31; 11(1): 11353. DOI: 10.1038/
s41598-021-90320-5. PMID: 34059737; PMCID:
PMC8166974.
Sawada U, Shimazu A, Kawakami N, Miyamoto
Y, Speigel L, Leiter MP. The Effects of the
Civility, Respect, and Engagement in the
Workplace (CREW) Program on Social Climate
and Work Engagement in a Psychiatric Ward inJapan: A Pilot Study. Nursing Reports. 2021
Jun(2):320-30.
Yang CC, Watanabe K, Kawakami N. The
Associations between Job Strain, Workplace
PERMA Profiler, and Work Engagement. J Occup
Environ Med. 2021 Dec 6. DOI: 10.1097/JOM.
0000000000002455.
Watanabe K, Kawakami N. Association between
sitting time at work and the onset of major
depressive episode: a 1-year prospective cohort
study using the Bayesian regression. BMC Public
Health. 2021 Oct 29;21(1):1960. DOI: 10.1186/
s12889-021-12059-y.
Orui M, Fukasawa M, Horikoshi N, Suzuki Y,
Kawakami N. The ongoing activities of
livelihood support counselors following nuclear
disaster under the COVID-19 restrictions: A
preliminary survey. Public Health Pract (Oxf).
2021 Nov;2:100107. DOI: 10.1016/j.puhip.2021.
100107.
Kawakami N, Imamura K, Watanabe K, Sekiya Y,
Sasaki N, Sato N; SMART-CBT Project Team.
Effectiveness of an Internet-Based MachineGuided Stress Management Program Based on
Cognitive Behavioral Therapy for Improving
Depression Among Workers: Protocol for a
Randomized Controlled Trial. JMIR Res Protoc.
2021 Sep 29;10(9):e30305. DOI: 10.2196/30305.
Takano A, Fukasawa M, Watanabe K, Nishi D,
Kawakami N. Adolescent Work Values and Drug
Use in Adulthood: A Longitudinal Prospective
Cohort Study. Subst Use Misuse. 2021;56(10):

15.

16.

17.

18.

19.

20.

21.

1483-1492. DOI: 10.1080/10826084.2021.1936
055.
Sato N, Watanabe K, Kawakami N. Mediating
Effects of Work Eudemonic Well-being for the
Association Between Psychosocial Work
Environment and Overall Eudemonic Well-being
Among Japanese Workers: A Cross-sectional
Study. J Occup Environ Med. 2021 Aug 1;63(8):e542-e548. DOI: 10.1097/JOM.00000000000022
76.
Sato N, Watanabe K, Nishi D, Kawakami N.
Associations Between Personal Values and WorkEngagement: A Cross-Sectional Study Using A
Representative Community Sample. J Occup
Environ Med. 2021 Jun 1;63(6):e335-e340. DOI:
10.1097/JOM.0000000000002209.
Yang CC, Lee KW, Watanabe K, Kawakami N.
The association between shift work and possible
obstructive sleep apnea: a systematic review andmeta-analysis. Int Arch Occup Environ Health.
2021 Nov; 94(8): 1763-1772. DOI: 10.1007/
s00420-021-01675-1.
Kawakami N, Sasaki N, Kuroda R, Tsuno K,
Imamura K. The Effects of Downloading a
Government-Issued COVID-19 Contact Tracing
App on Psychological Distress During thePandemic Among Employed Adults: Prospective
Study. JMIR Ment Health. 2021 Jan 12;8(1):e23699. DOI: 10.2196/23699.
Sasaki N, Yasuma N, Obikane E, Narita Z,
Sekiya J, Inagawa T, Nakajima A, Yamada Y,
Yamazaki R, Matsunaga A, Saito T, Imamura K,
Watanabe K, Kawakami N, Nishi D. Psychoeducational interventions focused on maternal or
infant sleep for pregnant women to prevent theonset of antenatal and postnatal depression: A
systematic review. Neuropsychopharmacol Rep.
41(1):2-13, 2021
Yasuma N, Imamura K, Watanabe K, Nishi D,
Kawakami N, Takano A. Association between
energy drink consumption and substance use inadolescence: A systematic review of prospective
cohort studies. Drug Alcohol Depend. 219:
108470, 2021
Sasaki N, Imamura K, Nishi D, Watanabe K,
Sekiya Y, Tsuno K, Kobayashi Y, Kawakami N.
Internet-based acceptance and commitment

319

22.

23.

24.

25.

26.

27.

28.

29.

therapy programme 'Happiness Mom' for wellbeing: a protocol for a randomised controlled trial.
BMJ Open. 26;11(2): e042167, 2021
Sasaki N, Obikane E, Vedanthan R, Imamura K,
Cuijpers P, Shimazu T, Kamada M, Kawakami N,
Nishi D. Development and Validation of
Implementation Outcome Scales for Digital
Mental Health (iOSDMH). JMIR Formative
Research 23;5(11):e24332, 2021
Asaoka H, Koido Y, Kawashima Y, Ikeda M,
Miyamoto Y, Nishi D. Longitudinal change indepressive symptoms among healthcare professionals with and without COVID-19 vaccine
hesitancy from October 2020 to June 2021 inJapan. Industrial Health (Epub ahead of print)
Sasaki N, Akiyama H, Kawakami N, Nishi D.
Preconception menstrual cycle disorder andantenatal depression: A cross-sectional study withpre-recorded information. J Psychosom Obstet
Gynaecol. (Epub ahead of print)
Asaoka H, Koido Y, Kawashima Y, Ikeda M,
Miyamoto Y, Nishi D. Longitudinal Change of
Psychological Distress among Healthcare
Professionals with and without PsychologicalFirst Aid Training Experience during the
COVID-19 Pandemic. International Journal ofEnvironmental Research and Public Health.
18(23):12474, 2021
Hidaka Y, Sasaki N, Imamura K, Tsuno K,
Kuroda R, Kawakami N. Changes in fears andworries related to COVID-19 during the
pandemic among current employees in Japan: a
5-month longitudinal study. Public health. 2021
Sep 1;198:69-74.
Hidaka Y, Watanabe K, Imamura K, Tatha O,
Kawakami N. Reliability and validity of theChinese version of the New Brief Job Stress
Questionnaire (New BJSQ) among workers in
China. Industrial health. 2021 Nov 1.
Komase Y, Watanabe K, Hori D, Nozawa K,
Hidaka Y, Iida M, Imamura K, Kawakami N.
Effects of gratitude intervention on mental healthand well-being among workers: A systematic
review. Journal of Occupational Health, 2021;63:
e12290. DOI: 10.1002/1348-9585.12290.
Komase Y, Watanabe K, Natsu S, Kawakami N.
The effect of perceived gratitude from others on

work engagement: a cross-sectional study.
Journal of Occupational and Environmental
Medicine. 2021; 63: e592-e595. DOI: 10.1097/
JOM.0000000000002294.
30. Komase Y, Watanabe K & Kawakami N. Effects
of a gratitude intervention program on work
engagement among Japanese workers: a protocol
for a cluster randomized controlled trial. BMC
Psychol 9, 35 (2021). DOI: 10.1186/s40359-02100541-6.

320

Department ofGerontological Nursing /Wound Care Management
Professor
Hiromi Sanada, Ph.D., R.N., W.O.C.N., F.A.A.N.

Associate Professor
Gojiro Nakagami, Ph.D., R.N.

Assistant Professor
Aya Kitamura, Ph.D., R.N., Yuko Mugita, Ph.D., R.N.

Project Research Associate
Kenneth Scott Barton, M.A.

Homepage

http://www.rounenkango.m.u-tokyo.ac.jp/index-e.html

Introduction and Organization
The Department of Gerontological Nursing wasestablished in June 2003, followed by theestablishment of the Department of Wound CareManagement in April 2006. We have been promoting
the education of undergraduate and graduate students,
clinical activities in hospitals relating to pressure
injuries and diabetic foot, and research activities on
the topics of gerontological nursing, wound caremanagement, and nursing science and engineering.
Our
department
has
establishedseveraldepartments: Department of Life Support Technology(Molten), Department of Advanced Skin Care (MissParis), Department of Advanced Nursing Technology,
Department of Skincare Science, and Department of
Imaging Nursing Science. We have been promoting
collaborative research among government, industry
and academia, as well as integrating multiple
disciplines across campus.
Especially noteworthy, the Department of Advanced
Nursing Technology, which was established in
December 2012, works as a social cooperation
program to promote team nursing intervention andresearch involving the clinical division, the nursing
department at the University of Tokyo Hospital, andthe Division of Health Sciences and Nursing at theGraduate School of Medicine. Through this program,nurses can scientifically study the subject of nursing,including research in epidemiological surveys andmolecular- and gene-level topics. Furthermore, thetechnology and medical equipment developed bycompanies can be evaluated in the hospital, offering
new nursing technologies suitable for needs in clinicalsites.
In April 2017, the Global Nursing Research Center(GNRC) was established with the aim to create atransdisciplinary
researchandeducational
environment that fosters young researchers in nursing
science in order to promote care innovation. Professor
Sanada has been the director, and faculty staff
members in our department have been involved in the
Division of Care Innovation in GNRC as a concurrent
position.
Gerontological Nursing and Wound CareManagement is currently headed by one professor andassisted by an associate professor, two research

321associates, a project research associate, a project
academic specialist, an assistant clerk, five part-time
lecturers for undergraduate courses, and sevenpart-time lecturers for graduate courses. The student
body consists of six doctoral course students and six
master’s course students. Our mission statement is“We wish to create a society that respects the beautyof aging and recognizes it as to be a joyful process inlife.”a) Introduction to surgical treatmentb) Introduction to radiologyc) Surgical anesthesiad) Perioperative managemente) Clinical conditionsf) Natural history and treatment of diseasesg) Nursing pharmaceutics
The above lectures were provided through cooperationfrom the departments at The University of Tokyo
Hospital.

Teaching activities
1. Undergraduate course
For undergraduate education, our department takes
part in lectures of Health Support Practice, Overview
of Clinical Medicine, and Observation of Human
Anatomy, as well as lectures, exercises, and clinicalpractice about gerontological nursing and nursing
science and engineering.
1) Health Support Practicum (W in 2nd yr; 1
credit)Nursing is a science of searching for ways to support
health and the achievement of self-actualization, and it
is practiced in various social situations, including
hospitals, healthcare centers or medical facilities. The
aim of this practicum is for students to understand thevariety and wide potential of nursing, and to learn themethods and practices for health support throughexperiential learning of various types of nursing fromthe earliest stages of their nursing course. In 2021, we
conducted an online practicum and the program
included themes related to:a) Policy creation for solving problems confronted innursingb) Health support servicec) Nursing-based hospital managementd) Development of medical devices for supporting
patients’ lives.
2) Overview of Clinical Medicine (S1 in 3rd yr; 2credits)
The aim of this series of lectures is to learn the basic
knowledge and thought processes for understanding
clinical medicine, and to learn the pharmaceutics
required for nursing practice. The main content
themes in the 2021 session included:3) Observation of Human Anatomy (A1 in 3rd yr; 1
credit)
The aim of this series of lectures is to gain a deeper
understanding of life and learn about human anatomy
through a careful examination of “death” and “disease,”
as conceptual opposites of “life” and “health.” Themain themes in the 2021 curriculum included:a) Introduction to anatomical pathologyb) Case studiesc) Introduction to anatomicopathological researchd) Anatomy using ultrasound equipmente) Visit to specimen room4) Gerontological Nursing (A2 in 3rd yr; 2 credits)
A series of lectures with the aim of understanding thephysical, psychological, and social characteristics ofthe elderly population; to learn fundamental theories
of gerontological nursing; and to promote anunderstanding of the ailments and conditions required
to provide proper care to the elderly. The main themes
covered in the 2021 session were as follows:a) Practical simulation for gerontological nursingb) Physical, psychological, and social characteristicsof the elderly from a nursing standpointc) Geriatric syndrome and nursing (i.e., dementia,
feeding and swallowing difficulty, pressure injury,
incontinence)d) Age-related changes in the physiological systeme) Aging and dementiaf) Aging and osteoporosisg) Aging and renal function, hypertension, and strokeh) Aging and cardiovascular disordersi) Aging and respiratory disordersj) Pharmacological management of the elderlyk) Use of ultrasonography in nursingl) Nutritional management for the elderly

322m) Relationship-building and communication skills
with the elderly
A portion of the above lectures was provided throughcooperation from the Department of GeriatricMedicine and other departments at The University ofTokyo Hospital.
5) Nursing Science and Engineering (S2 in 4th yr; 2credits)
Gaining a thorough understanding of a given medical
situation, as well as determining the appropriate
medical intervention for a patient require theknowledge and skills from Nursing Science andEngineering. These include the processes involved intranslational
research:clinicalobservation,
exploration of the mechanisms underlying the patient's
symptoms, development of objective measurement
methods, and the development of devices and systems
for intervention and the clinical evaluation. This seriesof lectures is to learn about cutting-edge research, andto understand the linkage between research andclinical activities. In 2021, lectures and exercises were
given on the necessity and significance of nursing
science and engineering, research methods in nursing
science and engineering, and their applications.
6) Clinical Practicum in Gerontological Nursing(A1 in 4th yr; 2 credits)
The aim of this practicum is to gain the holistic
understanding of the elderly, learn the perspective androle functions of nursing for the elderly, and be able tothink about the issues and future of gerontologicalnursing. In 2021, the practice was conducted online
and consisted mainly of online interviews andactivities with senior volunteers, case scenario
exercises, lectures on multidisciplinary cooperation ineach geriatric care setting (hospital, geriatric healthcare facility, and home), and remote observation of
actual geriatric nursing care.
2. Graduate course
1) Gerontological Nursing I (S1; 2 credits)
The main theme of Gerontological Nursing I in 2021
was to understand the latest research related to thecare of elderly persons and to discuss future perspectives in gerontological nursing from three viewpoints:
basic biology, engineering, and clinical nursing

research. Recent research papers were selected fromthese three fields and critically evaluated.
2) Gerontological Nursing II (A1; 2 credits)
Gerontological Nursing II provided lectures regarding
recent topics around gerontological medicine andnursing from broad viewpoints, including biological,
individual, and social aspects, by part-time lecturers
and specialists from each research field. The aim of
this course was to understand and learn scientificways of thinking about gerontological considerationsof the future Japanese community. The main titles in
2021 were as follows:a) Physiological activity and deficiency of
micronutrients - with a focus on zinc - andnutritional management of pressure injuries withcomplicationsb) Gerontological nursing: dysphagiac) Nutrition management in elderly nursingd) Diabetic foot ulcer management initiatives: anattempt at globalizatione) The meeting of research, clinical practice, andeducation: Kindness is not merely for the sake ofpatientsf) Prevention of pressure injury recurrence in theelderlyg) Effects of obesity on skinh) End-of-Life care for the elderly: creating aprosperous last years
3) Wound Care Management I (S2; 2 credits)
The main purpose of Wound Care Management I in
2021 was to learn and deepen understanding of thebasic knowledge required to carry out wound nursing
research, as well as to develop a broad interest in new
knowledge and acquire an attitude and methodology
for self-study. The topics were as follows:a) Structure and function of the skin; wound healingb) Prediction and prevention of woundsc) Basics of pressure injury, nursing efforts regarding
wound cared) Assessment of woundse) Treatment and care of woundsf) Institutions and policies related to wound care andmanagement
4) Wound Care Management II (A2; 2 credits)

323

The main theme of Wound Care Management II in
2021 was to obtain deeper insight in our own researchknowledge through lectures and discussion by
specialists from various basic and advanced research
fields in the Division of Care Innovation in GNRC.
5) Master’s theses
The following research themes were submitted in2021:
 “An expert knowledge algorithm and model
predicting wound healing trends for a decision
support system for pressure injury management inhome care nursing”
 “Development of biomarkers in first-void urine
samples for urinary tract infection assessment”
 “Expression of NPPB, ITGB6, CPNE4, EML5, and
ITSN1 in exudates of infected full-thickness
wounds in rats and of critically colonized pressure
injuries of patients”
6) Doctoral theses
The following research themes were submitted in2021:
 “Investigation of the role of dysbiotic wound
microbiota on the establishment of criticalcolonization”
 “Development of a method to distinctly identify
persistent and blanchable redness by skin blotting
in mice”
 “Integration of nurse call log data and electronic
medical record records and development of a fallrisk assessment method using the integrated
database” (in Japanese)

Research activities
1. Activity policy
Our gerontological nursing research focuses on those
suffering from geriatric syndromes, such as pressure
injuries, incontinence, malnutrition, pain, dysphagia
and dementia. Our wound care management research
focuses on pressure injuries, diabetic foot ulcers, andskin tears.
The majority of our clinical research has been
conducted at The University of Tokyo Hospital. We
regularly participate in pressure injury multidisciplinary team rounds.

In July 2021, Professor Sanada chaired the 30th
Annual Meeting of the Japanese Society for Wound,
Ostomy and Continence Management and the 9th Asia
Pacific Enterostomal Therapy Nurse Association
Conference (APETNA) (held simultaneously). With
the aim of advancing academic development andimproving the quality of clinical practice in the fieldof wound, ostomy, and incontinence management in
the Asia-Pacific region, she organized the conference
under the theme "Integrating Science and Art for Next
Generation WOC Management," which was held
online and on-demand. Integrating Science and Art for
Next-Generation WOC Management. More than 2,600
participants in total attended the conference, which
was very well received both domestically andinternationally.
In September 2021, we organized the 8th
introductory seminar for bioengineering nursing
research as a webinar. In this webinar, a new researchframework “Bioengineering Nursing,” consisting of
nursing biology (which investigates, in detail, themechanisms of a target phenomenon), nursing
engineering (which develops technologies for the
clarified target), and nursing translational research(which evaluates the technologies in the clinical field
and further explores new clinical problems) was
introduced to many nursing researchers and clinicalnurses. This seminar is held annually since 2013. In
2021, the seminar was held for four days with a totalof 1,983 participants.
Professor Sanada was retiring at the end of
FY2021 and held her final lecture, "Nursing Care
Innovation," in a hybrid format at the University ofTokyo's Yasuda Auditorium in March 2022. The
number of on-site participants exceeded 280 at thevenue and 850 online. It was an opportunity to convey
to the next generation her achievements over the years
and the suggestions she has gained from them, as wellas to express her gratitude to the many people she has
connected with through her educational and research
activities. In addition, the WUWHS Lifetime
Achievement Award was presented by the World
Union of Wound Healing Societies, a federation ofwound healing-related societies from around the world,
in recognition of her many years of contributions to
the field of wound healing.
Regarding international activities, our department

324

has been promoting collaborative research withresearchers in universities around the world. Our
counterparts include University of California, Los
Angeles (USA), Florida University (USA), Curtin
University (Australia), Nottingham Trent University(UK) and Universitas Muhammadiyah Pontianak.
Professor Sanada has been working as a member inboth the Continental Board for World Union of Wound
Healing Societies and the International Board of
Directors for International Lymphoedema Framework.

athletes・Survey on the relationship between the microbiota inthe bed environment and the development ofpressure injury infections
・Survey of the effectiveness of biofilm removal on
wound healing
・ Evaluation of the effectiveness of nurses whocompleted advanced nursing procedure training
・Development of a tele-nursing system and clinicalevaluation of its effectiveness2. Research fields and themes in 2021
1) Basic experimental studies:
・Development of a novel method for controllingwound infection focusing on gene expression ofbacteria and hosts
・Evaluation of wound condition using exudates
・Skin blotting for analyzing physiological status of
the skin・ Development of a new technique for detecting
wound biofilm
・Cutaneous wound healing and diabetes mellitus
・Research on scalp care science2) Nursing engineering:・Development of a new air mattress equipped withinterface pressure-sensing system and automaticpressure control
・ Non-invasive detection of tissue injury andpre-injury status using ultrasonography and thermography
・Development of apps using communication robots
for the elderly
・Development of an absorbent pad for the preventionof incontinence-associated dermatitis
・Development of an educational system for new
visiting nurses using XR technology
・ Development of a new peripheral intravenous
catheter for catheter failure prevention3) Clinical studies:
・Novel assessment technologies for pressure injuries
・Establishment of methods for predicting skin teardevelopment
・Establishment of a novel diagnosis method for silent
aspiration
・Establishment of a novel assessment method forconstipation using ultrasonography
・Survey of the skin condition of wheelchair basketball

Several awards were given for our research, as
follows:・2021 the Japanese Society for Wound, Ostomy, andContinenceManagement
Academic
Paper
Excellence Award (July, 2021)
Kunimitsu M, Nakagami G, Kitamura A,
Minematsu T, Ogai K, Sugama J, Takada C, Sanada
H. Temporal changes in the diversity andcomposition of the bed microbiota of patients withpressure ulcers.
・10th International Lymphedema Framework Japan
Research Council Best Paper Award (September,
2021)
Dai M, Shogenji M, Matsui K, Kimori K, Sato A,
Maeba H, Okuwa M, Konya C, Sugama J, Sanada
H. Validity of pocket ultrasound device to measure
thickness of subcutaneous tissue for improving
upper limb lymphoedema assessment.
・IEEE EMBS East and Central Japan Chapter/WestJapan Chapter Young Researcher Award (November,
2021)
Noyori S, Nakagami G, Noguchi H, Mori T, Sanada
H. A Small 8-Electrode Electrical Impedance
Measurement Device for Urine Volume Estimationin the Bladder. EMBC, 2021
・51st Japan Society for Wound Healing ResearchAward (November, 2021)
Koudounas S, Minematsu T, Mugita Y, Nakagami G,
Sanada H. Development of a rat model forincontinence-associated dermatitis in patients withurinary infection.
・ The 20th Japan Academy of Nursing Science
Academic Paper Award for Excellence (December,
2021)
Yoshida M, Kagaya H, Kamakura Y, Miura Y,
Saitoh E, Okawa Y, Sanada H. Safety and the325effectiveness of a new education program for nurses
to assess swallowing function using fiberoptic
endoscopic evaluation of swallowing (FEES).
・ The 20th Japan Academy of Nursing Science
Academic Paper Excellent Award (December, 2021)
Matsumoto M, Tsutaoka T, Nakagami G, Tanaka S,
Yoshida M, Miura Y, Sugama J, Okada S, Ohta H,
Sanada H. Deep learning-based classification ofrectal fecal retention and analysis of fecal properties
using ultrasound images in older adult patients.
・ The 20th Japan Academy of Nursing Science
Academic Paper Incentive Award (December, 2021)
Abe-Doi M, Murayama R, Komiyama C, Sanada H.
Incidence, risk factors, and assessment of
induration by ultrasonography after chemotherapy
administration through a peripheral intravenous
catheter.
・ WUWHS Lifetime Achievement Award Awards(March, 2022)
Sanada H

References
1.

2.

3.

4.

Astrada A, Nakagami G, Minematsu T, Goto T,
Kitamura A, Mugita Y, Sanada H. Concurrent
validity of biofilm detection by wound blotting
on chronic wounds. J Wound Care.
2021;30(Sup4): S4-S13.
Miura Y, Tamai N, Kitamura A, Yoshida M,
Takahashi T, Mugita Y, Tobita I, Arita M, Urai T,
Dai M, Noguchi H, Matsumoto M, Mukai K,
Nakagami G, Ota E, Sugama J, Sanada H.
Diagnostic accuracy of ultrasound examination in
detecting aspiration and pharyngeal residue inpatients with dysphagia: A systematic review andmeta-analysis. Jpn J Nurs Sci. 2021;18:e12396.
Sari WD, Minematsu T, Yoshida M,
Noguchi-Watanabe M, Tomida S, Kitamura A,
Abe M, Sanada H. Validity of skin blot
examination for albumin and nerve growth factor
β to detect itching of the skin in Indonesian older
adults. J Tissue Viability. 2021;30(1):42-50.
Tamai N, Minematsu T, Sanada H. Changes in
scalp epidermal thickness using in vivo
reflectance confocal microscopy in breast cancer
patients undergoing chemotherapy: a case series.
J Nurs Sci Eng. 2021;8:143-50.

5.

Shibata K, Ogai K, Ogura K, Urai T, Aoki M,
Arisnandi D, Takahashi N, Okamoto S, Sanada H,
Sugama J. Skin physiology and its microbiome asfactors associated with the recurrence of pressure
injuries. Biol Res Nurs. 2021;23(1):75-81.
6. Nagata T, Noyori S, Noguchi H, Nakagami G,
Kitamura A, Sanada H. Skin tear classification
using machine learning from digital RGB image.
J Tissue Viability. 2021;30(4):588-93.
7. Koudounas S, Mugita Y, Minematsu T, Nakagami
G, Weller C, Sanada H. Does the presence ofbacterial urinary infection contribute to thedevelopmentofincontinence-associateddermatitis? A scoping review. J Tissue Viability.
2021;30(2): 256-61.
8. Takahashi T, Shintani Y, Murayama R, Noguchi
H, Abe-Doi M, Koudounas S, Nakagami G, Mori
T, Sanada H. Ultrasonographic measurement ofblood flow of peripheral vein in the upper limb of
healthy participants: a pilot study. J Jpn WOCM.
2021;25(3).
9. Minematsu T, Dai M, Tamai N, Nakagami G,
Urai T, Nakai A, Nitta S, Kataoka Y, Kuang W,
Kunimitsu M, Tsukatani T, Oyama H, Yoshikawa
T, Takada C, Kuwata M, Sanada H. Risk scoring
tool for forearm skin tears in Japanese older
adults: A prospective cohort study. J Tissue
Viability. 2021;30(2):155-60.
10. Noguchi H, Miyahara M, Takahashi T, Sanada H,
Mori T. Modeling for change of daily nurse calls
after surgery in an orthopedics ward using
bayesian statistics. Comput Inform Nurs. 2021;
39(7):375-83.
11. Murayama R, Abe-Doi M, Kogure T, Takahashi T,
Kanno C, Ishigaki M, Sanada H. The influence of
peripheral intravenous catheterization on thesleep quality of ophthalmic inpatients: An
observational study. J Nurs Sci Eng.
2021;8:134-42.
12. Shimizu S, Yonezawa K, Haruna M, Sasagawa E,
Hikita N, Sanada H, Minematsu T. Relationshipbetween the skin barrier function of 2-week old
infants after bathing and facial skin problems
during the first 6 weeks of life: A prospective
observational cohort study. Jpn J Nurs Sci. 2021:
e12408.

326

13. Tsukatani T, Minematsu T, Dai M, Tamai N,
Nakagami G, Sugama J, Takada C, Sanada H.
Polymorphism analysis of candidate risk genes
for pressure injuries in older Japanese patients: A
cross-sectional study at a long-term care hospital.
Wound Repair Regen. 2021;29(5):741-51.
14. Nakagami G, Yokota S, Kitamura A, Takahashi T,
Morita K, Noguchi H, Ohe K, Sanada H.
Supervised machine learning-based prediction for
in-hospital pressure injury development using
electronic health records: A retrospective
observational cohort study in a university
hospital in Japan. Int J Nurs Stud.
2021;119:103932.
15. Matsumoto M, Tamai N, Miura Y, Okawa Y,
Yoshida M, Igawa Y, Nakagami G, Sanada H.
Evaluation of a point-of-care ultrasoundeducation program for nurse educators. J Contin
Educ Nurs. 2021;52(8):375-81.
16. Qin Q, Oe M, Ohashi Y, Shimojima Y, Imafuku
M, Dai M, Nakagami G, Yamauchi T, Yeo S,
Sanada H. Factors associated with the local
increase of skin temperature, ‘hotspot,’ of callus
in diabetic foot: A cross-sectional study. J
Diabetes Sci Technol. 2021;19322968211011181.
17. Dai M, Minematsu T, Ogawa Y, Takanishi Y,
Sugama J, Sanada H. Subjective thermal
sensation effect of cool feeling compression
stocking for patients with lower limb
Lymphedema: A preliminary pre-post study. J Jpn
WOCM. 2021; 25(1):10-7.
18. Mugita Y, Minematsu T, Nakagami G, Sanada H.
Promoting effect of acylated homoserine lactone
on the healing of tissue damage inincontinence-associated dermatitis model rats. J
Wound Care. 2021;30(Sup9a):XIi-XIxi.
19. Abe-Doi M, Murayama R, Komiyama C, Tateishi
R, Sanada H. Effectiveness of ultrasonography
for peripheral catheter insertion and catheter
failure prevention in visible and palpable veins. J
Vasc Access. 2021;11297298211022078.
20. Abe-Doi M, Murayama R, Kawamoto A,
Komiyama C, Doorenbos A, Sanada H. Damage
to subcutaneous tissue at the catheterization site
duringchemotherapy:A
prospective
observational study using ultrasonography. Jpn J
Nurs Sci. 2021; 18(4):e12436.

21. Kunimitsu M, Kataoka Y, Nakagami G, Weller
DC, Sanada H. Factors related to the compositionand diversity of wound microbiota investigatedusing culture-independent molecular methods: ascoping
review.
Drug
Discov
Ther.
2021;15(2):78-86.
22. Hsu WJ, Minematsu T, Nakagami G, Koudounas
S, Tomida S, Nakai A, Kunimitsu M, Nitta S,
Sanada H. Identification of microRNAs
responsive to shear loading in rat skin. Int Wound
J. 2021;19(2):351-61.
23. Dai M, Minemasu T, Ogawa Y, Nakagami G,
SanadaH.
Associationofdermalhypoechogenicity and a history of cellulitis inlower extremity lymphedema patients: A
cross-sectional observational study. Lymphat Res
Biol. 2021. https://doi.org/10.1089/lrb.2021.0004
24. Kunimitsu M, Nakagami G, Kitamura A,
Minematsu T, Mugita Y, Ogai K, Sugama J, Aoki
M, Takada C, Sanada H. Dissemination of
microbiota between wounds and the beds ofpatients with pressure injuries: A cross-sectional
study. Wound Pract Res. 2021;29(2):70-6.
25. Mugita Y, Koudounas S, Nakagami G, Weller C,
Sanada H. Assessing absorbent products’
effectiveness for the prevention and managementof incontinence-associated dermatitis caused byurinary, faecal or double adult incontinence: asystematic review. J Tissue Viability. 2021;30(4):599-607.
26. Yoshinaga N, Nakagami G, Fukahori H,
Shimpuku Y, Sanada H, Sugama J. Initial impactof the covid-19 pandemic on time Japanesenursing
faculty
devotetoresearch:cross-sectional survey. Jpn J Nurs Sci.
2021;19(1):e12454.
27. Dai M, Nakagami G, Sato A, Koyanagi H, Kohta
M, Moffatt C, Murray S, Franks P, Sanada H,
Sugama J. Association between access to
specialists and history of cellulitis among patientswith lymphedema: secondary analysis using the
National LIMPRINT Database. Lymphat Res
Biol 2021;19(5):442-6.
28. Matsumoto M, Karube M, Nakagami G,
Kitamura A, Tamai N, Miura Y, Kawamoto A,
Kurita M, Miyake T, Hayashi C, Kawasaki A,
Sanada H. Development of an automatic

327

29.

30.

31.

32.

33.

34.

35.

36.

ultrasound image classification system forpressure injury based on deep learning. Appl Sci.
2021; 11(17):7817.
Haba D, Nakagami G, Minematsu T, Sanada H.
Low-frequency
vibration
promotes
AMPK-mediated glucose uptake in 3T3-L1
adipocytes. Heliyon. 2021;7(9):e07897.
Koudounas S, Minematsu T, Mugita Y, Tomida S,
Nakai A, Nakagami G, Sanada H. Inhibiting
effect of synthetic urine on the growth andmobility of Pseudomonas aeruginosa, Escherichia
coli, Proteus mirabilis and Klebsiella pneumoniae
shifts to a promoting effect during culture. J Nurs
Sci Eng. 2021;8:220-9.
Hasegawa Y, Yoshida M, Sato A, Fujimoto Y,
Minematsu T, Sugama J, Sanada H. A change intemporal muscle thickness is correlated with pastenergy adequacy in bedridden older adults: A
prospective cohort study. BMC Geriatr. 2021;
21(1):182.
Yamane T, Nakagami G, Sanada H, Oishi Y.
Hydrocellular foam dressing regulates MMP1a,
MMP9, MMP10, MMP12 and MMP13 gene
expression in periwound skin. Jpn J PU. 2021;
23(4):313-7.
Takahashi T, Murayama R, Abe-Doi M, Miyahara
M, Kanno C, Nakagami G, Sanada H. Catheter
failure in the administration of hyperosmotic
drugs through a peripheral vein and vascular
selection: A retrospective cohort study. Drug
Discov Ther. 2021;15(5):236-40.
Maeda T, Tamai N, Minematsu T, Noguchi H,
Yabunaka K, Nakagami G, Neya M, Sanada H.
The relationship between pressure injuries anddynamic buttock pressure distributions duringperformance in wheelchair basketball athletes.
Wound Pract Res. 2021;29(4): 211-8.
Fujisawa C, Hamanoue M, Kawano Y, Murata D,
Akishima-Fukasawa Y, Okaneya T, Minematsu T,
Sanada H, Tsuburaya K, Isshiki T, Mikami T,
Hanawa T, Akasaka Y. The role for
miRNA146b-5p in the attenuation of fibrosis andangiogenesis by targeting PDGFRα in skinwounds.
J
InvestDermatol.
2021;S0022-202X(21)02619-1.
Kitamura A, Nakagami G, Matsumoto M,
Hayashi C, Kawasaki A, Sanada H. Effectiveness

37.

38.

39.

40.

41.

42.

43.

of a robotic mattress with automatic inner-air celladjustment and continuous pressure mapping on
prevention of pressure ulcer deterioration in a
critically ill patient with a pressure ulcer in thesacrum. J Jpn WOCM. 2021;25(4):689-96.
Kitamura A, Nakagami G, Minematsu T,
Kunimitsu M, Sanada H. Establishment of an
infected wound model by bacterial inoculation on
wound surface in rats. J Nurs Sci Eng.
2021;9:1-8.
Takizawa C, Kitamura A, Nakagami G,
Matsumoto M, Hayashi C, Kawasaki A, Sanada
H. The relationship between the temperature
distribution detected by thermography andsuspected deep tissue injuries. Jpn J PU. 2021;
24(1):14-28.
Higashimura S, Tamai N, Nakagami G, Tobe H,
Sanada H. A pilot epidemiological study on
chronic dehydration of older adults in home caresetting. J Nurs Sci Eng. 2022;9:123-35.
Matsumoto M, Misawa N, Tsuda M, Manabe N,
Kessoku T, Tamai N, Kawamoto A, Sugama J,
Tanaka H, Kato M, Haruma K, Sanada H,
Nakajima A. Expert consensus document:
diagnosis for chronic constipation with faecal
retention in the rectum using ultrasonography.
Diagnostics. 2022;12(2):300.
Takahashi T, Nakagami G, Murayama R,
Abe-Doi M, Matsumoto M, Sanada H. Automaticvein measurement by ultrasonography to prevent
peripheral intravenous catheter failure for clinicalpractice using artificial intelligence: development
and evaluation study of an automatic detection
method based on deep learning. BMJ open. 2022;
25(3):576-84.
Nitta S, Maeda T, Koudounas S, Minematsu T,
Weller C, Sanada H. Which objective
itch-assessment tools are applicable to patientswith cognitive impairments? A scoping review.
Int J Older People Nur. 2022;e12458.
Tanabe H, Oosawa K, Miura M, Mizuno S,
Yokota T, Ueda T, Zushi Y, Nagata M, Murayama
R, Abe-Doi M, Sanada H. Effect of a thin-tippedshort bevel needle for peripheral intravenous
access on the compressive deformation anddisplacement of the vein: a preclinical study. J
Vasc Acces. 2022; 11297298221075169.

328

44. Shintani Y, Murayama R, Abe-Doi M, Sanada H.
Incidence, causes, and timing of peripheral
intravenous catheter failure related to insertion
timing in the treatment cycle in patients withhematological malignancies: a prospective
descriptive study. Jpn J Nurs Sci. 2022;e12484.
45. Noyori S, Nakagami G, Sanada H. Non-invasive
urine volume estimation in the bladder byelectrical impedance-based methods: A review.
Med Eng Phys. 2021;101:103748.
46. Abe-Doi M, Oe M, Ikeda M, Murayama R,
Komiyama C, Sanada H. Factors affecting blood
glucose self-monitoring skill acquisition: Nursing
interventions for elderly individuals with diabetes(in Japanese). Jpn J Nurs Sci. 2021;8:122-33.
47. Mitsuhashi Y, Murayama R, Mahira T, Uchida M,
Oe M, Sanada H, Komiyama C. Effect of using aperipheral intravenous catheter with a backflow
prevention valve on the operator’s fear level andvenipuncture success (in Japanese). Jpn J Nurs
Sci. 2021;8:77-85.
48. Kitamura A, Nakagami G, Watanabe C, Aoki K,
Inada H, Konya C, Taniguchi T, Yoshida M,
Tansaka H, Sanada H. Efficacy of teleconsultations with Wound, Ostomy and Continence
Nurses for patients with pressure ulcers in thecommunity setting (in Japanese). J Jpn WOCM.
2021;25(3): 654-60.
49. Matsumoto M, Ishibashi K, Kitamura A, Tamai N,
Miura Y, Takahashi T, Higashimura S, Nakagami
G, Sanada H. Development of AI-based fecal
retention assessment method for rectal ultrasonography videos taken by home-visit nurses (inJapanese). Jpn J Nurs Sci. 2021;9:34-46.

International Health
1. International Social Medicine

330

Department of
Global Health Policy
Professor
Masahiro Hashizume, MD, PhD

Associate Professor
Chris Fook Sheng Ng, PhD

Project Assistant Professor
Shuhei Nomura, PhD
Ashraful Alam, PhD
Paul Lester Chua, PhD

Homepage

http://www.ghp.m.u-tokyo.ac.jp

Introduction and Organization
As of March 2022 the department, headed by Professor
Masahiro Hashizume, included the following staff
complement; one associate professor (Chris Fook
Sheng Ng); three project assistant professors (Shuhei
Nomura, Ashraful Alam and Paul Lester Chua); 2 postdoctoral fellows; 10 adjunct lecturers; 12 doctoral
students; and 5 master’s students.
The priority areas of research are:
- Health impacts of climate, climate change and air
pollution.
- Health outcome research (mortality, morbidity anddisability; health service research; health technology
assessment and cost-effectiveness; disease modeling; and comparative risk factor analysis);- Health system performance assessment, including
the analysis of health system inputs, outputs, andimpact;- Health and foreign policy (e.g. global healtharchitecture and governance, the G7 and global
health, donor commitments, and innovations in
global health).

Finally, the fundamental role of the department is to
produce the next generations of leaders in global health.

Education
All lectures in the department are conducted in English,
to ensure that student writing and presentation skills areheld to an international standard.
Master's program
The Master's program is a demanding, interdisciplinary
program emphasizing student-directed learning,problem-solving, and the acquisition of fundamental
public health skills required for global health practices(health policy, statistics, epidemiology, and social
sciences). Students are required to complete aminimum of 30 course credits and a master’s thesis.
Beyond the program and concentration requirements,
students are encouraged to consult with faculty
advisers to choose elective courses best suited to theirneeds.
PhD program
The PhD program is designed to train the next

331

generation of leaders in global health. PhD students are
required to complete a minimum of 24-course credits
and a doctoral thesis which needs to be published in apeer-reviewed journal. PhD students without MPH
degrees should take the lectures to acquire fundamental
public health skills such as health policy, biostatistics
and epidemiology.
Global Health Policy I and IIThis course introduces the principles and theories ofglobal health problems, as well as practical applicationsof quantitative methods (demography, statistics,
epidemiology and econometrics) to analyze andinterpret issues and challenges for policy.
The followings are the topics covered in the academic
year 2020:
Introduction to demographic analysis
Sustainable Development Goals: global policy
and health agenda
Overview of the global burden of disease
Global environmental change and health
Global health governance
Population ageing and its implications for healthsystems
Health system and innovation
Innovations in maternal and child health
Infectious disease surveillance system
Economic evaluation and cost-effective analysis
Cancer epidemiology and prevention
Comparative risk assessment
Air pollution and health
Universal health coverage
Planetary health
Equity in health and social inclusion
GHP seminar
Every Tuesday, 13:00-15:00
1) Journal clubStudents present a summary of research articles fromthe major medical, social science, economics journals,
which are relevant to global health policy. The major
objective is to share knowledge, evoke debates andfacilitate discussions.
2) Research seminar
A guest speaker or a master or doctoral student presents
his/her research. There is a 15-minute presentation-

followed by a 30-minute discussion.

Research
Projections of excess mortality due to climate change- a multi-country environmental epidemiology study.
Grant-in-Aid for Scientific Research (B) (Japan
Society for the Promotion of Science) PI: Masahiro
Hashizume
Climate Change and Human Health in Asia: Current
Impacts, Future Risks, and Health Benefits of
Mitigation Policies. E-Asia as part of Strategic
International Collaborative Research Program (Japan
Science and Technology Agency) PI: Masahiro
Hashizume.
Human resource development and the development of
infectious disease epidemiological methods for the
expansion of infectious disease surveillance systems,
including COVID-19. Health and Labour Science
Research (Ministry of Health, Labour and Welfare)
PI: Masahiro Hashizume.
Use of burden of disease for health care research in thewith/post-COVID-19 era and empirical analysis.
Grant-in-Aid for Scientific Research (B) (Japan
Society for the Promotion of Science) PI: Shuhei
Nomura.

Selected Publications
1.

2.

3.

Vicedo-Cabrera AM, Tobias A, Jaakkola JJK,
Honda Y, Hashizume M, Guo Y, Schwartz J,
Zanobetti A, Bell ML, Armstrong B, Katsouyanni
K, Haines A, Ebi KL, Gasparrini A. Global
mortality burden attributable to non-optimal
temperatures. Lancet. 2022;399(10330):1113.
Chua PLC, Ng CFS, Tobias A, Seposo XT,
Hashizume M. Associations between ambient
temperature and enteric infections by pathogen: asystematic review and meta-analysis. Lancet
Planet Health. 2022;6(3):e202-e218.
Chua PLC, Huber V, Ng CFS, Seposo XT,
Madaniyazi L, Hales S, Woodward A, Hashizume
M. Global projections of temperature-attributablemortality due to enteric infections: a modellingstudy. Lancet Planet Health. 2021;5(7):e436-e445.

332

4.

5.

6.

7.

8.

Chua PLC, Ng CFS, Madaniyazi L, Seposo X,
Salazar MA, Huber V, Hashizume M. Projecting
Temperature-Attributable Mortality and Hospital
Admissions due to Enteric Infections in thePhilippines.
Environ Health Perspect. 2022;
130(2):27011.
Onozuka D, Tanoue Y, Nomura S, Kawashima T,
Yoneoka D, Eguchi A, Ng CFS, Matsuura K, Shi
S, Makiyama K, Uryu S, Kawamura Y,Takayanagi S, Gilmour S, Hayashi TI, Miyata H,
Sera F, Sunagawa T, Takahashi T, Tsuchihashi Y,
Kobayashi Y, Arima Y, Kanou K, Suzuki M,
Hashizume M. Reduced mortality during the
COVID-19 outbreak in Japan, 2020: a two-stage
interrupted time-series design. Int J Epidemiol.
2022;51(1):75-84.
Sera F, Armstrong B, Abbott S, Meakin S, O'Reilly
K, von Borries R, Schneider R, Royé D,
Hashizume M, Pascal M, Tobias A, VicedoCabrera AM; MCC Collaborative Research
Network; CMMID COVID-19 Working Group,
Gasparrini A, Lowe R. A cross-sectional analysisof meteorological factors and SARS-CoV-2
transmission in 409 cities across 26 countries. Nat
Commun. 2021;12(1):5968.
Madaniyazi L, Armstrong B, Chung Y, Ng CFS,
Seposo X, Kim Y, Tobias A, Guo Y, Sera F, Honda
Y, Gasparrini A, Hashizume M: Multi-country
Multi-city (MCC) Collaborative Research
Network. Seasonal variation in mortality and therole of temperature: a multi-country multi-citystudy. Int J Epidemiol. 2021;51(1):122-133.
Vicedo-Cabrera AM, Scovronick N, Sera F, RoyéD, Schneider R, Tobias A, Astrom C, Guo Y,
Honda Y, Hondula DM, Abrutzky R, Tong S, deSousa Zanotti Stagliorio Coelho M, Saldiva PHN,
Lavigne E, Correa PM, Ortega NV, Kan H, Osorio
S, Kyselý J, Urban A, Orru H, Indermitte E,
Jaakkola JJK, Ryti N, Pascal M, Schneider A,
Katsouyanni K, Samoli E, Mayvaneh F, Entezari
A, Goodman P, Zeka A, Michelozzi P, de'Donato
F, Hashizume M, Alahmad B, Diaz MH, De La
Cruz Valencia C, Overcenco A, Houthuijs D,
Ameling C, Rao S, Ruscio FD, Carrasco-Escobar
G, Seposo X, Silva S, Madureira J, Holobaca IH,
Fratianni S, Acquaotta F, Kim H, Lee W, Iniguez
C, Forsberg B, Ragettli MS, Guo YLL, Chen BY,

Li S, Armstrong B, Aleman A, Zanobetti A,
Schwartz J, Dang TN, Dung DV, Gillett N, Haines
A, Mengel M, Huber V, Gasparrini A. The burdenof heat-related mortality attributable to recent
human-induced climate change. Nat Clim Chang.
2021;11(6):492-500.

333

Department of Community andGlobal HealthProfessor, Academic Leader
Masamine Jimba, MD, PhD, MPH

Lecturer
Akira Shibanuma, PhD

Assistant Professors
Junko Kiriya, PhD, Ken Ing Cherng Ong, PhD

Project Assistant Professors
Rogie Royce Carandang, RPh, MPH, MSc, PhD, Jennifer Lisa Sakamoto, MSc

Website: http://www.ich.m.u-tokyo.ac.jp/en/index.html
Introduction and Organization
The Department of Community and Global Health(formerly Department of International Community
Health) has been headed by four professors since
1993: Professors Gen Ohi (1993-1996), Som-Arch
Wongkhomthong (1996-1999), Susumu Wakai(1999-2006), and Masamine Jimba (2006-present).
The mission of the department is to seek equity
and social justice in health within and across nations.
To achieve this, we aim toward:
1. Investigating how to improve health status of themost vulnerable people, in particular, indeveloping countries
2. Undertaking research on the influence of globalization on health and social development
3. Investigating mechanisms to reduce health anddevelopment inequalities between and within
nations
Our research focuses on how to promote
community-based activities and how to link abottom-up approach to national and international
policies. As of March 2022, the members of thedepartment include the department chair andprofessor, 1 lecturer, 2 assistant professors, 2 project

assistant professors, 3 secretaries, 12 visiting
lecturers, 17 doctoral students, 18 master's degree
students, and 43 visiting scientists. More than half ofthe students in this department are international
students.

International Cooperation
Activities
As part of our international cooperation activities,
we provided technical assistance of developing thematernal and child health handbook in Russia. As
Regional Vice-President for Northern Part of Western
Pacific of International Union for Health Promotion
and Education, Professor Jimba contributed toenhancing health promotion at the global andregional level. Moreover, as the Immediate–Past
President of Asia-Pacific Academic Consortium for
Public Health, Professor Jimba took a leading role in
improving public health research and practices in theregion.

Education
The main objectives of our teaching activities are
the following two:3341) To train competent researchers who understandand complement the wise activities ofpractitioners in the field.
2) To train practitioners who can also wisely carryout research in the field.
The postgraduate curriculum is composed mainlyof community and global health advanced courses,
exercises and practical work. All curricula focus oncommunity health. Our main educational activities
other than the curriculum include technicalassistance in writing Master’s and doctoral theses.
We always encourage students to publish their theses
in international journals. In addition, we urge
students to gain experiences in the field and learn
about real global health from their experiences.
Because we have many international students, alllectures, practices, and discussions are carried out inEnglish. For those who do not have health/medical
background, we provide a wide variety of curriculafrom basics to advanced level.
We also provide training run by JICA and lecturesat other universities to young leaders from overseas.

The major directions of current research haveencompassed 1) health, nutrition, and development,2) health, human rights and human security, 3)
ecological approach in infectious disease control, 4)
health promotion, 5) disaster and health, 6) humanresources for health worldwide, and 7) maternal andchild health.
Our research has been conducted in various
countries, including Nepal, Myanmar, Thailand, Viet
Nam, Lao PDR, Cambodia, Indonesia, Ghana,
Uganda, Malawi, and Zambia.

Publications
1.

2.
3.

Research
The major objectives of our research activities are
the following two:4.

1) To promote research which has a significant
impact on international and local societies
2) To promote research which contributes toendogenous development

We aim to demonstrate research findings based oncommunity-based data directly collected from thefield. Therefore, we consider fieldwork very important. At the same time, our department aims tocontribute to policy making and promoting actions
for better health by making the most of communitybased research. We carry out research by working incollaboration with different research institutes, international organizations, JICA, NGOs, and universities
in low- and middle-income countries. We conduct
research mainly in low- and middle-income
countries, but we are also involved in research inJapan.

5.

6.
7.

8.

Health-seeking behaviours in a malaria endemic
district in Lao People's Democratic Republic: amixed methods study. Ong KIC, Khattignavong
P, Keomalaphet S, Iwagami M, Brey P, Kano S,
Jimba M. BMJ Open. 2021 Dec 13;11(12):e055350.
Obituaries: Susumu Wakai. Jimba M. BMJ. 2021;
375:n2701
Multilevel factors influencing contraceptive use
and childbearing among adolescent girls in Bara
district of Nepal: a qualitative study using thesocioecological model. Sekine K, Khadka N,
Carandang RR, Ong KIC, Tamang A, Jimba M.
BMJ Open. 2021 Oct 19;11(10):e046156.
Positive deviance for promoting dual-method
contraceptive use among women in Uganda: acluster randomised controlled trial. Kosugi H,
Shibanuma A, Kiriya J, Ong KIC, Mucunguzi S,
Muzoora C, Jimba M. BMJ Open. 2021 Aug
18;11(8):e046536.
Community-based model for the delivery of
antiretroviral therapy in Cambodia: a quasiexperimental study protocol. Tuot S, Teo AKJ,
Prem K, Chhoun P, Pall C, Ung M, Ly PS, Jimba
M, Yi S. BMC Infect Dis. 2021 Aug 6;21(1):763.
壁に耳あり、耳に壁あり（？）. 神馬 征峰. 国際保健医療. 2021;36(2):91-94.
［追悼 若井 晋先生］ 若井晋：次世代へのメッセージ. 神馬 征峰. 国際保健医療. 2021;
36(2):25-34.
Roles of the Maternal and Child Health
Handbook and Other Home-Based Records on
Newborn and Child Health: A Systematic Review.

335

9.

10.

11.

12.

13.

14.

15.

Carandang RR, Sakamoto JL, Kunieda MK,
Shibanuma A, Yarotskaya E, Basargina M, Jimba
M. Int J Environ Res Public Health. 2021 Jul
13;18(14):7463.
Evaluation of a package of continuum of careinterventions for improved maternal, newborn,and child health outcomes and service coveragein Ghana: A cluster-randomized trial. Shibanuma
A, Ansah EK, Kikuchi K, Yeji F, Okawa S,
Tawiah C, Nanishi K, Addei S, Williams J,
Asante KP, Oduro A, Owusu-Agyei S, Gyapong
M, Asare GQ, Yasuoka J, Hodgson A, Jimba M;
Ghana EMBRACE Implementation Research
Project Team. PLoS Med. 2021 Jun 25;18(6):e1003663.
Evaluating Local Multilingual Health Care
Information Environments on the Internet: A
Pilot Study. Miller R, Doria-Anderson N,
Shibanuma A, Sakamoto JL, Yumino A, Jimba M.
Int J Environ Res Public Health. 2021 Jun 25;
18(13):6836.
Difference in factors associated with continuumof care completion rate from pregnancy topostpartum period in rural Nepal: a communitybased, cross-sectional study. Silwal RC,
Shibanuma A, Poudyal AK, Ikeda S, Jimba M.
BMJ Open. 2021 Jun 16;11(6):e044928.
Community Theater for Health Promotion in
Japan. In Arts and Health Promotion: Tools andBridges for Practice, Research, and Social
Transformation. Sandhu H, Hirose N, Yui K,
Jimba M. Springer: Cham, Switzerland; 2021. p.
103-119.
DISASTERSHOCK How Schools Can Copewith the Emotional Stress of a Major Disaster: A
Manual for Principals and Teachers. Gerrard B,
Buchanan K, Buchanan T, De Young A,
Giampaoli J, Giraudo S, Jimba M, Toren NK,
Kenardy J, Korzeniowski C. Institute for SchoolBased Family Counseling: Oxford, United
Kingdom; 2021.
Factors associated with the length of stay athealth facilities after childbirth among mothers
and newborns in Dhading, Nepal: a crosssectional study. Ikeda S, Shibanuma A, Silwal R,
Jimba M. BMJ Open. 2021 May 4;11(5):e042058.
Understanding frailty among older people living

16.

17.

18.

19.

20.

21.

22.

in old age homes and the community in Nepal: A
cross-sectional study. Shah R, Carandang RR,
Shibanuma A, Ong KIC, Kiriya J, Jimba M. PLoS
One. 2021 Apr 29;16(4):e0251016.
Identifying the causal effect of child marriage on
unmet needs for modern contraception andunintended pregnancy in Nepal: a cross-sectional
study using propensity score matching. Sekine K,
Carandang RR, Ong KIC, Tamang A, Jimba M.
BMJ Open. 2021 Apr 24;11(4):e043532.
EMBRACE intervention to improve thecontinuum of care in maternal and newborn
health in Ghana: The RE-AIM framework-based
evaluation. Kikuchi K, Gyapong M, Shibanuma
A, Asah E, Okawa S, Addei S, Nanishi K, Tawiah
C, Yasuoka J, Yeji F, Oduro A, Owusu-Agyei S,
Quansah-Asare G, Hodgson A, Jimba M; Ghana
EMBRACE Implementation Research Team. J
Glob Health. 2021 Mar 27;11:04017.
Rapidly modifiable factors associated with full
vaccination status among children in Niamey,
Niger: A cross-sectional, random clusterhousehold survey. Kondo Kunieda M, Manzo ML,
Shibanuma A, Jimba M. PLoS One. 2021 Mar 31;
16(3):e0249026.
Satisfaction of Malaria Patients with Care by
Community Health Workers Trained in
Microscopy: A Mixed-Methods Study in Palawan,
the Philippines. Akiko Matsumoto-Takahashi EL,
Tongol-Rivera P, Villacorte EA, Angluben RU,
Jimba M, Kano S. Am J Trop Med Hyg. 2021 Mar
22:tpmd190507. doi: 10.4269/ajtmh.19-0507.
Japanese health and safety information foroverseas visitors: protocol for a randomized
controlled trial. Nishikawa M, Yamanaka M,
Shibanuma A, Kiriya J, Jimba M. BMC Public
Health. 2021 Mar 21;21(1):558.
Assessing depressive symptoms among people
living with HIV in Yangon city, Myanmar: Does
being a member of self-help group matter? Than
MW, Zaw NT, Minn K, Saw YM, Kiriya J, Jimba
M, Win HH, Shibanuma A. PLoS One. 2021 Mar
18;16(3):e0248807.
Parent-adolescent communication on sexual andreproductive health and the utilization ofadolescent-friendly health services in Kailali,
Nepal. Bhatta BR, Kiriya J, Shibanuma A, Jimba

336

23.

24.

25.

26.

M. PLoS One. 2021 Feb 19;16(2):e0246917.
Impact of Haemophilus influenzae type b
combination vaccination on asthma symptoms
and pneumonia in 5-year-old children in rural
Bangladesh: a longitudinal study and comparison
with a previous cross-sectional study. Takeuchi H,
Hasan SMT, Zaman K, Takanashi S, Hore SK,
Yeasmin S, Ahmad SM, Alam MJ, Jimba M,
Iwata T, Khan MA. Respir Res. 2021 Feb 3;
22(1):35.
Parental migration and psychological well-beingof left-behind adolescents in Western Nepal.
Kharel M, Shibanuma A, Kiriya J, Ong KIC,
Jimba M. PLoS One. 2021 Jan 28;16(1):e0245873.
Factors associated with breast cancer screening
intention in Kathmandu Valley, Nepal. Bhandari
D, Shibanuma A, Kiriya J, Hirachan S, Ong KIC,
Jimba M. PLoS One. 2021 Jan 22;16(1):e0245856.
Nurse-Led Mobile Phone Voice Call Reminderand On-Time Antiretroviral Pills Pick-Up in
Nepal: A Randomized Controlled Trial. Ayer R,
Poudel KC, Kikuchi K, Ghimire M, Shibanuma
A, Jimba M. AIDS Behav. 2021 Jan 3;25(6):1923-1934.

International Health
2. International Biomedical Sciences

338

Department of Human Genetics
Professor
Akihiro Fujimoto, Ph.D.

Homepage

http://www.humgenet.m.u-tokyo.ac.jp/index.html

Introduction and Organization
The Department of Human Genetics wasestablished in 1992. Currently, the department has 1
professor, 5 graduate student, and 1 undergraduate
students. We also accept a few graduate students fromother Universities for their PhD studies.

Teaching activities
For students at the Graduate School of International
Health, courses that cover basic principles as well as
the clinical application of human genetics areprovided.
As to undergraduate students, a series of lectures isgiven to each of the sophomore (Human Genetics I,
compulsory) and junior (Human Genetics II, elective)classes at the School of Health Sciences. A series oflectures is also provided to the first year (M0) students
at the School of Medicine (compulsory).

genomic, transcriptomic and epigenomic data toevaluate diversity in the human genome, as well as
identifying variants and elucidating their functional
importance and potential therapeutic applications. Our
approach is holistic, focusing not only on data analysis,
but also on practical experiments to reach our goal of
uncovering new knowledge.

References
1.

2.

3.

Research activities
Human Genetics is a field focusing on the diversityof the human genome, and can include studies into themolecular mechanisms of genetics, evolutionary
history of homo sapiens, cancer genome, as well as
susceptibility genes for common and rare diseases.
The findings of such genetic studies have provenuseful in many applications, from supporting clinicaldiagnosis of diseases to drug development and therapy.
Recent advancements in genomic analyses haveallowed us to obtain enormous amounts of genetic andtranscriptomic data. Such data will continue to growin size and utilization in society, reflecting theincreasing importance of the field of human genetics.
Our department dives headlong into analyses of4.

Fujimoto, A. et al. Whole-genome sequencing
with long reads reveals complex structure andorigin of structural variation in human genetic
variations and somatic mutations in cancer.
Genome Medicine 13(1) 65-65 (2021).
Mizuno, K. et al. Clinical impact of detecting
low-frequency variants in cell-free DNA on
treatment of castration-resistant prostate cancer.
Clinical cancer research (2021)
Mizuno, S. et al. Immunogenomic pan-cancer
landscape reveals immune escape mechanisms
and immunoediting histories SCIENTIFICREPORTS 11(1) (2021).
Ashouri, S. et al. Characterization of intermediatesized insertions using whole-genome sequencing
data and analysis of their functional impact on
gene expression. Human Genetics (2021).

339

Department of Developmental
Medical Sciences
Professor
Masashi Mizuguchi, M.D., Ph.D.

Associate Professor
Teruyuki Tanaka, M.D., Ph.D.

Research Associate
Sayaka Takanashi, M.D., Ph.D.

Homepage

Ai Hoshino, M.D., Ph.D.

http://www.sih.m.u-tokyo.ac.jp/devt.html

Introduction and Organization
Founded in 1966 as the Department of Maternal andChild Health, our department was the first one
established in Japan. With the subsequent expansionof research activities and the foundation of the
Graduate School of Medicine, it was renamed in 1998
as the Department of Developmental Medical
Sciences. Up to now, it has been engaged in experimental and epidemiologic studies to provide thescientific bases for all the activities to promote thephysical and mental health of mothers and children.
The experimental studies include those on the nervousand endocrine systems, infection, immunity andmetabolism, whereas the epidemiologic studies deal
with development, mother-to-child relationship,vaccination and health promotion. In 2007, joined by
new members, the department has entered a new era,putting more emphasis than ever on the research on
developmental disorders of the human nervous
system.
At present, our department consists of one professor,
one associate professor, two research associates, one
assistant clerk, one technical assistant, seventeen
visiting lecturers, fifteen visiting researchers, andeight graduate students (including one overseas
student) and one research student.
Our department gives lectures to undergraduate andpostgraduate students, have weekly meetings of thewhole department and of individual research groups,
communicate with other investigators inside oroutside the University of Tokyo, and have seminars
and meetings with researchers invited from abroad.
We have collaborated with many laboratories in the
United States, Canada, Brazil, Italy, Greece, China,
Taiwan, Korea, Thailand, Viet Nam, Laos, Malaysia,
Myanmar, Indonesia, Bangladesh, Pakistan, Sri Lanka
and Australia, in order to promote the mothers’ andchildren’s health all over the world. We also haveaccepted many young students from these countries,
for the purpose of bringing up professionals whoeither perform medical research or lead local healthpolicies.

Teaching activities
1. Undergraduate course, Faculty of Medicine, Schoolof Integrated Health Sciences
1) Human growth and development
2) Immunity and defense mechanism3) Infectious diseases
4) Topics in life and environmental sciences
5) Maternal and child health6) School health7) International health8) Experiments in life sciences
9) Exercises in life sciences

34010) Introduction to general health science
2. Graduate course, the Graduate School of Medicine,
School of International HealthIn addition to lectures and laboratory courses by ourown staff, special lectures are given by experts both
inside and outside the University.

Research activities(1) Clinical, genetic and pathologic studies of acuteencephalopathy: Acute necrotizing encephalopathy, acute encephalopathy with biphasic seizures
and late reduced diffusion, acute encephalitis
with refractory, repetitive partial seizures, andclinically mild encephalitis/encephalopathy witha reversible splenial lesion.
(2) Pharmacological studies on the pathogenesis andtreatment of developmental disorders, such as
autism spectrum disorder and attention deficit/
hyperactivity disorder, using genetically engineered animals.
(3) Medical genetic studies on congenital anomalies
caused by abnormal intracellular signal transduction, such as tuberous sclerosis, Noonan
syndrome and Ellis-van Creveld syndrome.
(4) Molecular pathologic and translational studies onchildhood intractable epilepsy and developmental
disorders, such as CDKL5 deficiency disorder,using genetically engineered animals.
(5) Molecular genetic and cell biologic studies
combined with post-genomic approaches on molecules regulating neuronal migration, such as
Doublecortin and Cdk5.
(6) Studies on the nutrition, immunity, brain andepigenetics of human fetuses and neonates.
(7) International studies on the maternal and childhealth.
(8) Studies on the virulence, drug resistance andvaccines of herpesviruses and poxviruses.
(9) Molecular epidemiology of pediatric viral
infections, in particular gastrointestinal diseases(rotavirus, norovirus, sapovirus and bocavirus),
respiratory infections (influenza, RS virus andrhinovirus), exanthematous diseases (rubella) andHIV infection.

References
1.

2.

3.

4.

5.

6.

Hoque SA, Khandoker N, Thongprachum A,
Khamrin P, Takanashi S, Okitsu S, et al.
Distribution of rotavirus genotypes in Japan from2015 to 2018: Diversity in genotypes before andafter introduction of rotavirus vaccines. Vaccine.
2020;38(23):3980-6.
Kasai M, Shibata A, Hoshino A, Maegaki Y,
Yamanouchi
H,
Takanashi
JI,
et al.
Epidemiologicalchangesof
acute
encephalopathy in Japan based on national
surveillance for 2014-2017. Brain Dev. 2020;
42(7):508-14.
Nguyen PHA, Yamada S, Shibamura M, Inagaki
T, Fujii H, Harada S, et al. New Mechanism of
Acyclovir Resistance in Herpes Simplex Virus 1,
Which Has a UAG Stop Codon between the Firstand Second AUG Initiation Codons. Jpn J InfectDis. 2020;73(6):447-51.
OkitsuS,
KhamrinP,
Takanashi
S,
Thongprachum A, Hoque SA, Takeuchi H, et al.
Molecular detection of enteric viruses in the stool
samples of children without diarrhea in
Bangladesh. Infect Genet Evol. 2020;77:104055.
Shibamura M, Yoshikawa T, Yamada S, Inagaki T,
Nguyen PHA, Fujii H, et al. Association ofhuman cytomegalovirus (HCMV) neutralizing
antibodies with antibodies to the HCMV
glycoprotein complexes. Virol J. 2020;17(1):120.
Shibata A, Kasai M, Terashima H, Hoshino A,
Miyagawa T, Kikuchi K, et al. Case-control
association study of rare nonsynonymous variantsof SCN1A and KCNQ2 in acute encephalopathy
with biphasic seizures and late reduced diffusion.
J Neurol Sci. 2020;414:116808.

341

Department of Human Ecology
Professor
Masahiro UMEZAKI, Ph.D.

Associate Professor
Shoko KONISHI, Ph.D.

Research Associates
Satoko KOSAKA, Ph.D.
Lena TAKAYASU, Ph.D.

Homepage: http://www.humeco.m.u-tokyo.ac.jp/en/
Introduction and Organization
The Department of Human Ecology was founded when
Kenji Uraguchi was appointed Professor of the Human
Ecology Department on April 1, 1965. Following
Professor Uraguchi’s retirement on March 31, 1966,
Professor Haruo Katsunuma (also appointed Professor of
the Public Health Department, School of Medicine)
became a joint Professor of the Human Ecology
Department. Tsuguyoshi Suzuki was appointed as an
Associate Professor and worked in the Department until
August 31, 1971, when he was transferred to the Facultyof Medicine, Tohoku University, as a Professor. After
Professor Katsunuma left the Department on March 31,
1972, Professor Akira Koizumi became the head of the
Human Ecology Department on April 1, 1972. Professor
Koizumi was transferred to the Public Health Program,
School of Medicine, on March 31, 1976, and Associate
Professor Shosuke Suzuki served as a department headfrom April 1, 1976, to April 15, 1979.
Tsuguyoshi Suzuki was appointed Professor of the
Human Ecology Program on April 16, 1979. He founded
the theoretical framework of the current human ecology
curriculum, which is based on studying the mechanisms
by which humans adapt to the environment. After
Associate Professor Shosuke Suzuki was transferred to
the Faculty of Medicine, Gunma University, as Professor
on July 31, 1981, Ryutaro Ohtsuka was appointed
Associate Professor on September 1, 1981. Associate

Professor Ohtsuka established a methodology forcollecting quantitative information on demography,
nutrition, and subsistence, targeting small-scale
populations based on extensive fieldwork, themethodology of which continues to be utilized by current
department members. Following the retirement ofProfessor Tsuguyoshi Suzuki on March 31, 1992, Ryutaro
Ohtsuka was appointed professor on April 1, 1992.
Chiho Watanabe was appointed as an Associate
Professor in December 1997. He expanded methodologies
that examine relations between the environment andhealth by utilizing various tools, such as measuringbiomarkers in biological specimens collected in the field
and animal experiments. Professor Ohtsuka retired on
March 31, 2005, and Chiho Watanabe was appointed as a
Professor on April 1, 2005. Masahiro Umezaki was
appointed as an Associate Professor in August 2005.
While relying on quantitative research based onfieldwork, he has also been exploring new research topics,
including the application of spatial information scienceson health sciences, the roles of gut microbiota in humannutrition, mitigation/alleviation strategies of depopulation
and aging in human populations, and medical
anthropology. Professor Chiho Watanabe was transferredfrom the University of Tokyo to the National Institute ofEnvironmental Studies on April 1, 2017. Masahiro
Umezaki was appointed Professor as of January 1, 2018.
Shoko Konishi was appointed Associate Professor as ofJune 1, 2018. Dr. Konishi has been studying the342

associations
betweenfecundity,
fertility,andenvironmental factors from the perspectives of population
studies, environmental sciences, anthropology, andsociology.
In the fiscal year 2021, the Department had four faculty
members: Drs. Umezaki, Konishi, Kosaka, and Takayasu.
The Department also had 14 visiting lecturers for both
graduate or undergraduate courses. Professor Umezaki
held additional roles in the Earth Observation Data
Integration and Fusion Research Initiative (EDITORIA)
at the University of Tokyo.

system (GIS)/global positioning system (GPS) analyses.
Our study fields include Asian-Oceanian (including
Japan) rural and urban communities, focusing on
population, nutrition, growth, the environment, andsustainability. Experimental studies have been conductedon the effects of perinatal exposure to heavy metals,
emphasizing the factors that modify these effects. Almost
all our studies require a transdisciplinary approach. We
collaborate with various local and international research
institutes. The following is a list of the major activities
conducted in the past year:

Teaching activities

1. Adaptation to low-protein diet
The inconsistency between the protein-deficient
diets of Papua New Guinea highlanders and theirmuscular physique is well known. Moreover, although
their protein intake is less than biologically adequate,
disorders related to protein deficiency have rarely beenreported. We speculate that the population has adapted
to a low-protein diet by utilizing air nitrogen fixed byintestinal bacteria and/or by intensive “recycling” of theurea that passes into the gastrointestinal tract. Recent
advances in sequencing techniques have enabled us to
examine the adaptation of this population to a lowprotein diet in a more direct way. We evaluated the gut
microbiota of healthy individuals in four Papua New
Guinea communities with varying degrees of protein
deficiency. The association between the gut microbiota
and variations in protein intake and nutritional
biomarkers was investigated. Shotgun metagenomic
analysis further demonstrated that some genes related
to nitrogen fixation and urease were enriched in Papua
New Guinea communities compared with othercountries. Gnotobiotic animal experiments haverevealed different nutritional responses to a low-protein
diet depending on the type of gut microbiotatransplanted.

This Department is one of six in the School ofInternational Health. Human Ecology Special Lecture I
focuses on the basic components of human ecology, suchas demography, nutrition, and environment, andintroduces the notion of human ecosystems. Human
Ecology Special Lecture II emphasizes recent topics andongoing research in human ecology and related areas.
With these graduate student classes, we attempt todescribe human ecology as a basic component ofinternational health and providing current issues and theapproaches used in this field. The graduate course lectures
are provided in English.
The Department oversees a part of the School ofIntegrated Health Sciences, providing undergraduate
course lectures on human ecology, environment andhealth, demography, international health, and medical
anthropology. We are also responsible for organizing
pharmacology, toxicology, physiology, and environmental
and human engineering. We focus on introducing globalscale issues, such as population explosion, food security,and environmental issues, regarding problems faced by
the Asia-Pacific region (including Japan). We also
explore the relationship between human activities andenvironmental chemical contamination.

Research activities
Human ecology investigates the human population in
the context of their respective ecologies and the global
context. Mostly, our research tackles tasks in the field of
human environmental health and/or population ecology,
but with a more comprehensive and broader context.
Therefore, we must adopt different approaches, including
fieldwork, experimentation, and geographic information

2. Adaptive strategy to aging and depopulation
Japan is experiencing post-demographic transition(i.e., low fertility, aging, and population decrease).
Targeting Japanese rural communities, the frontrunnersof this global issue, we conducted population
projections and studies on their food habits, nutritional
intake, and subjective perceptions of health. We also
conducted a study to identify mitigation and alleviation
strategies for aging and depopulation that have been

343

formulated in local communities.
A case study in Nagasaki city, focusing on theresidential zones on a steep slope and residents’ aging,suggested that older people lived on steep slopes andwithout direct roadway access.
3. Nutrition and eating behaviors
Field surveys were conducted annually in the samevillages in West Java, Indonesia. Although we did notconduct a field survey in 2021, we performed further
analysis and discussion of previously collected data.
We also performed animal experiments to elucidate
the determinants of eating behavior. Our experiment
revealed that mice preferred a high-fat diet to a highcarbohydrate diet after the consumption of soluble fiber
for a certain period.
4. Interdisciplinary Investigation on the Technology, theEnvironment, and Fertility (IITEF)
Japan has the highest number of assisted
reproductive technologies in the world. Our ongoingproject is to test the hypothesis that exposure totechnology and environmental chemicals is linked toincreased infertility in the country. A total of 198 maleparticipants were recruited from two hospitals in Tokyoand Tsukuba. A questionnaire survey was conducted togather information regarding lifestyle and sexualfunction. Urine and semen specimens were collected.
The urinary concentrations of elements (cadmium,selenium, etc.) and phthalate esters were measured.
Sperm mitochondrial DNA copy number was alsomeasured.
Urinary
isoflavone
andparabenconcentrations will be measured.
Additionally, the IITEF project administered a largescale online questionnaire survey targeting 8,000 men
living across Japan. The participants were males aged 20
to 54 years who responded to questions onsocioeconomic status and sexual behavior. The findings
have been reported at academic conferences.
5. Health transition in Lao People’s Democratic
Republic
The diet in the northern parts of Laos has beencharacterized by the consumption of large amounts ofrice with dishes made of wild plants. Wild plants with
bitter and even astringent tastes, which are supposed tocontain more phytochemicals, are preferred overdomesticated vegetables. Phytochemicals are suspected
to play a role in nutritional adaptation among local
people through their interactions with intestinalbacteria. As people have gradually become involved in
the market economy, their diet has changed toward
more consumption of animal meat and oil, and lessconsumption of phytochemicals. Our research project
investigated the potential health impacts of such dietarychanges in northern Laos. The questionnaire survey andsampling of biological specimens were conducted inthree communities in the Oudomxay Province (oneperi-urban and two farming communities). By
evaluating biomarkers of oxidative stress, chronic
inflammation, and gut microbiota composition in threecommunities at different levels of modernization, wesought to clarify the biological link between dietarytransition
andtherecentemergenceof
noncommunicable diseases in rural Laos. To examine
the phytochemical intake from wild plants, we
identified species of wild edible plants and assessed
their phytochemicals.
6. Potential fetal microbiome transfer from intrauterine
exposure
Mounting evidence shows that bacteria in
fertilization products (analyzed using DNA-based
technologies) challenges the sterile womb hypothesis.
We conducted cultivation-based and 16S rRNA
sequence analyses using a mouse model of mid- and lategestation, which suggested the presence of bacteria in
fetal, placental, and uterine tissues. This low-abundance
fetal microbiome appears to be volatile and transient innature, contrasting the relatively stable bacterial
composition that matures during infancy. The similarity
between the bacterial compositions of maternal andfetal tissues suggests vertical transmission, which has
also been previously described in other animals andgerm-free animal models. The existence of this fetal
microbiome is hypothesized to be associated withimmunocompetence in mothers and the development of
immunity in fetuses. We have published a review article
on fetal microbiomes.
7. Mouse gut microbiome transitions
The gut microbiome and aging have been
discussed based on the average flora of people ofdifferent ages. Few studies have been conducted on the344

microbiome of the same individual over a long period oftime. We conducted experiments on mice from shortly
after birth to just before death to determine the changes
in the gut microbiome related to pregnancy and lifespan.
There are certain phylogenetic trends in bacteria thatpersist in the gut for long periods, and these persistentmicrobes are thought to relate strongly to host
homeostasis.
Determinants of chronic inflammation in rural
population in Japan
Chronic inflammation is linked to various
noncommunicable diseases and controlling it can
improve health among older people. Various factors(e.g., age, diet, chemical exposure, etc.) have beenreported as associated with chronic inflammation, but acomplete picture of the determinants of chronic
inflammation has not yet been clarified. We conducted astudy to assess chronic inflammation and investigate its
determinants among residents in rural areas in Japan(Ojika city, Nagasaki), where the population aging rate
is high. Nutrient intake was assessed using a foodfrequency questionnaire, and several biomarkers were
measured to assess chronic inflammation and traceelement exposure.

5.

8.

6.

7.

8.

9.

References
1.

2.

3.

4.

Kosaka S, Nakao R, Ohnishi M, Umezaki M. The
proportion of older population in Nagasaki, Japan, ishigher in areas with poor walkability andaccessibility. Jpn J Health Hum Ecol. 2021;87:237245.
Mizuno Y, Konishi S, Imai H, Fujimori E, Kojima N,
Kajiwara C, Yoshinaga J. Telomere length andurinary 8-hydroxy-2′-deoxyguanosine and essentialtrace element concentrations in female Japanese
university students. J Environ Sci Health A Tox
Hazard Subst Environ Eng. 2021;56(12):1328-1334.
Mizuno Y, Shimizu-Furusawa H, Konishi S, Inaoka
T, Ahmad SA, Sekiyama M, Abdoellah OS,
Gunawan B, Parajuli RP, Ikemoto Y, Lam TD,
Watanabe C, Umezaki M. Associations between
urinary heavy metal concentrations and bloodpressure in residents of Asian countries. Environ
Health Prev Med. 2021;26(1):101.
Mizuno Y, Masuoka H, Kibe M, Kosaka S,

Natsuhara K, Hirayama K, Kounnavong NIS,
Tomita S, Umezaki M. Impact of modernization on
urinary concentrations of arsenic, cadmium, lead,and selenium in rural residents of Northern Laos. Am
J Hum Biol. 2021;34(4): e23685.
Konishi S, Kariya F, Hamasaki K, Takayasu L,
Ohtsuki H. Fecundability and sterility by age:
Estimates using time to pregnancy data of Japanese
couples trying to conceive their first child with andwithout fertility treatment. Int J Environ Res Public
Health 2021;18(10): 5486.
Mizuno Y, Hur K, and Umezaki M. Assessment of
intra- and inter-assay variation in dried blood spot
telomere length measurements by qPCR. Anthropol
Sci. 2021;129(1)99-102.
Mizuno Y, Konishi S, Goto C, Yoshinaga J, Hidaka
M, Imai H. Association between nutrient intake andtelomere length in Japanese female university
students. Biomarkers 2021;1-34.
Khasnobish A, Takayasu L, Watanabe KI, Nguyen
TT, Arakawa K, Hotta O, Joh K, Nakano A, Hosomi
S, Hattori M, Suda W. Dysbiosis in the salivary
microbiome associated with IgA nephropathy:
A Japanese cohort study. Microbes Environ 2021;
36(2):ME21006.
Suda W, Ogata Y, Takayasu L, Shindo C, Watanabe
K. Complete genome and plasmid sequences of threefluviibacter phosphoraccumulans polyphosphateaccumulating bacterioplankton strains isolated fromsurface river water. Microbiol Resour Announc
2021;10(9):e01474-20.

345

Department of
Biomedical Chemistry
Professor
Tomoyoshi Nozaki, Ph.D., MD

Associate Professor
Yoh-ichi Watanabe, Ph.D.

Assistant Professor
Jeelani Ghulam, Ph.D., Santos Herbert Jimenez, Ph.D.

Homepage

http://www.biomedchem.m.u-tokyo.ac.jp/

Introduction and Organization
Aim of our department is to contribute to global
health and welfare from basic research. Our department, formerly named Biochemistry and Nutrition
was renamed on April 1st, 1996 to The Department of
Biomedical Chemistry as newly affiliating with
Biomedical Science Division of International Health,Graduate School of Medicine, The University ofTokyo. Former Prof. Kiyoshi Kita (Professor
Emeritus) has been retired in March 2016, and Dr.
Tomoyoshi Nozaki, National Institute of Infectious
Diseases, has been assigned as a new professor in
October, 2016, and became a full-time processor in
August, 2017.

Teaching activities
Teaching activities in our department cover a broad
spectrum of biochemistry-oriented life sciences frompremise to frontiers and in either conceptual orexperimental point of view
Graduate Course: Biomedical Chemistry I, IIThis course is comprised of lectures and seminars toprovide basic concepts and newer vistas for understanding biomedical chemistry with special reference
to biochemistry and molecular biology. These include
the structure and function of biomolecules, metabo-lism, its regulation, and underlying mechanism ateither molecular, cellular and systemic level.
Undergraduate Course: Basic Life Science, Life
Science and Genome Science I & II, Nutrition,
Laboratory Practice for Life Science Ⅰ& II, Seminarin Environmental and Human Life Sciences,
Microbiology II (Parasitology).

Research activities
Our major research interests include virulencemechanisms and metabolism of protozoa, particularly
Plasmodium spp. causing malaria and Entamoeba
histolytica causing amebic dysentery. We mainly focus
on vesicular trafficking, phagocytosis, autophagy,proteases, amino acid metabolisms, RNA maturation,translation, drug development, and organellogenesis.
Our research approaches are very robust, and include
biochemistry, molecular and cell biology, live imaging,
multi-omics including metabolomics, and reverse
genetics. Our present research themes include: Molecular elucidation of pathogenesis of parasites
 Biochemical and biological analyses of metabolism and organelles unique to parasites
 Analysis of vesicular traffic, protein secretion, andphagocytosis/trogocytosis in parasites
 Genome wide analysis and comparison of parasite
strains

346

 Drug discovery and development against protozoan
infections such as malaria and amebiasis
 Elucidation of divergence of RNA maturation andtranslation

6.

References
1.

2.

3.

4.

5.

Iwasaki, A., Ohtomo, K., Kurisawa, N., Shiota, I.,
Rahmawati, Y., Jeelani, G., Nozaki, T., Suenaga,
K. Isolation, structure determination and total
synthesis of Hoshinoamide C, an anti-parasitic
lipopeptide from the marine cyanobacterium
Caldora penicillata. J Nat Prod. 84:126-135, 2021.
doi: 10.1021/acs.jnatprod.0c01209.
Pramisandi, A., Kurnia, K., Chrisnayanti, E.,
Bernawati, P., Dobashi, K., Mori, M., Mahsunah,
A. H., Nonaka, K., Matsumoto, A., Kristiningrum,
Hidayati, D. N., Dewi, D., Prabandari, E. E.,
Amalia, E., Nurkanto, A., Inaoka, D. K., Waluyo,D., Kita, K., Nozaki, T., Ōmura, S., Shiomi, K.
Gentisyl alcohol and homogentisic acid:
Plasmodium falciparum dihydroorotate dehydrogenase inhibitors isolated from fungi. J. Gen.
Appl. Microbiol., 67, 114-117, 2021. doi 10.
2323/jgam.2020.08.004
Taku, I., Hirai, T., Makiuchi, T., Shinzawa, N.,
Iwanaga, S., Annoura, T., Nagamune, K., Nozaki,T., Saito-Nakano, Y. Rab5b-associated Arf1
GTPase regulates export of N-myristoylated
adenylate kinase 2 from the endoplasmic
reticulum in Plasmodium falciparum. Front Cell
Inf Microbiol 10:610200, 2021. doi: 10.3389/
fcimb.2020.610200..
Saito-Nakano, Y., Wahyuni, R., Nakada-Tsukui,K., Tomii, K., Mitra, B. N., Nozaki, T. Rab7D
small GTPase is involved in phago-, trogocytosis
and cytoskeletal reorganization in the enteric
protozoan Entamoeba histolytica. Cell. Microbiol.
232, e13267, 2021. doi.org/10.1111/cmi.13267
Jeelani, G., Nozaki, T. Eukaryotic translation
initiation factor 5A and its hypusination play animportant role in proliferation and potentially in
differentiation of the human enteric protozoan
parasite Entamoeba histolytica. PLoS Pathog.,
17(2):e1008909, 2021. doi: 10.1371/journal.ppat.
1008909.

7.

8.

9.

10.

11.

12.

13.

Nurkanto, A., Jeelani, G., Santos, H. J., Mori, M.,
Annoura, T., Tozawa, Y., Shiomi, K., Nozaki, T.
Characterization of Plasmodium falciparum
pantothenate kinase and identification of its
inhibitors from microbial natural products. Front
Cell Inf Microbiol. 11:639065, 2021. doi: 10.
3389/fcimb.2021.639065
Watanabe, N., Nakada-Tsukui, K., and Nozaki, T.
Diversity of phosphoinositide binding proteins in
Entamoeba histolytica. Parasitol Int (review) 83:
102367, 2021. doi: 10.1016/j.parint.2021.102367.
Das, K., Watanabe, N., and Nozaki, T. Two
StAR-related lipid transfer proteins play specificroles in endocytosis, exocytosis, and motility inthe parasitic protist Entamoeba histolytica. PLoS
Pathog, 17(4): e1009551, 2021. doi: 10.1371/
journal.ppat.1009551.
Das, K., Sardar, S., Ghosal, A., Saito-Nakano, Y.,
Dutta, S., Nozaki, T., Ganguly, S. Multilocus
sequence typing (MLST) of Entamoeba
histolytica identifies a genetic marker associatedwith disease outcomes. Parasitol Int 83:102370,
2021. doi: 10.1016/j.parint.2021.102370..
Santos, H. J. and Nozaki, T. Interorganellar
communication and membrane contact sites inprotozoan parasites. Parasitol Int (review) 83:
102372, 2021. doi: 10.1016/j.parint.2021.102372
Hartuti, E. D., Sakura, T., Tagod, M. S. O.,
Yoshida, E., Wang, X., Mochizuki, K., Acharjee,
R., Matsuo, Y., Tokumasu, T., Mori, M., Waluyo,D., Shiomi, K., Nozaki, T., Hamano, S., Shiba, T.,
Kita, K., Inaoka, D., K. Identification of
3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothi
azin-6-imine derivatives as novel selective
inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Int J Mol Sci 22:7236,
2021. doi: 10.3390/ijms22137236.
Takahashi, H., Iwasaki, A., Kurisawa, N., Suzuki,
R., Jeelani, G., Matsubara, T., Sato, T., Nozaki,T., Suenaga, K. Motobamide, an antitrypanosomal cyclic peptide from the marine cyanobacterium
Leptolyngbya sp. J Nat Prod. 84:1649-1655,
2021. doi: 10.1021/acs.jnatprod.1c00234.
Kurisawa, N., Otomo, K., Iwasaki, A., Jeelani, G.,
Nozaki, T., and Suenaga, K. Isolation and total
synthesis of Kinenzoline, an antitrypanosomal
linear depsipeptide isolated from a marine

347

14.

15.

16.

17.

18.

19.

Salileptolyngbya sp. cyanobacterium. J Org
Chem, 86(18):12528-12536, 2021. doi: 10.1021/
acs.joc.1c00817.
Acharjee, R. Talaam, K. K., Hartuti, E. D.,
Matsuo, Y., Sakura, T., Gloria, B. M., Hidano, S.,
Kido, Y., Mori, M., Shiomi, K., Sekijima, M.,
Nozaki, T., Umeda, K., Nishikawa, Y., Hamano,
S., Kita, K., Inaoka, D. K. Biochemical studies of
mitochondrial malate:quinone oxidoreductase
from Toxoplasma gondii. Int J Mol Sci. 22(15):7830, 2021. doi: 10.3390/ijms22157830
Waluyo D, Prabandari EE, Pramisandi A,
Hidayati DN, Chrisnayanti E, Puspitasari DJ,
Dewi D, Suryani, Kristiningrum, Oktaviani AN,
Afrianti KR, Nonaka K, Matsumoto A, Tokiwa T,
Adipratiwi N, Ariyani T, Hartuti ED, Putri TZ,
Rahmawati Y, Inaoka DK, Miyazaki Y, Sakura T,
Nurlaila N, Siska E, Kurnia K, Bernawati P,
Melinda M, Mahsunah AH, Nugroho NB, Mori
M, Dobashi K, Yamashita M, Nurkanto A,
Watanabe A, Shiomi K, Wibowo AE, Nozaki T.
Exploring natural microbial resources for the
discovery of anti-malarial compounds. Parasitol
Int. 85:102432. doi: 10.1016/j.parint.2021.
102432.
Ebihara, A., Iwasaki, A., Miura, Y., Jeelani, G.,
Nozaki, T., Suenaga, K. Isolation and total
synthesis of Bromoiesol sulfates, antitrypanosomal arylethers from a Salileptolyngbya
sp. marine cyanobacterium. J. Org. Chem.
86(17):11763-11770, 2021. doi: 10.1021/acs.joc.
1c01214.
Iwasaki, A., Teranuma, K., Kurisawa, N.,
Rahmawati, Y., Jeelani, G., Nozaki, T., Gerwick,W., Suenaga, K. First total synthesis andstructure activity relationship of Iheyamide A, ananti-trypanosomal linear peptide isolated from a
Dapis sp. marine cyanobacterium. J. Nat. Prod.
84(9):2587-2593, 2021. doi: 10.1021/acs.jnatprod.
1c00792.
Nakada-Tsukui, K. and Nozaki, T. Trogocytosis
in unicellular eukaryotes. Special Issue: Newphase of phagocytosis and a bite of trogocytosis.
Cells. 10(11), 2975, 2021. doi.org/10.3390/cells
10112975
Bharadwaj, R., Tushar, Ahmad, A., Inampudi, K.,
Nozaki, T.*, Somlata*. An atypical EhGEF

regulates phagocytosis in Entamoeba histolytica
through EhRho1. PLoS Pathog 17(11):e1010030.
(*double correspondence) doi: 10.1371/journal.
ppat.1010030.
20. Peng, R., Yoshinari, S., Kawano-Sugaya, T.,
Jeelani, G., Nozaki, T. tRNA splicing in theunicellular parasitic amoebozoan: identificationand functional characterization of divergent 3'phosphate tRNA ligase from Entamoeba
histolytica. Front Cell Inf Microbiol, section
Parasite and Host, 11:746261, 2021. doi: 10.
3389/fcimb.2021.746261.

School of Public Health
1. Epidemiology and Health Sciences

349

Department of Social andPreventive Epidemiology
Professor
Satoshi Sasaki, M.D., Ph.D.

Associate
Kentaro Murakami, Ph.D.

Homepage

http://www.nutrepi.m.u-tokyo.ac.jp/

Introduction and Organization
The Department of Social and Preventive Epidemiology is a new department which was established at thesame time of the establishment of the School of Public
Health, the University of Tokyo (April 2007).
Epidemiology is a study of quantitatively assessing
health status and disease development in populations
and statistically analyzing the relationship of risk
factors with the development of certain disease. In
addition to traditional risk factors including alcohol
drinking, smoking, nutrition, and physical activity,
gene and factors controlling gene and socioeconomic
factors are also important topics in epidemiologic
research. Epidemiologic data are needed for
conducting the assessment of certain treatment
including medicine and estimating situation of diseasedevelopment.
Epidemiology not only provides research methodology
in the field of public health but also is considered apractical study for public health and thus a central fieldof health science. However, both education andresearch systems have long been insufficient in Japan.
Social and preventive epidemiology is a study of
epidemiologically clarifying the relationship between
various phenomena in human society (including
individual lifestyle) and certain disease.
The Department of Social and Preventive Epidemiology particularly focuses on nutrition, which isessential for individual and population health, as a main
research topic and epidemiologically researches

various issues related to nutrition (nutritional epidemiology), playing a central role in this research field inJapan.
The Department currently consists of one professor andone associate.

Teaching activities
We have the following two lectures in the School of
Public Health.
Epidemiological research and practice
Practice and assessment in public health
Both are strongly associated with practical tasks inpublic health field, aiming at giving students opportunities for acquiring abilities of conducting publichealth activities and tasks based on theory of
epidemiology.
We have also several lectures for students in otherschools.

Research activities
Our main topic is basic research for development andapplication of research methodology in the field of
nutritional epidemiology. Based on this basic research,
we also conduct a wide range of epidemiologic
research for investigating the relationship of nutrition
with health and disease. As a characteristic of thisresearch field, we conduct many multi-center studies
with various kinds of disease.

350

Another characteristic is collection of research findings(scientific papers) derived from epidemiologic research
all over the world on the association of nutrition withhealth and disease, which is applied for health control
through nutrition improvement and disease control.

8.

9.

References
1.

2.

3.

4.

5.

6.

7.

Sugimoto M, Murakami K, Asakura K, Masayasu
S, Sasaki S. Diet-related greenhouse gas emissions
and major food contributors among Japanese
adults: comparison of different calculation
methods. Public Health Nutr 2021; 24(5): 973-83.
Tajima R, Murakami K, Asakura K, Fujiwara A,
Uechi K, Sugimoto M, Wang HC, Masayasu S,
Sasaki S. Snacking in Japanese nursery-school
children aged 3-6 years: its characteristics andcontribution to overall dietary intake. Public
Health Nutr 2021; 24(5): 1042-51.
Ohfuji S, Matsuura T, Tamori A, Kubo S, Sasaki S,
Kondo K, Ito K, Fukushima W. Lifestyles
Associated with Prognosis After Eradication of
Hepatitis C Virus: A Prospective Cohort Study inJapan. Dig Dis Sci 2021; 66(6): 2118-28.
Shinozaki N, Yuan X, Murakami K, Sasaki S.
Development, validation and utilisation of dishbased dietary assessment tools: a scoping review.
Public Health Nutr 2021; 24(2): 223-42.
Kobayashi Y, Ohfuji S, Kondo K, Fukushima W,
Sasaki S, Kamata N, Yamagami H, Fujiwara Y,
Suzuki Y, Hirota Y. Association of Dietary Fatty
Acid Intake With the Development of Ulcerative
Colitis: A Multicenter Case-Control Study inJapan. Inflamm Bowel Dis 2021; 27: 617-28.
Miyake Y, Tanaka K, Okubo H, Sasaki S,
Tokinobu A, Arakawa M. Maternal metal intake
during pregnancy and childhood behavioral
problems in Japan: the Kyushu Okinawa Maternaland Child Health Study. Nutr Neurosci 2021; :Online ahead of print.
Murakami K, Livingstone B, Masayasu S, Sasaki
S. Eating patterns in a nationwide sample ofJapanese aged 1-79 years from MINNADE study:
eating frequency, clock time for eating, time spenton eating and variability of eating patterns Public
Health Nutr 2021; 3(5): 1-13.

10.

11.

12.

13.

14.

15.

Okuda M, Fujiwara A, Sasaki S. Composition of
Dietary Fatty Acids and Health Risks in Japanese
Youths. Nutrients 2021; 13: 426.
Sari DW, Noguchi-Watanabe M, Sasaki S, Sahar J,
Yamamoto-Mitani N. Estimation of sodium andpotassium intakes assessed by two 24-hour urine
collections in a city of Indonesia. Br J Nutr 2021;
126(10): 1537-48.
Miyake Y, Tanaka K, Okubo H, Sasaki S,
Tokinobu A, Arakawa M. Maternal consumptionof soy and isoflavones during pregnancy and riskof childhood behavioural problems: the Kyushu
Okinawa Maternal and Child Health Study. Int J
Food Sci Nutr 2021; 72: 1118-27.
Okuda M, Sasaki S. Assessment of foods
associated with sodium and potassium intake inJapanese youths using the brief-type selfadministered diet history questionnaire. Nutrients
2021; 13(7): 2345.
Nishida Y, Nakamura H, Sasaki S, Shirahata T,
Sato H, Yogi S, Yamada Y, Nakae S, Tanaka S,
Katsukawa F. Evaluation of energy intake bybrief-type
self-administereddiethistoryquestionnaire among male patients with stable/at
risk for chronic obstructive pulmonary disease.
BMJ Open Respir Res 2021; 8(1): e000807.
Oono F, Matsuura N, Saito A, Fujiwara A,
Takahashi O, Sasaki S, Iida K. Association of
Hours of Paid Work with Dietary Intake andQuality in Japanese Married Women: A CrossSectional Study. Nutrients 2021; 13(9): 3005.
Ishikawa-Takata K, Nakae S, Sasaki S, Katsukawa
F, Tanaka S. Age-Related Decline in Physical
Activity Level in the Healthy Older Japanese
Population. J Nutr Sci Vitaminol (Tokyo) 2021;
67: 330-8.
Fukuoka S, Arita R, Mizoguchi T, Kawashima M,
Koh S, Shirakawa R, Suzuki T, Sasaki S,
Morishige N. Relation of Dietary Fatty Acids andVitamin D to the Prevalence of Meibomian GlandDysfunction in Japanese Adults: The HiradoTakushima Study. J Clin Med 2021; 10: 350.

351

Department of Clinical
Epidemiology and
Health Economics
Professor
Hideo Yasunaga, MD, PhD.

Assistant Professor
Hiroki Matsui, MPH.

Homepage

http://www.heer.m.u-tokyo.ac.jp/

Introduction and Organization
The Department of Clinical Epidemiology and Health
Economics was established in April 2007, as a part ofMaster of Public Health (MPH) program under the
new School of Public Health (SPH). The Department
is also affiliated with the Division of Social Medicine
for doctoral education.
The mission of the Department is two folds; to help
health professionals obtain scientifically sound basis
and skills for evidence-based practice, and toempirically evaluate the clinical practice, health caresystem/policy for further improvement of the qualityof health care. For this purpose, the Department puts aunique emphasis on quantitative analytic methods andinter-disciplinary theories across clinical epidemiology, health service research, health economics andhealth policy.

Teaching activities
Under the MPH program, the Department is responsible for 6 courses, one on introduction to clinicalmedicine for non-MD students, two on clinicalepidemiology, two on health economics, and one on
healthcare organization management.
The lecture course on clinical epidemiology provides
a quick review on elementary to intermediate levels of
epidemiology such as research design, bias and error,

and causal inference.
Health economics course provides an intermediatelevel of micro-economics and health economics
theories of consumer choice, insurance, and humancapital, and enhances discussion to apply these
theories to behaviors of providers and consumers. The
3-day intensive course offers students an opportunity
for hands-on training of actual cost-effectivenessanalysis of health care and technologies.

Research activities
Current activities in this Department cover a broad
range of health services research, including clinicalepidemiological studies, economic evaluation ofhealth technology and health policy, quality of life
research, and hospital administration and quality
assurance.
The Department also contributes to clinical and healthservice research using a large claim database based on
the Japanese original patient classification system,
Diagnosis Procedure Combination (DPC). DPC database allows a unique and detailed analysis on theprocess of care in acute care hospitals in this country.
DPC database also provides resource diagnosis in
hospital levels as well as regional levels, whencombined with other public data sources such as thePatient Survey, and Hospital Census.

352

References
1.

2.

3.

4.

5.

6.

7.

8.

Aso S, Matsui H, Fushimi K, Yasunaga H.
Dexmedetomidine and mortality from sepsis
requiring mechanical ventilation. Journal of
Intensive Care Medicine. 2021;36(9):1036-1043
Chinen T, Sasabuchi Y, Matsui H, Yasunaga H.
Association between third-generation fluoroquinolones and Achilles tendon rupture: a selfcontrolled case series analysis. Annals of Family
Medicine. 2021;19(3):212-216.
Awano N, Jo T, Yasunaga H, Inomata M, Kuse N,
Tone M, Morita K, Matsui H, Fushimi K, Nagase
T, Izumo T. Body mass index and in-hospitalmortality in patients with acute exacerbation of
idiopathic pulmonary fibrosis. ERJ Open
Research. 2021;7(2):00037-2021.
Enomoto Y, Iwagami M, Tsuchiya A, Morita K,
Abe T, Kido T, Uda K, Inokuchi R, Yasunaga H,
Inoue Y, Tamiya N. Dexmedetomidine use andmortality in mechanically ventilated patients withsevere burns: a cohort study using a national
inpatient database in Japan. Burns. 2021;47(7):1502-1510.
Hamada S, Nakajima M, Kaszynski RH,
Kumazawa R, Matui H, Fushimi K, Goto H,
Yamaguchi Y, Yasunaga H. In-hospital mortality
among patients with invasive non-group A
β-hemolytic
Streptococcus
treatedwithclindamycin combination therapy: A nationwide
cohort study. Acute Medicine & Surgery. 2021;
8(1):e634.
Hasegawa S, Okada A, Aso S, Kumazawa R,
Matsui H, Fushimi K, Yasunaga H, Nangaku M.
Association between diabetes and major bleeding
complications of renal biopsy. Kidney International Reports. 2021;7(2):232-240.
Hashimoto Y, Michihata N, Yamana H, Shigemi
D, Morita K, Matsui H, Yasunaga H, Aihara M.
Intraocular pressure-lowering medications during
pregnancy and risk of neonatal adverse
outcomes: a propensity score analysis using alarge database. British Journal of Ophthalmology.
2021;105(10):1390-1394.
Hashimoto Y, Michihata N, Matsui H, Ishimaru
M, Fushimi K, Yasunaga H, Aihara M, Takao M,
Obata R. Recent trends in vitreoretinal surgery: a

9.

10.

11.

12.

13.

14.

15.

nationwide database study in Japan, 2010–2017.
Japanese Journal of Ophthalmology. 2021;65(1):54-62
Hatachi T, Michihata N, Inata Y, Takeuchi M,
Matsui H, Fushimi K, Yasunaga H. Prognostic
factors among children with acute encephalitis/
encephalopathy associated with viral and otherpathogens. Clinical Infectious Disease. 2021;
73(1):76-82.
Hattori Y, Tahara S, Aso S, Matsui H, Fushimi K,
Yasunaga H, Morita A. Prophylactic steroid
administration and complications after transsphenoidal pituitary surgery: a nationwide
inpatient database study in Japan. British Journalof Anaesthesia. 2021;127(2):e41-e43.
Hirose N, Morita K, Nakamura M, Fushimi K,
Yasunaga H. Association between the duration ofphysical restraint and pulmonary embolism in
psychiatric patients: A nested case–control study
using a Japanese nationwide database. Archives
of Psychiatric Nursing 2021;35(5):534-540.
Hirose N, Morita M, Jo T, Hagiwara Y, Matsui H,
Fushimi K, Yasunaga H. Differences in disease
severity and in-hospital mortality in patients
hospitalized for pneumonia with and without
intellectual disability: A matched-pair retrospective cohort study using nationwide in-patient
database. Journal of Intellectual & Developmental Disability. 2021;47(1):65-73.
Honda A, Michihata N, Iizuka Y, Mieda T,
Takasawa E, Ishiwata S, Matsui H, Fushimi K,
Yasunaga H, Chikuda H. Clinical features andpost-treatment complications of isolated C2
odontoid fractures: a retrospective analysis usinga national inpatient database in Japan. European
Spine Journal. 2021;30(12):3631-3638.
Hoshina K, Kato M, Ishimaru S, Michihata N,
Yasunaga H, Komori K, Japanese Committee for
Stentgraft Management. Effect of the urgency
and landing zone on rates of in-hospital death,stroke, and paraplegia after thoracic endovascularaortic repair in Japan. Journal of Vascular Surgery.
2021;74(2):556-568.e2.
Ikawa F, Isobe N, Michihata N, Oya S, Ohata K,
Saito K, Yoshida K, Fushimi K, Yasunaga H,
Tominaga T, Kurisu K. Inhospital complications
after surgery in elderly patients with

353

16.

17.

18.

19.

20.

21.

22.

asymptomatic or minor symptom meningioma: anationwide registry study. World Neurosurgery.
2021;148:e459-e470.
Itoh H, Kaneko H, Kiriyama H, Kamon T, Fujiu
K, Morita K, Michihata N, Jo T, Takeda N,
Morita H, Yasunaga H, Komuro I. Metabolically
Healthy Obesity and the Risk of Cardiovascular
Disease in General Population: Analysis of a
Nationwide Epidemiological Database. Circ J
2021;85:914-920
Itoh H, Kaneko H, Kiriyama H, Kamon T, Fujiu
K, Morita K, Yotsumoto H, Michihata N, Jo T,
Takeda N, Morita H, Yasunaga H, Komuro I.
Reverse J-shaped relationship between bodymass index and in-hospital mortality of patients
hospitalized for heart failure in Japan. Heart andVessels. 2021;36(3):383-392.
Itoh H, Kaneko H, Fujiu K, Kiriyama H, Morita
K, Kamon T, Michihata N, Jo T, Takeda N,
Morita H, Yasunaga H, Komuro I. Risk Factors
and Lifestyles in the Development of Atrial
Fibrillation Among Individuals Aged 20-39 Years.
American Journal of Cardiology. 2021;155:
40-44.
Iwagami M, Kumazawa R, Miyamoto Y, Ito Y,
Ishimaru M, Morita K, Hamada S, Tamiya N,
Yasunaga H. Risk of Cancer in Association with
Ranitidine and Nizatidine vs Other H2 Blockers:
Analysis of the Japan Medical Data Center
Claims Database 2005-2018. Drug Safety. 2021;
44(3):361-371.
Jimba T, Kaneko H, Yano Y, Itoh H, Yotsumoto H,
Seki H, Morita K, Kiriyama H, Kamon T, Fujiu K,
Michihata N, Jo T, Takeda N, Morita H,
Nishiyama A, Node K, Yasunaga H, Komuro
I.Relation of the Metabolic Syndrome to Incident
Colorectal Cancer in Young Adults Aged 20 to 49
Years. American Journal of Cardioloy 2021;158:
132−138.
Jin X, Tamiya N, Uda K, Yasunaga H. The impactof additional payments on functional decline
among long-term care health facility residents inJapan. Age and Ageing. 2021;50(6):2055-2062.
Jo T, Michihata N, Yamana H, Morita K,
Ishimaru M, Yamauchi Y, Hasegawa W,
Urushiyama H, Uda K, Matsui H, Fushimi K,
Yasunaga H, Nagase T. Risk of drug-induced

23.

24.

25.

26.

27.

28.

interstitial lung disease in hospitalised patients: anested case–control study. Thorax. 2021;76(12):1193-1199.
Kaneko H, Itoh H, Kamiya K, Morita K,
Sugimoto T, Konishi M, Kiriyama H, Kamon T,
Fujiu K, Michihata N, Jo T, Takeda N, Morita H,
Yasunaga H, Komuro I. Acute-Phase Initiation of
Cardiac Rehabilitation and Clinical Outcomes in
Hospitalized Patients for Acute Heart Failure. Int
J Cardiol. 2021;340:36-41.
Kaneko H, Yano Y, Itoh H, Morita K, Kiriyama H,
Kamon T, Fujiu K, Michihata N, Jo T, Takeda N,
Morita H, Nishiyama A, Node K, Bakris G,
Miura K, Muntner P, Viera AJ, Oparil S,
Lloyd-Jones DM, Yasunaga H, Komuro K.
Untreated
Hypertension
andSubsequent
Incidence of Colorectal Cancer: Analysis of a
Nationwide Epidemiological Database. Journal of
American Heart Association. 2021;10(22):e022479.
Kaneko H, Yano Y, Itoh H, Morita K, Kiriyama H,
Kamon T, Fujiu K, Michihata N, Jo T, Takeda N,
Morita H, Node K, Carey RM, Lima JAC, OparilS, Yasunaga H, Komuro I. Association of Blood
Pressure Classification Using the 2017 American
College of Cardiology/American Heart Association Blood Pressure Guideline With Risk of Heart
Failure and Atrial Fibrillation. Circulation. 2021;
143(23):2244-2253.
Kaneko H, Itoh H, Yotsumoto H, Kiriyama H,
Kamon T, Fujiu K, Morita K, Michihata N, Jo T,
Takeda N, Morita H, Yasunaga H, Komuro I.
Impact of hospital volume on clinical outcomesof hospitalized heart failure patients: Analysis ofa nationwide database including 447,818 patientswith heart failure. BMC Cardiovascular
Disorders. 2021;21:49
Kaneko H, Itoh H, Kiriyama H, Kamon T, Fujiu
K, Morita K, Michihata N, Jo T, Takeda N,
Morita H, Yasunaga H, Komuro I. Possible
association between eating behaviors andcardiovascular disease in the general population:
Analysis of a nationwide epidemiological
database. Atherosclerosis 2021;320:79-85.
Kaneko H, Itoh H, Morita K, Sugimoto T,
Konishi M, Kamiya K, Kiriyama H, Kamon T,
Fujiu K, Michihata N, Jo T, Takeda N, Morita H,

354

29.

30.

31.

32.

33.

34.

35.

Yasunaga H, Komuro I. Early Initiation of
Feeding and In-hospital Outcomes in Patients
Hospitalized for Acute Heart Failure. American
Journal of Cardiology 2021;145:85-90.
Kaneko H, Itoh H, Kiriyama H, Kamon T, Fujiu
K, Morita K, Michihata N, Jo T, Takeda N,
Morita H, Yasunaga H, Komuro I. Lipid Profile
and Subsequent Cardiovascular Disease among
Adults Aged < 50 Years. American Journal of
Cardiology 2021;142:59-65.
Kaneko H, Itoh H, Kiriyama H, Kamon T, Fujiu
K, Morita K, Michihata N, Jo T, Takeda N,
Morita H, Yasunaga H, Komuro I. Fasting plasma
glucose and subsequent cardiovascular disease
among young adults: Analysis of a nationwide
epidemiological database. Atherosclerosis 2021;
319:35-41.
Kaneko H, Itoh H, Yotsumoto H, Kiriyama H,
Kamon T, Fujiu K, Morita K, Kashiwabara K,Michihata N, Jo T, Morita H, Yasunaga H,
Komuro I. Cardiovascular Health Metrics of
87,160 Couples: Analysis of a Nationwide
Epidemiological Database. Journal of Atherosclerosis and Thrombosis. 2021;28(5):535-543.
Katsuki R, Jo T, Yasunaga H, Ishimaru M,
Sakamoto T. Outcomes of Self-expandable Metal
Stent as Bridge to Surgery versus Emergency
Surgery for Left-sided Obstructing Colon Cancer:
A Retrospective Cohort Study. Am J Surg. 2021;
221(1):168-173.
Katsuki Y. Jo T, Yasunaga H, Kumazawa R, Uda
K. Outcomes of Laparoscopic versus Open
Pancreatoduodenectomy: A Nationwide Retrospective Cohort Study. Surgery. 2021;169(6):1427-1433.
Kawata M, Taketomi S, Inui H, Matsui H,
Fushimi K, Yamagami H, Yasunaga H, Tanaka S.
Type of bone graft and primary diagnosis wereassociated with nosocomial surgical site infection
after high tibial osteotomy: analysis of a national
database. Knee Surgery, Sports Traumatology,
Arthroscopy. 2021;29(2):429-436.
Kim HS, Cheng HS, Yamana H, Lee S, Yoon NH,
Lin YC, Fushimi K, Yasunaga H. Variations in
Hip Fracture Inpatient Care in Japan, Korea, andTaiwan: An Analysis of Health Administrative

36.

37.

38.

39.

40.

41.

42.

Data. BMC Health Services Research. 2021;
21(1):694.
Kiriyama H, Kaneko H, Itoh H, Kamon T, Morita
K, Jo T, Fujiu K, Daimon M, Takeda N, Morita H,
Yasunaga H, Komuro I. Surgical Treatment for
Infective Endocarditis in the Aging Society: aNationwide Retrospective Study in Japan. OpenHeart. 2021;8(1):e001627.
Kitamura T, Nakajima M, Kawamura I,
Kaszynski RH, Ohbe H, Sasabuchi Y, Matsui H,
Fushimi K, Fukamizu S, Yasunaga H. Safety andeffectiveness of intracardiac echocardiography inventricular tachycardia ablation: A nationwide
observational study. Heart and Vessels. 2021;
36(7):1009-1015.
Koizumi M, Ishimaru M, Matsui H, Fushimi K,
Yamasoba T, Yasunaga H. Factors associatedwith the occurrence of stomal stenosis aftertracheostomy in adults. Auris Nasus Larynx.
2021;48(5):973-977.
Kondo Y, Ohbe H, Aso S, Matsui H, Fushimi K,
Tanaka H, Yasunaga H. Efficacy of prophylactic
antibiotics during extracorporeal membrane
oxygenation: A nationwide cohort study. Annalsof the American Thoracic Society. 2021;18(11):1861-1867.
Konishi T, Fujiogi M, Michihata N, Kumazawa R,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Outcomes of nonoperative treatment
for gastroduodenal ulcer perforation: anationwide study of 14,918 inpatients in Japan.
Journal of Gastrointestinal Surgery 2021;25(11):2770-2777
Konishi T, Fujiogi M, Michihata M, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Association between body massindex and localization of breast cancer: resultsfrom a nationwide inpatient database in Japan.
Breast Cancer Research and Treatment. 2021;
185(1):175-182.
Konishi T. Fujiogi M, Michihata N, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Comparison of short-term surgicaloutcomes between men and women with breast
cancer: a retrospective study using nationwide
inpatient data in Japan. Breast Cancer Research
and Treatment. 2021;186(3):731-739.

355

43. Konishi T, Fujiogi M, Michihata N, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Comparing outcomes of nonoperative treatment for adhesive small bowel
obstruction with and without antibiotics. Journalof Infection and Chemotherapy. 2021;27(5):690695.
44. Konishi T, Fujiogi M, Michihata N, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Comparisons of postoperative
outcomes after breast cancer surgery in patientswith and without renal replacement therapy: amatched-pair cohort study using a Japanesenationwide inpatient database. Breast Cancer.
2021;28(5):1112-1119.
45. Konishi T, Fujiogi M, Michihata N, Niwa T,
Morita K, Matsui H, Fushimi K, Tanabe M, Seto
Y, Yasunaga H. Impact of body mass index on
short-term outcomes after differentiated thyroid
cancer surgery: a nationwide inpatient databasestudy in Japan. European Thyroid Journal. 2021;
11(1):e210081.
46. Konishi T, Fujiogi M, Michihata N,
Tanaka-Mizutani H, Morita K, Matsui H,
Fushimi K, Tanabe M, Seto Y, Yasunaga H.
Breast cancer surgery in patients withschizophrenia: short-term outcomes from anationwide cohort. British Journal of Surgery.
2021;108:168–173.
47. Kurakawa K, Okada A, Manaka K, Konishi T, Jo
T, Ono S, Uda K, Michihata N, Matsui H,
Fushimi K, Yamaguchi S, Yamauchi T, Nangaku
M, Yasunaga H, Kadowaki T. Clinicalcharacteristics and incidences of benign andmalignant insulinoma using a national inpatient
database in Japan. Journal of Clinical
Endocrinology & Metabolism. 2021;106(12):3477-3486.
48. Makito K, Matsui H, Fushimi K, Yasunaga H.
Spinal epidural hematoma and abscess after
neuraxial anesthesia: a historical cohort study
using the Japanese Diagnosis Procedure
Combination database. Canadian Journal of
Anesthesia. 2021;68(1):42-52.
49. Matsuda K, Jo T, Toyama K, Nakazaki K, Matsui
H, Fushimi K, Yasunaga H. Efficacy ofrecombinant human soluble thrombomodulin in

50.

51.

52.

53.

54.

55.

56.

induction therapy for acute promyelocytic
leukemia. Thrombosis Research. 2021;202:173175.
Matsuda K, Ise M, Shimura A, Honda A,
Masamoto Y, Jo T, Yasunaga H, Kurokawa M.
Use of wide-spectrum antimicrobials with blood
culture tests during chemotherapy as an accurate
marker of febrile neutropenia in the DPC
database: A validation study. Journal of Infection
and Chemotherapy. 2021;27(10):1541-1542.
Matsuda K, Jo T, Toyama K, Nakazaki K, Matsui
H, Fushimi K, Yasunaga H, Kurokawa M. Risk
factors for early in-hospital death in patients whodeveloped coagulopathy during induction therapy
for acute promyelocytic leukemia: a nation-wide
analysis in Japan. Annals of Hematology. 2021;
100(10):2613-2619.
Matsuda K, Jo T, Miyauchi M, Toyama K,
Nakazaki K, Matsui H, Fushimi K, Yasunaga H,
Kurokawa M. Difference of preventing effects of
G-CSF according to age in patients withmalignant lymphoma: a nation-wide analysis inJapan. Journal of Infection and Chemotherapy.
2021;27(8):1151-1155.
Matsuzaki S, Kaneko H, Yano Y, Itoh H, Fukui A,
Morita M, Kiriyama H, Kamon T, Fujiu K, Seki
H, Michihata N, Jo T, Takeda N, Morita H,
Nakamura S, Yokoo T, Nishiyama A, Node K,
Yasunaga H, Komuro I. Association Between
Blood Pressure Classification Using the 2017
ACC/AHA Blood Pressure Guideline and Retinal
Atherosclerosis. American Journal of Hypertension. 2021;34(10):1049-1056.
Miyamoto Y, Ohbe H, Ishimaru M, Matsui H,
Fushimi K, Yasunaga H. Effect of tranexamic
acid in patients with colonic diverticular
bleeding: a nationwide inpatient database study.
Journal of Gastroenterology and Hepatology
2021;36(4):999-1005.
Miyamoto Y, Ohbe H, Goto T, Yasunaga H.
Association between intensive care unit
admission of a patient and mental disorders in the
spouse: a retrospective matched-pair cohort study.
Journal of Intensive Care. 2021;9(1):69.
Miyano S, Michihata N, Sada K, Uda K, Matsui
H, Fushimi K, Nangaku M, Yasunaga H.
Comparison of fracture risk between proton

356

57.

58.

59.

60.

61.

62.

pump inhibitors and histamine-2 receptor
antagonists in AAV patients: A nested casecontrol study. Rheumatology. 2021;60(4):17171723.
Mizuno S, Sachiko Ono 2, Hideo Yasunaga 3,
Hirotaro Iwase 4. Factors associated withmethamphetamine use in Japanese people whodied of unnatural causes: Analysis using forensic
autopsy reports. Forensic Science International.
2021;327:110946.
Mongkonchoo K, Yamana H, Aso S, Machidad
M, Takasaki Y, Jo T, Yasunaga H,
Chongsuvivatwong Y, Liabsuetrakul T. Predictionof outpatient visits and expenditure under the
Universal Coverage Scheme in Bangkok using
subscriber's attributes: a random forest analysis.
Public Health in Practice. 2021;2:100190.
Morita K, Fukahori H, Ogawara H, Iwagami M,
Matsui H, Okura T, Itoh S, Fushimi K, Yasunaga
H. Outcomes of a financial incentive scheme fordementia care by dementia specialist teams inacute-care hospitals: a difference-in-differences
analysis of a nationwide retrospective cohort
study in Japan. International Journal of Geriatric
Psychiatry. 2021;36(9):1386-1397.
Nakamura K, Ohbe H, Ikeda K, Uda K, Furuya H,
Furuta S, Nakajima M, Sasabuchi Y, Matsui H,
Fushimi K, Yasunaga H, Nakajima H.
Intravenous
cyclophosphamidein
acuteexacerbation of rheumatoid arthritis-related
interstitial lung disease: a propensity-matchedanalysis using a nationwide inpatient database.
Seminars in Arthritis and Rheumatism. 2021;
51(5):977-982.
Naruse K, Shigemi D, Hashiguchi M, Imamura
M, Yasunaga H, Arai T. Placental abruption ineach phenotype of hypertensive disorders ofpregnancy: a retrospective cohort study using anational
inpatientdatabaseinJapan.
Hypertension Research. 2021;44(2):232-238.
Nozawa H, Ishizawa T, Yasunaga H, Ishii H,
Sonoda H, Emoto S, Murono K, Sasaki K, Kawai
K, Akamatsu N, Kaneko J, Arita J, Hasegawa K,
Ishihara S. Open and/or laparoscopic one-stage
resections of primary colorectal cancer andsynchronous liver metastases –an observational
study. Medicine. 2021;100(11):e25205.

63. Oda K, Aso S, Hattori Y, Yamaguchi F, Matsui H,
Fushimi K, Yasunaga H, Morita A. Snowfall
reduces the risk of chronic subdural hematoma
onset: Analysis of an administrative database inJapan. Surgial Neurology International 2021;12:
69.
64. Ohbe H, Nakamura K, Uda K, Matsui H,
Yasunaga H. Effect of early rehabilitation on
physical function in patients undergoing coronary
artery bypass grafting: a nationwide inpatient
database study. Journal of Clinical Medicine
2021;10(4):618
65. Ohbe H, Matsui H, Fushimi K, Yasunaga H.
Small-bore feeding tube versus large-bore sump
tube for early enteral nutrition in mechanicallyventilated patients: a nationwide inpatient
database study. Clinical Nutrition. 2021;40(6):4113-4119.
66. Ohbe H, Matsui H, Fushimi K, Yasunaga H.
Epidemiology of Chronic Critical Illness inJapan: A Nationwide Inpatient Database Study.
Crit Care Med 2021;49(1):70-78
67. Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H.
Clinical trajectories of suicide attempts andself-harm in patients admitted to acute-care
hospitals in Japan: a nationwide inpatient
database study. Journal of Epidemiology. 2021;
31(3):231-236.
68. Ohbe H, Sasabuchi Y, Yamana H, Matsui H,
Yasunaga H. Intensive care unit versus
high-dependency care unit for mechanicallyventilated patients with pneumonia: a nationwide
comparative effectiveness study. The Lancet
Regional Health - Western Pacific. 2021;13:
100185.
69. Ohbe H, Yasunaga H. Spouse’s cardiovasculardisease as a risk factor for cardiovascular diseasein middle-aged adults: a matched-pair cohort
study. Circulation: Cardiovascular Quality andOutcomes. 2021;14(8):e007649.
70. Ohbe H, Iwagami M, Sasabuchi Y, Yasunaga H.
Increased risk of infective endocarditis after
traumatic skin wound. Heart. 2021;107(23):18681874
71. Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H.
Effect of Daikenchuto for mechanicallyventilated patients with enteral feeding

357

72.

73.

74.

75.

76.

77.

78.

intolerance: a propensity score-matched analysis
using a nationwide administrative inpatient
database. Journal of Parenteral and Enteral
Nutrition. 2021;45(8):1703-1713
Ohbe H, Matsui H, Yasunaga H. Intensive careunit versus high-dependency care unit forpatients with acute heart failure: a nationwide
propensity score-matched cohort study. J
Intensive Care. 2021;9(1):78.
Ohbe H, Yamana H, Matsui H, Yasunaga H.
Development and validation of a procedure-basedorgan failure assessment model for patients in theintensive care unit: an administrative databasestudy. Acute Medicine & Surgery. 2021;8(1):e719.
Okada A, Ono S, Yamaguchi S, Yamana H,
Kurakawa K, Michihata N, Matsui H, Nangaku
M, Yamauchi T, Yasunaga H, Kadowaki T.
Association between nutritional guidance or
ophthalmological examination and discontinuation of physician visits in patients with newly
diagnosed diabetes: a retrospective cohort study
using a nationwide database. Journal of Diabetes
Investigation. 2021;12(9):1619-1631.
Okada A, Yamana H, Morita K, Sato Y,
Yamaguchi S, Kurakawa K, Michihata N, Matsui
H, Fushimi K, Nangaku M, Yamauchi T,
Yasunaga H, Kadowaki T. Potassium concentration in initial fluid therapy and in-hospitalmortality of patients with diabetic ketoacidosis.
Journal of Clinical Endocrinology & Metabolism.
2021;106(5):e2162-e2175.
Okubo Y, Horimukai K, Michihata N, Morita K,
Matsui H, Fushimi K, Yasunaga H. Association
between early antibiotic treatment and clinicaloutcomes in children hospitalized for an asthma
exacerbation. Journal of Allergy and Clinical
Immunology. 2021:114-122.e14.
Okubo Y, Michihata N, Morisaki N, Yoshida K,
Matsui H, Fushimi K, Yasunaga H. Effects of
glucocorticoids on hospitalized children with
anaphylaxis. Pediatric Emergency Care. 2021;
37(5):255-259.
Ono S, Ishimaru M, Ida Y, Yamana H, Ono Y,
Hoshi K, Yasunaga H. Validity of diagnoses andprocedures in Japanese dental claims data. BMC
Health Services Research. 2021;21(1):1116.

79. Otaka S, Aso S, Matsui H, Fushimi K, Yasunaga
H. Association between parenteral nutrition in theearly phase and outcomes in patients withabdominal trauma undergoing emergency
laparotomy: A retrospective nationwide study.
Clinical Nutrition ESPEN 2021;41:371-376
80. Otaka S, Aso S, Matsui H, Fushimi K, Yasunaga
H.. Associations between early parenteralnutritionandin-hospitaloutcomesinunderweight patients with gastrointestinal surgery.
Clinical Nutrition ESPEN 2021;43:464-470.
81. Sakamoto T, Fujiogi M, Matsui H, Fushimi K,
Yasunaga H. Comparing perioperative mortality
andmorbidityofminimally
invasiveesophagectomy versus open esophagectomy foresophageal cancer: a nationwide retrospective
analysis. Annals of Surgery. 2021;274(2):324330.
82. Sakamoto Y, Yamauchi Y, Jo T, Michihata N,
Hasegawa W, Takeshima H, Matsui H, Fushimi K,
Yasunaga H, Nagase T. In-hospital mortality
associated with community-acquired pneumonia
due to methicillin-resistant Staphylococcus
aureus: a matched-pair cohort study. BMC
Pulmonary Medicine. 2021;21(1):345.
83. Sako A, Yasunaga H, Matsui H, Fushimi K, Yanai
H, Gu Y, Ohmagari N. Hospitalization for
Urinary Tract Infections in Japan, 2010–2015: A
Retrospective Study Using a National Inpatient
Database. BMC Infectious Diseases. 2021;21(1):1048.
84. Sato D, Goto T, Uda K, Kumazawa R, Matsui H,
Yasunaga H. Impact of national guidelines for
antimicrobial stewardship to reduce antibiotic use
in upper respiratory tract infection andgastroenteritis. Infection Control & Hospital
Epidemiology 2021;42:280 – 286
85. Sato Y, Morita K, Okada A, Matsui H, Fushimi K,
Yasunaga H. Factors affecting in-hospitalmortality of diabetic ketoacidosis patients: A
retrospective cohort study. Diabetes Research andClinical Practice 2021;171:108588.
86. Sawada R, Yamana H, Shinoda Y, Tsuda Y,
Matsui H, Fushimi K, Kobayashi H,
Matsubayashi Y, Yasunaga H, Tanaka S, Haga N.
Predictive factors of 30-day mortality after
surgery for spinal metastasis: Analysis of a

358

87.

88.

89.

90.

91.

92.

93.

94.

nationwide database. Journal of Orthopaedic
Science. 2021;26(4):666-671.
Seki M, Kaneko H, Morita H, Itoh H, Morita K,
Matsuoka S, Kiriyama H, Kamon T, Fujiu K,
Michihata N, Jo T, Takeda N, Yano Y, Nakamura
S, Node K, Yasunaga H, Komuro I. Relation ofSerum Uric Acid and Cardiovascular Events in
Young Adults Aged 20-49 Years. American
Journal of Cardiology 2021;152:150-157.
Shigemi D, Isogai S, Uda K, Aso S, Matsui H,
Fushimi K, Yasunaga H. Association between
rehabilitation during hospitalization and perinatal
outcomes among pregnant women withthreatened preterm birth. The Journal of
Maternal-Fetal & Neonatal Medicine. 2021;
34(7):1028-1033
Shigemi D, Hashimoto Y, Michihata N, Yasunaga
H. Effect of Japanese herbal Kampo medicines
on live birth rate in women with recurrent
pregnancy loss. International Journal of
Gynecology and Obstetrics. 2021;153(3):489495.
Shigemi D, Hashimoto Y, Michihata N, Yasunaga
H. Impact of maternal depression and anxietyrelated disorders on live birth rate in women withrecurrent pregnancy loss. Human Fertility. 2021;
20;1-8.
Shigemi D, Morishima T, Yamana H, Yasunaga H,
Miyashiro I. Validity of initial cancer diagnoses
in the Diagnosis Procedure Combination data inJapan. Cancer Epidemiology. 2021;74:102016.
Shinozaki N, Morita K, Matsui H, Jo T, Yasunaga
H. Semisolid versus liquid nutrients and 30-day
readmission in gastrostomy tube-fed patients: apropensity-matchedanalysis.
Journalof
Parenteral and Enteral Nutrition. 2021;45(4):720-728.
Shiozawa M, Kaneko H, Itoh H, Morita K, Okada
A, Matsuoka S, Kiriyama H, Kamon T, Fujiu K,
Michihata N, Jo T, Takeda N, Morita H,
Nakamura S, Node K, Yasunaga H, Komuro I.
Association of Body Mass Index with Ischemicand Hemorrhagic Stroke. Nutrients. 2021;13(7):2343.
Shirane S, Michihata N, Yoshiuchi K, Ariyoshi K,
Iwase S, Morita K, Matsui H, Fushimi K,
Yasunaga H. Evaluation of quality indicators near

death in older adult cancer decedents in Japan: A
nationwide retrospective cohort study. Japanese
Journal of Clinical Oncology. 2021;51(11)1643–
1648.
95. Suzuki T, Michihata N, Aso S, Yoshikawa T,
Saito K, Matsui H, Fushimi K, Yasunaga H.
Sodium-containing versus sodium-trace preparations of IVIG for children with Kawasaki diseasein the acute phase. European Journal of Pediatrics.
2021 ;180(11):3279-3286.
96. Takano A, Yamana H, Ono S, Matsui H,
Yasunaga H. Outpatient treatment following
alcohol screening at health checkups and change
in drinking patterns among excessive drinkers
with lifestyle-related diseases. Preventive
Medicine Reports. 2021;24:101549.
97. Takiguchi T, Ohbe H, Nakajima M, Sasabuchi Y,
Tagami T, Matsui H, Fushimi K, Yokobori S,
Yasunaga H. Intermittent versus continuous
neuromuscular
blockadeduringtargettemperature management after cardiac arrest: anationwide observational study. Journal of
Critical Care 2021;62:276-282.
98. Takeuchi Y, Kumamaru H, Hagiwara Y, Matsui H,
Yasunaga H, Miyata H, Matsuyama Y.
Sodium-glucose cotransporter-2 inhibitors andthe risk of urinary tract infection among diabetic
patients in Japan: Target trial emulation using anationwide administrative claims database.
Diabetes, Obesity and Metabolism. 2021;23(6):1379-1388.
99. Tanaka G, Jo T, Tamiya H, Sakamoto Y,
Hasegawa W, Matsui H, Fushimi K, Yasunaga H,
Nagase T. Factors affecting in-hospital mortalityof non-tuberculous mycobacterial pulmonary
disease. BMC Infectious Diseases 2021;21:698.
100. Taniguchi K, Ohbe H, Yamakawa K, Matsui H,
Fushimi K, Yasunaga H. Recombinant
thrombomodulin in disseminated intravascular
coagulation associated with stage IV solid
tumors: a nationwide observational study inJapan. Thrombosis and Haemostasis. 2021;
121(1):36-45.
101. Tsuchiya A, Tsutsumi Y, Yasunaga H, Yasuda S,
Yuzawa K, Kushimoto S. Long-term Functional
Outcomes, Quality of Life, and Patient Trajectory

359

in 1 Trauma Survivors: A Study Protocol. Annalsof Clinical Epidemiology. 2021;3(2):59–66.
102. Ugata Y, Michihata N, Matsui H, Fushimi K,
Yasunaga H. Impact of proton pump inhibitors on
mortality and severe esophageal injury after
catheter ablation for atrial fibrillation: anationwide retrospective study using propensity
score matching. Heart and Vessels. 2021;36(11):1730-1738.
103. Urushiyama H, Jo T, Hasegawa W, Ando T,
Sakamoto Y, Uda K, Matsui H, Fushimi K,
Yasunaga H, Nagase T. Preoperative use of
pirfenidone and reduced risk of postoperative
severe respiratory complications in patients with
idiopathic pulmonary fibrosis: propensity scorematched analysis using a nationwide database inJapan. Respirology. 2021;26(6):590-596.
104. Yagi M, Morita K, Matsui H, Michihata N,
Fushimi K, Koyama T, Fujitani J, Yasunaga H.
Outcomes after Intensive Rehabilitation for
Mechanically-ventilated Patients: A Nationwide
Retrospective Cohort Study. Archives of Physical
Medicine and Rehabilitation. 2021;102(2):280289.
105. Yamamoto N, Ohbe H, Tomita Y, Yorifuji T,
Nakajima M, Sasabuchi Y, Miyamoto Y, Matsui
H, Noda T, Yasunaga H. Associations between
early surgery and postoperative outcomes inelderly patients with distal femur fracture: a
retrospective cohort study. Journal of Clinical
Medicine. 2021;10(24):5800.
106. Yamana H, Iba A, Tomio J, Ono S, Jo T,
Yasunaga H. Treatment of latent tuberculosis
infection in patients receiving biologic agents.
Journal of Infection and Chemotherapy. 2021;
27(2):243-249.
107. Yamana H, Ono S, Michihata N, Jo T, Yasunaga
H. Association between maoto use and hospitalization for seasonal influenza in a nonelderly
cohort in Japan. Internal Medicine. 2021;60(21):3401-3408.
108. Yamana H, Imai S, Yamasaki K, Horiguchi H,
Ario K, Komatsu T, Sugimoto R, Katsushima S,
Naganuma A, Mano Y, Yamashita T, Kamitsukasa
H, Tsuruta S, Jo T, Yasunaga H, Fushimi K,
Yatsuhashi H. Prognosis of patients with livercirrhosis: a multi-center retrospective observa-

tional study. Hepatology Research. 2021;51(12):1196-1206.
109. Yamazaki R, Ohbe H, Matsuda Y, Kito S, Morita
K, Matsui H, Fushimi K, Yasunaga H. Earlyelectroconvulsive therapy in patients with major
depressive disorder: a propensity score-matchedanalysis using a nationwide inpatient database inJapan. The Journal of ECT. 2021;37(3):176-181.
110. Yasui H, Michihata N, Matsui H, Fushimi K,
Iwase S, Yoshiuchi K, Sakata Y, Yasunaga H.
Association between ambulance use andhospitalization costs among heart failure patients.
Heart and Vessels. 2021;36(5):654-658.
111. Yokoyama A, Sakamoto Y, Jo T, Urushiyama H,
Tamiya H, Tanaka G, Matsui H, Fushimi K,
Yasunaga H, Nagase T. Pulmonary disease as arisk factor for transfusion-related acute lunginjury. ERJ Open Research. 2021;7(3):000392021.
112. Yoshihara S, Yamana H, Akahane M, Kishimoto
M, Nishioka Y, Noda T, Matsui H, Fushimi K,
Yasunaga H, Kasahara K, Imamura T.
Association between Prophylactic Antibiotic Use
for Transarterial Chemoembolization and Occurrence of Liver Abscess: A Retrospective Cohort
Study. Clinical Microbiology and Infection.
2021; 27(10):1514.e5-1514.e10.
113. Yoshii E, Yamana H, Ono S, Matsui H, Yasunaga
H. Association between allergic or autoimmune
diseases and incidence of endometriosis: A nested
case-control study using a health insurance
claims database. Am J Reprod Immunol. 2021;
86(5):e13486.

360

Department of HealthCommunication
Professor
Takahiro Kiuchi, M.D., Ph.D.

Associate Professor
Tsuyoshi Okuhara, Ph.D., MPH

Homepage

http://www.umin.ac.jp/hc/

Introduction and Organization
The Department of Health Communication wasestablished as a part of the newly developed School of
Public Health (professional graduate school) in April
2007, which was derived from the University Hospital
Medical Information Network (UMIN) Center. It
consists of two faculty members: a professor and an
associate professor.
Health communication is a major discipline in schoolof public health, especially in the US, and there aremany graduate programs and research centers forhealth communication. On the other hand, there havebeen few such departments in Japan, although theimportance of the health communication discipline has
gradually been recognized among the academic
society as well as among general public. Our department was established one of the few departments
specialized in health communication in Japan.

Teaching Activities
The Department of Health Communication, within the
School of Public Health, is a professional graduate
program that aims to foster the development of
medical and public health professionals as well as
researchers. We strive to make the most of our
professional activities and experience at UMIN Center.
We provide lectures and practical instruction in the
program. The following is the current curriculum:[Health Communication Lectures]
1. Introduction to health communication
2. Evaluation and research in health communication
3. Media and communication (1): Television
4. Media and communication (2): News paper
5. Media and communication (3): Internet
6. Improving communication based on empiricalresearch
7. Patient and public education
8. Communication with foreign patients
9. Communication for behavioral changes
10. Entertainment education
11. Visual communication
12. Communicating for policy and advocacy
13. Communication in group and organization
14. Group discussion[Health Communication Practice]
1. Health writing (1) Creating a document to support
patients and families.
2. Health writing (2) Creating a document toencourage behavior change
3. MBTI (Myers-Briggs Type Indicator) (1)(2)(3)4. Mass communication: Media doctor
5. Coaching
6. Health writing (3) Presentation and discussion[Medical research and CDISC standards]
1. Introduction to data management in clinicalresearch
2. Introduction to CDISC standards

361

3.
4.
5.
6.
7.

Standardization of case report form – CDASH
Data and metadata – Define.xml
Standardization of dataset for analysis – AdaM
Electronic application by CDISC standards
Standardization of data format – SDTM

In the undergraduate program, we present lectures
entitled “Medical Literature Informatics” and “healthcommunication.”

Research Activities(1) Research related to UMIN activities
The research that continues from the UMIN center ischaracterized by the following.
■ A focus on health informatics and communication
The Department of Health Communication is the only
research institute in Japan that carries out healthinformatics and communication-related research,
addressing areas such as the Internet and satellite
communications.
■ Targeting health information science, not healthcare information practiceCurrently, main topics of the research at most medical
informatics programs in Japan focus on information
for healthcare practice, such as hospital information
systems, electronic medical record systems, telemedicine, and electronic billing systems. In contrast,
the Department of Health Communication has focusedon information systems for medical science, such as
medical literature databases, data registries for clinicalstudies, and information systems for medical
education.
Most systems developed at the UMIN Center havebeen subjects for research. In particular, we publishedand reported systems utilizing advanced technologies
and having scientifically meaningful concepts at
academic conferences.
■ Information Systems for Clinical Epidemiologic
Studies
We have developed and applied information systems
for clinical epidemiological studies. Recently, we havefocused on research in electronic formats andstandardization that are related to clinical research,such as the Clinical Data Interchange Standards
Consortium (CDISC). We utilized the achievements
attained by the medical research data center at the
UMIN.
■ Research Regarding the Security of an Information
Network
The study addresses a Virtual Private Network (VPN),
and secure transactions with electronic mail(encryption), which have been also utilized for systemmanagement at the UMIN Center.
(2) Research on health communication
Currently, “health communication” is becoming animportant concept in the distribution of clinical results
for the improvement of population-based clinicaloutcomes. We have conducted health communication
research focusing on knowledge and skills in“informatics” and “communication.” The following
are current research topics at the Department of HealthCommunication.
■ Research on communication to support behavioral
change of healthcare consumers
Communication that is easy for patients and citizens
to understand and that supports more appropriate
decision-making and behavioral change by patientsand citizens is the foundation of effective medical careand public health. We are developing and evaluating
messages that support behavioral change of healthcare
consumers.
■ Research on Media
Mass media and social media have a social influence;
however, their quality of information varies. We
analyze the health care information distributed bymass media and social media, and examine the impact
of media information on health care consumers..
■ Research on Patient-Professional Relationship andCommunication
Communication between patients and health care
professionals is the foundation of effective health care.
We investigate the relationship of patient and provider

362

characteristics with their communication behaviors,
and impacts of the communication on patient
outcomes.
■ Research on Health Literacy
The increase in media reports and the rapid expansionof the Internet have rendered various sources of healthinformation more available to the general public. Thus,
skills in understanding and applying information
about health issues may have a substantial impact on
health behaviors and health outcomes. These skills
have recently been conceptualized as health literacy.
We investigate its relationship with patient andprovider communication, and patient health behaviors
and outcomes.

References
1.

2.

3.

4.

5.

6.

Okuhara T, Okada H, Goto E, Kiuchi T.
Readability assessment of HPV vaccination andcervical cancer information: a systematic scoping
review. Healthcare. 2021; 9(10):1246.
Okuhara T, Okada H, Goto E, Kiuchi T. Urgent
need for writing education in schools of medicine
and public health to address vaccine hesitancy.
International Journal of Medical Education.
2021; 12:166-168.
Okuhara T, Okada H, Kiuchi T. Lessons Learned
from a Writing to Learn Program for Public
Health Students at the University of Tokyo.
Journal of Medical Education and Curricular
Development. 2021;8:23821205211032014.
Iye R, Okuhara T, Okada H, Yokota R, Kiuchi T.
A content analysis of video advertisements for
dietary supplements in Japan. Healthcare. 2021;
9(6):742.
Okuhara T, Ishikawa H, Ueno H, Okada H,
Kiuchi T. Readability assessment of vaccine
information: a systematic review for addressing
vaccine hesitancy. Patient Education andCounseling. 2021;105(2):331-338.
Okada H, Morita T, Kiuchi T, Okuhara T,
Kizawa Y. Health Care Providers' Knowledge,
Confidence, Difficulties, and Practices after
Completing a Communication Skills Training
Program for Advance Care Planning Discussion
in Japan. Annals of Palliative Medicine. 2021;

7.

10(7):7225-7235.
Shirabe R, Okuhara T, Yokota R, Okada H, GotoE, Kiuchib T. Changes in Anxiety and StressAmong Pregnant Women During the COVID-19
Pandemic: Content Analysis of a Japanese Social
Question-and-Answer Website. JMIR Pediatrics
and Parenting 2021;4(3):e27733.

School of Public Health
2. Behavioral Health Sciences

364

Departments ofHealth and Social Behavior &Health Education and HealthSociology
Professor in health and social behavior
Hideki Hashimoto, M.D., D.PH.

Lecturer
Daisuke Takagi, Ph. D. (health and social behavior)
Masamitsu Kamada, Ph. D.(health education and health sociology)

Homepage http://webpark1166.sakura.ne.jp/
Introduction and Organization
The department originated as one of the firstdepartments dedicated to health education andbehavioral science in Japan, led by former Prof.
Emeritus Tadao Miyasaka, who had double degrees of
M.D. from the University of Tokyo and MPH in healtheducation from Harvard School of Public Health in1950s. He was succeeded by a sociologist, former
Prof. Kyoichi Sonoda who founded the first healthsociology department affiliated with the medical
school in Japan. Since then, the program has beenleading research focusing on socio-behavioral aspectsof health in this country. The legend was extended byformer Prof. Chieko Kawada who raised academic andpractical attention on the concept of empowerment
and adult pedagogy in health education. Since 1997,
the department was further evolved by Prof. Ichiro
Kai who integrated diverse health and social science
disciplines into social gerontology program, and by
Associate Prof. Yoshihiko Yamazaki who ledsociological research projects on salutogenesis, social
stigma, power, and agency in health settings. The
departments were reorganized under the newly
established School of Public Health since 2007. In

2012, the Department of Social Gerontology has beenrenamed as the Department of Health and Social
Behavior to apply a life-course perspective to a wider
range of social conditions and human well-being.
The new department intends to further integrate
health science (medicine and public health) and social
science (economics, sociology, and psychology) toreveal a causal mechanism linking social structure andindividual health for realizing health equity as afundamental goal to human security.

Teaching activities
The departments offer four courses in the master
degree program for public health, and seven courses
in the undergraduate program for the Integrated
Health Sciences track.
1. Graduate Courses, School of Public Health
1) Health and Society I & II: The course wasconsiderably renewed to focus on inequity,
discrimination,socialexclusion,andsociopolitical activities to overcome thesechallenges through community building. The
renewed course invites adjunctive lecturers
specialized in ageism, gender discrimination,

365

child poverty, and foreign residents in Japan,
each focusing a specific topic of social
determinants of health. Class II offers morepractical topics to make change in social
problems through advocacy, social business, andcommunity management, through small group
work and student presentation of small projects.
2) Health Education: The course provides basic
knowledge on relevant behavioral theories forhealth promotion and behavioral modification,
followed by case method learning on healtheducational intervention in community, school,
and work places. The case discussion was
facilitated by invited lecturers to reach practicallessons for effective communication.
3) Health Sociology: Sociology in medicine andsociology applied to health issues are treated in
the systemic course of lectures, covering social
model of health, medical gaze and socializationof health professionals, phenomenology ofchronic ills, and culture and health.
4) Comparative health systems in Asia: Started in
2020, jointly offered by Prof. Soonman Kwon in
Seoul National University. The course provides
basic frame/theory for comparative analysis ofhealth systems and offers specific country cases
for in-class discussion.
2. Undergraduate Courses, School of Integrated
Health Sciences
1) Introduction to social survey and practice;
Provides introductory lecture on sampling,
psychometrics, design of social survey andquestionnaires. Students are asked to conduct amini social survey within class on the theme theychoose as relevant in their class experience.
2) Health and Society (former Health sociology);
Lecture series on social model of healthgeneration, social relationship and health,chronic illness experience, and social stigma.
3) Health education
Case scenario based practicum and lectures on
health promotion intervention in clinical, school,
and worksite settings.
4) Social security and welfare program: Lecture
series on the history and the current systems ofhealth care security and welfare policies in thiscountry.
5) Integrated Lectures of Public Health Sciences I(jointly offered by the faculty of Health
Sciences)
6) Scientific writing
7) Critical reading/writing of epidemiologicalstudies8) Integrated Practicum of Public Health Sciences
II (jointly offered with Department of Medical
Ethics).

Research activities
The Department has contributed to an ongoing
research of socioeconomic status and health/functions
among elderly population in the collaboration with the
School of Economics of the University of Tokyo andthe Research Institute of Economic, Industry, andTechnology. The Japanese Study of Ageing andRetirement (J-STAR) is a sister study with the U.S.
Health and Retirement Study, Study of Health,Ageing, and Retirement in Europe (SHARE), EnglandLongitudinal Survey of Ageing (ELSA), and theirglobal sisters in Asian countries. The scope of JSTAR
is diverse; contribution of health for successful ageing,social economic conditions and access to health care,household economy and its impact on life styles suchas eating habits and nutrition, impact of retirement
onto cognitive function, etc..
Since 2010, the Department has launched anotherpanel study of younger generation, the Japanese studyof Stratification, Health, Income, and Neighborhood(J-SHINE) in collaboration with researcher groups on
neuroscience, economics, sociology, and social
psychology. The aim of this comprehensive panel
study is to identify a mechanism how socio-economic
environments get to “under-skin” to cause social
gradient of health across socio-economic positions. In
the year of 2011, the JSHINE conducted a
supplemental survey to respondent’s spouse andchildren. Main and supplement surveys were followedin 2012 and 2013, respectively. Obtained panel data
are made open to a broader range of researchers under
the data-control committee, to share analytic schemeand to enhance inter-disciplinary studies so as tobetter identify common factors as well as uniquefactors affecting health inequality in Japanese context.

366

Following third follow-up for children conducted in
2015-2016, and third follow-up of respondent adults
in 2017. Facing the COVID-19 pandemic since early
2020, JSHINE project conducted an additional survey
in 2020 December to evaluate the social,
psychological, and economic impact incurred by the
pandemic and related social restriction policies.
The department kept a close relationship with thestudy project of a large cohort for social epidemiology
in gerontology, called Japan Gerontological
Evaluation Study (JAGES) that covers more than 30
municipalities and approximately 200,000 participating old people in the community. The project purports
to reveal social relationship and its impact on healthin later life.
Dr. Takagi, in collaboration with Niigata University,
is preparing for a social epidemiological survey ofcommunity-dwelling older adults in Myanmar andMalaysia. In these countries that have distinctive
stage of economic development, culture, and ageing
rate, this study aims at verifying applicability of theexisting social models of health and building new
theories based on each country’s context. A
probability proportionate sampling of sites andselection of local investigators have been completed
in 2017, and interview surveys is underway in 2020
before COVID-19 and political difficulty started.
Dr. Kamada, in collaboration with Tokyo Medical
University, Harvard University, and Unnan
Municipality authority has been conducting acommunity-based intervention program to enhance
exercise habits. He is also actively engaged indeveloping a gamification program throughsmartphone to enhance walking habits among thecommunity.
Prof. Hashimoto started a joint project with the Tokyo
Metropolitan Government on the information
management in the field of welfare programs to tackle
child maltreatment. The project purports to develop
standardized information systems and support skills
development for effective case recording to enhanceinter-sector communication and improve the qualityof welfare activities.

Other Social activities
The department continued to join the public healthcenter to support efficient information management
during the pandemic surge of COVID19 in Adachi
Ward in Metropolitan Tokyo.

Publications
Peer reviewed journals
1. Kamada M, Hayashi H, Shiba K, Taguri M,
Kondo N, Lee IM, Kawachi I. Large-scale
fandom-based gamification intervention toincrease physical activity: a quasi-experimental
study. Medicine & Science in Sports & Exercise.
54(1):181-188, 2022. DOI: 10.1249/MSS.0000
000000002770
2. Bauman AE, Kamada M, Reis RS, Troiano RP,
Ding D, Milton K, Murphy N, Hallal PC. An
evidence-based assessment of the impact of the
Olympic Games on population levels of physicalactivity. Lancet. 398(10298), 456-464, 2021. doi:
10.1016/S0140-6736(21)01165-X.
3. Tobías A, Casals M, Saez M, Kamada M, Kim Y.
Impacts of ambient temperature and seasonalchanges on sports injuries in Madrid, Spain: atime-series regression analysis. BMJ Open Sport
Exerc Med. 7(4):e001205, 2021. DOI: 10.1136/
bmjsem-2021-001205.
4. Sasaki N, Obikane E, Vedanthan R, Imamura K,
Cuijpers P, Shimazu T, Kamada M, Kawakami N,
Nishi D. Implementation Outcome Scales for
Digital Mental Health (iOSDMH): scale
development and cross-sectional study. JMIR
Formative Research. 5(11):e24332, 2021. doi:10.
2196/24332
5. Abe T, Okuyama K, Hamano T, Kamada M,
Isomura M, Nabika T, Miyazaki R. Association
between hilliness and walking speed incommunity-dwelling older Japanese adults: A
cross-sectional study. Arch Gerontol Geriatr.
97:104510, 2021. doi:10.1016/j.archger.2021.
1045106. Saito Y, Tanaka A, Tajima T, Ito T, Aihara Y,
Nakano K, Kamada M, Inoue S, Miyachi M, Lee
IM, Oguma Y. A community-wide intervention
to promote physical activity: A five-year quasiexperimental study. Prev Med. 150:106708, 2021.
doi:10.1016/j.ypmed.2021.106708

367

7.

8.

9.

10.

11.

12.

13.

14.

Shiba K, Torres JM, Daoud A, Inoue K,
Kanamori S, Tsuji T, Kamada M, Kondo K,
Kawachi I. Estimating the impact of sustainedsocial participation on depressive symptoms inolder adults. Epidemiology. 32(6):886-895, 2021.
doi: 10.1097/EDE.0000000000001395
Amagasa S, et al. Smartphone and wearable
device use in physical activity evaluation in
healthcare scienc. Jpn J Public Health. 68(9):585-596, 2021.
Masuda R, Lanier P, Peisner-Feinberg E,
Hashimoto H. A Quasi-Experimental Study of
the Effects of Pre-Kindergarten Education on
Pediatric Asthma. Int J Environ Res Public
Health. 2021 Oct 5;18(19):10461. doi: 10.3390/
ijerph181910461.
Kim H, Jeon B, Doetter L, Tamiya N, Hashimoto
H. (2021). Same same but different? Comparing
institutional performance in the long‐term caresystems of Japan and South Korea. Social Policy& Administration. 10.1111/spol.12761.
Kanamori, M., Hanazato, M., Takagi, D., Kondo,
K., Ojima, T., Amemiya, A., & Kondo, N. (2021).
Differences in depressive symptoms by rurality
in Japan: A cross-sectional multilevel study
using different aggregation units of municipalities and neighborhoods (JAGES). International
Journal of Health Geographies, 20:42.
Nishio, M., Takagi, D., Shinozaki, T., & Kondo,
N. (2021). Community social networks, individual social participation and dietary behavior
among older Japanese adults: Examining
mediation using nonlinear structural equation
models for three-wave longitudinal data.
Preventive Medicine, 149:106613.
Sasaki, Y., Shobugawa., Y, Nozaki., I, Takagi, D.,
Nagamine, Y., Funato, M., Chihara, Y.,
Shirakura, Y., Lwin, K. T., Zin, P. E., Bo, T. Z.,
Sone, T., Win, H. H. (2021). Rural-urban
differences in the factors affecting depressive
symptoms among older adults of two regions in
Myanmar. International Journal of Environmental Research and Public Health, 18:2818.
Sasaki, Y., Shobugawa, Y., Nozaki, I., Takagi, D.,
Nagamine, Y., Funato, M., Chihara, Y.,
Shirakura, Y., Lwin, K. T., Zin, P. E., Bo, T. Z.,
Sone, T., Win, H. H. (2021). Association

between depressive symptoms and objective/
subjective socioeconomic status among older
adults of two regions in Myanmar. PloS ONE, 16:e0245489.
Book chapter
1. Takagi D. (2021).Social network and social
contagion. In Inada Y. eds. Human relationshipwith Social capital view (pp. 64-80). Nippon
Hyoronsha.

School of Public Health
3. Health Services Sciences

369

Department of Clinical
Information Engineering
Professor
Hiroshi Oyama, M.D., Ph.D.

Assistant professor
Ayako Kohyama-Koganeya, Ph.D.

Project Assistant Professor
Toki Saito, Ph.D.

Homepage:

http://park.itc.u-tokyo.ac.jp/CIEMedUTokyo/wp/

Introduction and Organization
Information engineering significantly impacts
computer hardware, software, and data processing. It
is a discipline that seeks objective data andemphasizes the conception of new data transfer
methods, storage, processing, and input/output. It also
targets research on developing computer devices andsystems.
Reviewing the history of the application ofcomputers in medicine, calculating machines forsupporting scientists and technologists first appearedin the 1950s. In the 1960s, computers were used foraccounting and various statistics. The personal
computer appeared in the 1980s and was adopted for
personal use in many professions. The systematizationof large hospitals, such as university hospitals, pushedahead rapidly.
In the 1990s, the computer began to help humanthinking, such as in presentations, design, anddiscovery. When computers became connected
through the internet, the distribution of information
became very easy and rapid, both within organizations
and internationally.
In 2003, a high-quality, "finished" sequence of thehuman genome was completed. At the dawn of thetwenty-first century, bioinformatics appeared as a new
discipline, one that uses applied mathematics,
informatics, statistics, computer science, and bio-chemistry to solve biological problems. In medicine,advanced information technologies have been applied
to health information infrastructures, electrical clinicalguidelines, and knowledge navigation systems.
In response to the needs of the time, the Departmentof Clinical Information Engineering (CIE) wasestablished at the School of Public Health in April
2007. Its predecessor was the clinical informationengineering division of clinical bioinformatics, using
Special Coordination Funds for Promoting Scienceand Technology from Japan's Ministry of Education,
Culture, Sports, Science, and Technology.

Teaching activities
The Department of Clinical Information Engineering
aims to nurture talented people with special
knowledge and skills at an international level to apply
advanced information technologies to practicalprojects in clinical medicine and the health sciences. It
offers courses on information system design,development methodology, evaluation, and project
management in biomedicine, health care, and publichealth in the School of Public Health, and data mining
and virtual reality for clinical decision-making insocial medicine.
Famous visiting lecturers and researchers from the
National Cancer Center and other universities havegiven lectures here, furthering our hope of becoming a

370

world leader in this field.
The education of graduate students is based on
weekly conferences at which the students present theirresearch projects' progress and discuss their future
directions.

References
1.

Research activities
Our research covers biomedical computer applications
that focus on biomedical data (collection, analysis,
and representation). It constitutes a combination of
information science, computer science, and clinicalscience designed to assist in managing and processing
data, information, and knowledge to support thepractice and delivery of clinical care. Our laboratory
is engaged in the following research activities:

2.

A)

4.

Computer Graphics & Virtual Reality (VR) for
Medical Science: Our research has three goals: toimprove the living conditions of in-patients withlimited physical activity by providing virtual
experiences; to develop new diagnostic methods
using medical imaging, and to develop a surgicaledutainment and preoperative surgical planningsupport system in virtual space.
The advantages of simulating surgicalprocedures using VR techniques include (1)practicing
thesurgicalprocedure
andimage-based training; (2) planning the surgicalprocedure for individual patients preoperatively
using VR images modeled from the patient's
preoperative computed tomography (CT) or
magnetic
resonance(MR)images,incollaboration with the Department of Neurosurgery; (3) allowing supervisors to evaluate aprocedure objectively; and (4) helping patientsand their families to better understand thesurgical procedure before and after the operation.
B)
Social Information Engineering for Public
Health (Public Health Informatics): Ourlaboratory research new tools and methodologies
for applying information, computer science, andtechnology to public health practice, research,and learning. We are studying differences in thecomputerization of public health in the US andJapan.

3.

5.

6.

Lem WG, Kohyama-Koganeya A, Saito T,
Oyama H. Effect of a Contact-based Educational
Intervention Using Virtual Reality on the Public
Stigma of Depression: A Randomized Controlled
Pilot Study. JMIR Form Res (forthcoming).
doi:10.2196/28072
Lem WG, Kohyama-Koganeya A, Saito T,
Oyama H. Virtual reality-based anti-stigma(VRAS) application for depression stigma
education. JMVR Vol 18. No.1, 2021.
Nagayo, Y., Saito, T., & Oyama, H. (2021). A
Novel Suture Training System for Open Surgery
Replicating Procedures Performed by Experts
Using Augmented Reality. Journal of Medical
Systems, 45(5), 1-9.
Nomura, S., Kin, T., Kunimatsu, A., Shojima, M.,
Watanebe, Y., Suzuki, Y., …, Oyama, H. & Saito,
N. (2021). Registration Method Between PhaseContrast Magnetic Resonance Angiography andTime-of-Flight Magnetic Resonance Angiography — A Preliminary Study. Journal of
Medical Imaging and Health Informatics, 11(1),33-39.
Koike, T., Kin, T., Tanaka, S., Sato, K., Uchida,T., Takeda, Y., …, Oyama, H. & Saito, N. (2021).
Development of a New Image-Guided Neuronavigation System: Mixed-Reality Projection
Mapping Is Accurate and Feasible. Operative
Neurosurgery.
Koike, T., Kin, T., Tanaka, S., Takeda, Y.,
Uchikawa, H., Shiode, T., … Oyama, H. & Saito,
N. (2021). Development of Innovative Neurosurgical Operation Support Method Using
Mixed-Reality Computer Graphics. World
neurosurgery: X, 11, 100102.

371

Department of Global
Environmental Health
Associate Professor
Yoonhee Kim, Ph.D.

Homepage https://sites.google.com/m.u-tokyo.ac.jp/envhealth/Introduction and Organization
The Department of Global Environmental Health(GEH) started under the School of Public Health(SPH), Graduate School of Medicine, in April 2018and has contributed to the master’s program (MPH). It
has been affiliated with the School of International
Health (SIH), Graduate School of Medicine since July
2018 as an Associate Department, and takes doctoral
students.
The GEH aims:
1. To study relationships between environmental
exposure and human health
2. To produce well-educated professionals with theacademic knowledge and ability to undertake
environmental epidemiological research

Education
This department provides two postgraduate courses
under SPH: 1) Environmental Health and 2) Methods
for Environmental Health Research. The former is an
introductory course in environmental epidemiologythat introduces basic concepts and methods to assess a
potential relationship between environmental stressors
and health outcomes at both individual and populationlevels. It also provides state-of-the-art scientificknowledge and interpretation for health risk/impact
assessment in environmental health perspectives. The
latter is an advanced course dealing with statisticaland epidemiological methodologies in environmental
epidemiology that provides the theory and practice ofa specific method to estimate the short-term effects ofenvironmental risk factors on human health.
Journal ClubGEH has participated in a weekly conference call withmultiple schools/institutes* to read and discuss articles
in environmental epidemiology.
*

Seoul National University, Korea Advanced Institute of Science &Technology (KAIST), National Institute for Environmental Studies,
University of Tsukuba, Kyoto University, and Nagasaki University

GEH R Seminar
Every other Tuesday, 11:00-12:30
Graduate students present fundamental knowledge andskills of R language and its applications that theylearned from R textbooks and/or research articles inenvironmental epidemiology. Sharing the basic andadvanced methodologies and discussion help students
develop their capacity to implement research projects.
All course lectures, thesis advising, and discussions inseminars are carried out in English.

Research
Our research interests particularly focus on climatechange and air pollution in human populations in thefield of environmental epidemiology. We address thescientific questions of how they link, quantify thehealth risks of a specific environmental factor, andfurther investigate social determinants that could
potentially modify the exposure-response relationships.
Our research collaborations include:

372

1. Global perspectives of seasonal variability ofsuicide and the short-term associations between
suicide and ambient temperature and air pollution
using a large-scale daily time-series databaseacross 26 countries, as a part of the Multi-Country
Multi-City Collaborative Research Network
2. Health risk assessment of climate change and air
pollution in northeast Asian countries
3. Nationwide studies on the short-term associations
between suicide and ambient temperature and air
pollution in Finland
4. Establishment of an early warning system for
malaria incidence in southern Africa

Publications
1.

2.

3.

4.

5.

Tobías A, Casals M, Saez M, Kamada M, Kim Y.
Impacts of ambient temperature and seasonalchanges on sports injuries in Madrid, Spain: atime-series regression analysis. BMJ Open Sport& Exercise Medicine 2021:7:e001205.
Kim Y, Park EH, Ng CFS, Chung Y, Hashimoto
K, Tashiro K, Hasunuma H, Doi M, Tamura K,
Moriuchi H, Nishiwaki Y, Kim H, Yi S-M, Kim
H, Hashizume M. Respiratory function declines
in children with asthma associated with chemical
species of fine particulate matter (PM2.5) inNagasaki, Japan. Environ Health 2021:20:110.
Tobías A, Hashizume M, Honda Y, Sera F, Ng
CFS, Kim Y, Roye D, Chung Y, Dang TN, Kim
H, Lee W, Íñiguez C, Vicedo-Cabrera A, et al.
Geographical Variations of the Minimum Mortality
Temperature at a Global Scale: A Multicountry
Study. Environmental Epidemiology 2021:5:e169.
Madaniyazi L, Chung Y, Kim Y, Tobias A, Ng
CFS, Seposo X, Guo Y, Honda Y, Gasparrini A,
Armstrong B, Hashizume M. Seasonality ofmortality under a changing climate: a time-series
analysis of mortality in Japan between 1972 and2015. Environ Health Prev Med. 2021:3:26:69.
Lee W, Ebi KL, Kim Y, Hashizume M, Honda Y,
Hashimoto H, Choi HM, Choi M, Kim H.
Heat-mortality risk and the population concentration of metropolitan areas in Japan: a nationwide
time-series study. International Journal of
Epidemiology 2021:50:602–612.

6.

Yu J, Park J, Choi T, Hashizume M, Kim Y,
Honda Y, Chung Y. Nonparametric Bayesianfunctional meta-regression: applications inenvironmental
epidemiology.
Journalof
Agricultural, Biological, and Environmental
Statistics 2021:26: 45–70.

Endowed Department

374

Department of Artificial
Intelligence in Healthcare
Project Associate Professor
Yoshimasa Kawazoe, M.D., Ph.D.

Project Research Associate
Emiko Shinohara, Ph.D.

Project Research Associate
Mai Hirabayashi, Ph.D.

Project Research Associate
Daisaku Shibata, Ph.D.

Project Researcher
Kiminori Shimamoto, M.E.

Homepage https://ai-health.m.u-tokyo.ac.jp/
Introduction and Organization
Practical applications based on the development of AI
technology call for a fundamental transformation of
the industrial structure. The global spread of
COVID-19 has significantly changed the way medicalcare, economy, and society operate. To maintain andfurther develop the quality of the Japanese society,which some consider to be in decline because of thefalling birth rate, rational and efficient social
management based on information and communications technology (ICT) as well as artificial intelligence(AI), become indispensable. This course wasestablished in 2018 at the University of Tokyo
Hospital Department of Planning, Information andManagement (Graduate School of Medicine
Department of Biomedical Informatics) as acollaborative course, to explore the form of new
medical services while promoting the development ofunderlying technologies, such as, ICT and AI. The
objective has been to contribute to human resource
development by forming a support base forresearchers involved in this field, and to develop joint
research beyond the boundaries of faculties anduniversities to contribute to the development of
medical care.

Teaching activities
We have promoted activities to train researchers aswell as students in this area inside and outside theuniversity. In 2021, we were in charge of the medical
informatics course at the University of Tokyo Facultyof Medicine designed for 4th-year students. We havealso taught courses to Graduate School of Medicine
School of Public Health professional master's degree
students and have contributed to courses on medical
RWD human resources development projects forworking adults. The courses have focused on
AI-related technologies in medical informatics. We
have provided research guidance to doctoral studentsof the Graduate School of Medicine Department of
Biomedical Informatics as well as Reproductive,
Developmental and Aging Sciences; researchguidance was provided at the individual level.

375

Research activities
Development of natural language
technique for medical treatment

processing

Symptoms and clinical findings, the relationshipbetween these and treatment actions are freely
described in the medical records of patients, unlike thetest values. The structuring and analysis of suchtextual information are expected to contribute to newclinical medical discoveries and medical safety. The
development of a natural language processing
technique for structuring text information requires anannotated text corpus with an annotated target text andspecific information on the subject of interest(symptoms, findings, etc.). In this course, we plan totarget case reports of intractable diseases designatedby the Ministry of Health, Labor and Welfare with theaim of developing a case report corpus thatconsistently
andcomprehensively
annotates
expressions that indicate the clinical condition ofpatients and the treatments that have been performed.
By using the annotated information, we aim to extract
information, such as the name of the patient's disease,the presence (or absence) of the kind of symptoms, thelocation of the symptoms, whether they are mild orsevere, whether they are related to the treatment
performed, the outcome at discharge, etc., from thetext for subsequent analysis. We are also developing amachine learning model that accurately reproduces theannotated information. The natural language
processing technique we are planning on developing
will be able to create text for the clinical fields of
medical records, structuring the details of the data.

glomerulus. Precise quantification of lesion area maylead to prediction of renal function prognosis based on
pathological images and new interpretation ofpathological findings.

Social activities
1.
2.

3.

4.

References
1.

2.

Research to support renal pathological diagnosis
With the development of deep neural networks, AI
development research in medical imaging has become
widespread. To date, we have received a Health Labor
Sciences Research Grant. Under multi-institutional
collaboration, we have been developing technology todetect minute glomeruli from digital pathologicalslides (whole slide images) along with research toclassify the pathological findings of the detected
glomeruli. In 2020, we further developed this researchand proceeded with the evaluation of theinteroperability of the developed technology acrossmultiple facilities to quantify the lesion area of theGave lectures at various seminars, describing ICT
related issues in the medical field utilizing AI.
Participated in the HL7-FHIR (Fast Healthcare
Interoperability Resources) implementation study
working group established under the Japan
Association of Medical Informatics ResearchGroup "Academic Research Group for Next
Generation Healthcare Record System,” andstudied the details necessary for proceeding with
the implementation of HL7-FHIR in Japan.
Involved in the discussions of the collection ofclinical information and the construction of
information systems as a member of the
Designated Core Hospitals for Cancer Genomic
Medicine Working Group (RPWG).
Promoted the standardization of disease names
registered in electronic medical records under the
standard disease name master working group.

3.

4.

Kawazoe Y, Shibata D, Shinohara E, Aramaki E,
Ohe K. A clinical specific BERT developed using ahuge Japanese clinical text corpus. PLoS One. 2021
Nov 9;16(11): e0259763.
Seki T, Kawazoe Y, Ohe K. Machine learningbased prediction of in-hospital mortality using
admission laboratory data: A retrospective, singlesite study using electronic health record data. PLoS
ONE. 2021;16(2): e0246640.
Ma X, Imai T, Shinohara E, Kasai S, Kato K,
Kagawa R, Ohe K. EHR2CCAS: A framework formapping EHR to disease knowledge presenting
causal chain of disorders – chronic kidney disease
example. J Biomed Inform. 2021 Mar; 115:103692.
Ishii, Futoshi, Reiko Hayashi, Emiko Shinohara,
Motomi Beppu. Application of Network Analysis toMultiple Causes of Death Data in Japan. The 29th
International Population Conference (IPC2021),
International Union for the Scientific Study ofPopulation (IUSSP), Dec. 9, 2021.

376

Health Economy and Society
PolicyProject Professor
Tomoyuki Takura, Ph.D, MEng.

Project Lecturer
Sayaka Horiuchi, MPH, MD
Mariko Tsuji, MD
Ayako Fuchigami, MD

Homepage

http://plaza.umin.ac.jp/hehp/

Introduction and Organization

Education

Health Economy and Society policy is a donatedfund course established in 22nd Century Medical andResearch Center in February 2017, which is donated by
10 companies, Development Bank of Japan Inc.,
Chugai Pharmaceutical Co., Ltd., Baxter Limited,
Nihon Medi-Physics Co., Ltd., Medibrain Corporation,
Asahi Kasei Medical Co., Ltd., NIPRO Corporation,
Toray Medical Co., Ltd., JMS Co., Ltd., and Terumo
Corporation, and is cooperating with Department of
Cardiac Surgery, Division of Nephrology and Endocrinology, and Department of Clinical Epidemiology &Health Economics as cooperating course.
The social structure has been changing over recent
years and it can be assumed that policies related to the
medical system and medical industry are at a
crossroads in Japan and may undergo dramatic changes
in the future. Our department was established to discuss
future healthcare systems (medical practices andsystems, economy and industry), particularly in termsof theory construction and validation studies pertaining
to the "evaluation of the value of the healthcare field"
and other topics. Concretely, we promote theoreticaland methodological research on health technology
assessment, cost effectiveness analysis, and thehealthcare industry structure, and aim to evaluate thevalue of healthcare technologies and healthcare
systems.

We also promote manpower training programs(Program for “The movements of medical value“: 18times in total) in health technology assessment withcollaboration departments, which is an extension
course. This program includes healthcare economics(pharmaceutical affairs system, financial and insurance
system, hospital accounting, cost-effectivenessevaluation, microeconomics) and data science (medical
big data, bayesian statistics, markov chain monte carlo
method, software analysis) and research ethics.

Research activities
We are engaging in the following research in orderto promote rational and evidence-based medical
resource investment, to support medical practice, andto promote advances in medical technology.
1) The evaluation of the cost effectiveness of various
therapies, including (but not limited to) VAD therapy
for severe heart failure, hemodialysis therapy forend-stage renal failure and radiological diagnostics.
2) A study of the socioeconomic impact of chronic pain
and health behavior (adherence) on the disease
burden and the financial burden (includinginternational comparison).
3) Testing and developing methods for evaluating labor377

productivity (e.g., the productivity of cardiology
doctors) by applying data envelopment analysis(DEA) techniques.
Moreover, we are also working on a project todevelop a forecasting model for health technology
assessment (HTA) and disease prevention that makes
use of big data and AI as data science. We have also
started a study that applies computational finance toforecast the market value of research and development
projects.

References
1.

2.

3.

4.

5.

Shohei Okazaki, Kei Shibuya, Yuhei Miyasaka,
Hidemasa Kawamura, Tomoyuki Takura, Tatsuya
Ohno. Cost-Effectiveness of Carbon-Ion Radiotherapy versus Stereotactic Body Radiotherapy for
Non-Small Cell Lung Cancer. Cancer Science.
2012;113(2):674-683. doi: 10.1111/cas.15216.
Tomoyuki Takura, Keiko Goto, Asao Honda.
Development of a predictive model for integrated
medical and long-term care resource consumption
based on health behaviour: application of healthcare big data of patients with circulatory diseases.
BMC medicine. 2021;19(1):15. doi: 10.1186/
s12916-020-01874-6.
Tomoyuki Takura, Akira Yuasa, Naohiro Yonemot,
Sven Demiya, Hiroyuki Matsuda, Nozomi Ebata,
Koichi Fujii, Muneaki Ishijima. Cost-effectiveness analysis of the treatment strategies with orwithout opioid medications in surgery-eligible
patients with osteoarthritis in Japan. Pharmaco
Economics - Open. 2021; 6(1): 33-45. doi: 10.
1007/s416 69-021-00292-5.
Tomoyuki Takura, Study Group: Research on
Appropriate Medical Treatment Prices for
Foreigners Visiting Japan. Preliminary Examination of an Appropriate Price Calculation Method
and Medical Treatment Costs for Foreign Visitors
in Japan. Int. J. Environ. Res. Public Health. 2021;
18(11):5837. doi: 10.3390/ijerph18115837.
Tomoyuki Takura, Hiroyoshi Yokoi, Nobuhiro
Tanaka, Naoya Matsumoto, Eri Yoshida, Tomoaki
Nakata, J-CONCIOUS Investigators. Healtheconomics-based verification of functional
myocardial ischemia evaluation of stable coronary

artery disease in Japan: A long-term longitudinal
study using propensity score matching. J Nucl
Cardiol. 2021. In press. doi: 10.1007/s12350-02002502-9.
6. Kaname Ueda, Tomoyuki Takura, Shinji Fujikoshi,
Juliana Meyers, Saurabh P Nagar, Hiroyuki
Enomoto. Long-Term Pain Management and
Health Care Resource Use Among an Employed
Population in Japan with Knee Osteoarthritis
Combined with Low Back Pain. Pain Med. 2021;
22(12):3041-3050. doi: 10.1093/pm/pnaa424.
7. Tomoyuki Takura. The Economic Aspects ofMedical Big Data. CANCER SCIENCE. 2021;
112(11):147-147.
8. Shiro Imagama, Hideki Murakami, Takashi Kaito,
Yukihiro Matsuyama, Toshihiko Yamashita,
Mamoru Kawakami, Kazuhisa Takahashi,
Munehito Yoshida, Seiji Ohtori, Toshihiko
Taguchi, Hirotaka Haro, Hiroshi Taneichi,
Masashi Yamazaki, Gen Inoue, Kotaro Nishida,
Hiroshi Yamada, Daijiro Kabata, Ayumi Shintani,
Motoki Iwasaki, Manabu Ito, Naohisa Miyakoshi,
Kazuo Yonenobu, Tomoyuki Takura, Joji Mochida,
Project Committee of the Japanese Society for
Spine Surgery and Related Research (JSSR).
Impact of background factors on outcomes ofpharmacological therapy for chronic low backpain: A nationwide multicenter prospective study.
J Orthop Sci. 2021 ;26(1):92-102. doi: 10.1016/j.
jos.2020.02.003.
9. Tomoyuki Takura. Adherence improves long-term
prognosis and medical costs in Japan. GaBi –online. 2021; 19(2). https://gabionline.net/generics/
research/Adherence-improves-long-term-prognosisand-medical-costs-in-Japan. (Accessed August 28,
2022)
10. Gen Inoue, Takashi Kaito, Yukihiro Matsuyama,
Toshihiko Yamashita, Mamoru Kawakami,
Kazuhisa Takahashi, Munehito Yoshida, Shiro
Imagama, Seiji Ohtori, Toshihiko Taguchi,
Hirotaka Haro, Hiroshi Taneichi, Masashi
Yamazaki, Kotaro Nishida, Hiroshi Yamada,
Daijiro Kabata, Ayumi Shintani, Motoki Iwasaki,
Manabu Ito, Naohisa Miyakoshi, Hideki
Murakami, Kazuo Yonenobu, Tomoyuki Takura,
Joji Mochida. Comparison of the Effectiveness of
Pharmacological Treatments for Patients with

378

Chronic Low Back Pain: A Nationwide,
Multicenter Study in Japan. 2021;5(4):252-263.
doi: 10.22603/ssrr.2020-0083.

379

Department of medical researchand the management ofmusculoskeletal pain
Professor
Koh Matsudaira, M.D,Ph.D.

Associate Professor
Hiroyuki Oka, M.D,Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/research/center22/contribute/undouki_toutu.html

Introduction and Organization
The department of medical research and the
management of musculoskeletal pain was establishedat the 22nd Century Medical and Research Centre
thanks to donations from ippon Zoki PharmaceuticalCo., Ltd., AYUMI Pharmaceutical Corporation, ONO
PHARMACEUTICAL CO., LTD., Chugai Pharmaceutical Co., Ltd., SOMPO Holdings, Inc., NuVasive
Japan Co., Ltd., Promotion of Practical Use of AI
Medical Diagnosis Support Equipment, MS&AD
InterRisk Research & Consulting, Inc, Inotech Co.,
Ltd., The Association for Preventive Medicine inJapan, DeNA Co., Ltd., Ibuki LLC. The department is
a collaboration among the Department ofOrthopaedics, the Department of Rehabilitation
Medicine. Currently, our aims are to design analgorithm for diagnosing and treating most types ofmusculoskeletal pain that do not have establishedtreatment guidelines and to elucidate evidence for the
possibility of developing causal therapies.
In the “Comprehensive Survey of Living Conditions”
and the “Survey on the Status of Occurrence of
Diseases at Work,” which were published by the
Health, Labour, and Welfare Ministry, the issues
affecting the locomotive apparatus over the years,
particularly low back pain and joint pain, have beenranked as the top complaints among citizens and as acause of absence from work. Musculoskeletal pain,

mainly low back pain and joint pain, is an issue with ahigh complaint rate that causes tremendous social
loss.
The course on medical research and the
management of musculoskeletal pain was madeavailable to provide more knowledge on highly
prevalent musculoskeletal pain and to become a coreprogramme in leading multidisciplinary clinicalresearch.
To achieve these goals, we will closely collaborate
with the Department of Orthopaedics, Department of
Spinal Surgery, Department of Rehabilitation. On thebasis of an extensive epidemiological survey, we will
identify risk factors that contribute to determining thetherapeutic strategy for treating musculoskeletal pain
as well as the prognosis. In addition, on the basis ofthese determined risk factors, we will develop andpropose diagnostic tools/algorithms as well as
prevention and treatment programmes. Then we willcollect and analyse clinical data and systematise thediagnosis, prevention, and treatment of chronic pain –mainly musculoskeletal pain.

Research activities
We will explore the risk factors that contribute todetermining the therapeutic strategy for treatingmusculoskeletal pain and the prognosis.

380

Prospects for future research

3.

1) Systematization of chronic pain, mainly motororgan pain (collection and analysis of clinical data)
A manual that can realize back pain prevention in thefield of industrial health, treatment and work balance
support for workers who have diseases that cause
motor pain, such as cancer patients, support forbalancing chronic pain and work/reducing healthcosts.
2) Development of diagnostic tools and treatment
programs for musculoskeletal pain
Development of back pain preventive exercise,development of sensor for presenting posture toprevent back pain, development of quantitativeevaluation system for knee oseteoarthritis X-ray basedon a large database, clinical information, and medical
images of musculoskeletal diseases. Developed asystem that predicts sarcopenia and muscle weakness
with high accuracy by using medical equipment(non-invasive and simple ultrasound and artificial
intelligence), spinal canal and paraspinal muscle oflumbar spine for quantitative evaluation of fatty
degeneration in humans (joint research with Dr.
Jeremy Fairbank, University of Oxford).
3) Fostering clinicians who are familiar withmusculoskeletal pain assessment and treatment, andenlightening the general public with evidence-basedknowledge about musculoskeletal pain

4.

5.

6.

References
1.

2.

Okada S, Oka H, Iwasaki H, Tsutsui S, Yamada H.
New diagnostic support tool for lumbosacralforaminal stenosis using radiographs of thelumbar spine. J Clin Neurosci. 2022 Feb;96:8-11.
doi: 10.1016/j.jocn.2021.12.009. Epub 2021 Dec
22. PMID: 34953440.
Yamada K, Fujii T, Kubota Y, Wakaizumi K, Oka
H, Matsudaira KO. Negative effect of anger onchronic pain intensity is modified by multiple
mood states other than anger: A large
population-based cross-sectional study in Japan.
Mod Rheumatol. 2021 Aug 12: roab035. doi:
10.1093/mr/roab035. Epub ahead of print. PMID:
34910207.

7.

8.

Horii C, Iidaka T, Muraki S, Oka H, Asai Y,
Tsutsui S, Hashizume H, Yamada H, Yoshida M,
Kawaguchi H, Nakamura K, Akune T, Oshima Y,
Tanaka S, Yoshimura N. The cumulative
incidence of and risk factors for morphometricsevere vertebral fractures in Japanese men andwomen: the ROAD study third and fourth
surveys. Osteoporos Int. 2022 Apr;33(4):889-899.
doi: 10.1007/s00198-021-06143-7. Epub 2021
Nov 19. PMID: 34797391.
Teraguchi M, Hashizume H, Oka H, Cheung JPY,
Samartzis D, Tamai H, Muraki S, Akune T,
Tanaka S, Yoshida M, Yoshimura N, Yamada H.
Detailed Subphenotyping of Lumbar Modic
Changes and Their Association with Low Back
Pain in a Large Population-Based Study: The
Wakayama Spine Study. Pain Ther. 2022 Mar;11(1):57-71. doi: 10.1007/s40122-021-00337-x.
Epub 2021 Nov 15. PMID: 34782999; PMCID:
PMC8861214.
Hira K, Nagata K, Hashizume H, Asai Y, Oka H,
Tsutsui S, Takami M, Iwasaki H, Muraki S,
Akune T, Iidaka T, Kawaguchi H, Nakamura K,
Yoshida M, Tanaka S, Yoshimura N, Yamada H.
Relationship of sagittal spinal alignment with low
back pain and physical performance in thegeneral population. Sci Rep. 2021 Oct 18;
11(1):20604. doi: 10.1038/s41598-021-00116-w.
PMID: 34663811; PMCID: PMC8523667.
Anan T, Kajiki S, Oka H, Fujii T, Kawamata K,
Mori K, Matsudaira K. Effects of an Artificial
Intelligence-Assisted Health Program on Workers
With Neck/Shoulder Pain/Stiffness and Low
Back Pain: Randomized Controlled Trial. JMIR
Mhealth Uhealth. 2021 Sep 24;9(9):e27535. doi:
10.2196/27535. PMID: 34559054; PMCID: PMC
8501409.
Nishizawa A; PO, Katsuhira J, Watanabe M, Oka
H, Matsudaira K. A simple method for estimating
the intervertebral disc compressive force basedon the posture analysis of community-dwellingolder adults. J Phys Ther Sci. 2021 May;33(5):423-428. doi: 10.1589/jpts.33.423. Epub 2021
May 15. PMID: 34083882; PMCID: PMC
8165360.
Ishii K, Oka H, Honda Y, Oguro D, Konno Y,
Kumeta K, Nishihara S, Matsuyama H, Kaneko I,

381

9.

10.

11.

12.

13.

Takeuchi Y, Watanabe Y, Kawano H, Ogata N.
Accuracy and reliability of a smartphone
application for measuring the knee joint angle. J
Phys Ther Sci. 2021 May;33(5):417-422. doi:
10.1589/jpts.33.417. Epub 2021 May 15. PMID:
34083881; PMCID: PMC8165359.
Yoshimoto T, Fujii T, Oka H, Kasahara S,
Kawamata K, Matsudaira K. Pain Status and Its
Association with Physical Activity, PsychologicalStress, and Telework among Japanese Workers
with Pain during the COVID-19 Pandemic. Int J
Environ Res Public Health. 2021 May 24;18(11):5595. doi: 10.3390/ijerph18115595. PMID:
34073863; PMCID: PMC8197253.
Otsuka Y, Iidaka T, Horii C, Muraki S, Oka H,
Nakamura K, Izumo T, Rogi T, Shibata H, Tanaka
S, Yoshimura N. Dietary Intake of Vitamin E andFats Associated with Sarcopenia in CommunityDwelling Older Japanese People: A CrossSectional Study from the Fifth Survey of the
ROAD Study. Nutrients. 2021 May 20;13(5):1730.
doi: 10.3390/nu13051730. PMID: 34065253;
PMCID: PMC8161000.
Kasahara S, Niwa SI, Matsudaira K, Sato N, Oka
H, Fujii T, Konno SI, Kikuchi SI, Yamada Y.
High Attention-Deficit/Hyperactivity Disorder
Scale Scores Among Patients with Persistent
Chronic Nonspecific Low Back Pain. Pain
Physician. 2021 May;24(3):E299-E307. PMID:
33988951.
Nagata K, Nakamoto H, Kato S, Takeshita Y,
Kawamura N, Ono T, Higashikawa A, Fukushima
M, Azuma S, Hara N, Oka H, Matsudaira K,
Tanaka S, Oshima Y. Minimum clinicallyimportant change for outcome scores among
patients aged 75 or over undergoing lumbar spine
surgery. Eur Spine J. 2021 May;30(5):1226-1234.
doi: 10.1007/s00586-021-06815-2. Epub 2021
Mar 20. PMID: 33743055.
Taniguchi T, Harada T, Iidaka T, Hashizume H,
Taniguchi W, Oka H, Asai Y, Muraki S, Akune T,
Nakamura K, Kawaguchi H, Yoshida M, Tanaka
S, Yamada H, Yoshimura N. Prevalence andassociated factors of pistol grip deformity inJapanese local residents. Sci Rep. 2021 Mar 16;
11(1):6025. doi: 10.1038/s41598-021-85521-x.
PMID: 33727622; PMCID: PMC7966377.

14. Tonosu J, Oka H, Watanabe K, Abe H,
Higashikawa A, Kawai T, Yamada K, Nakarai H,
Tanaka S, Matsudaira K. Characteristics of the
spinopelvic parameters of patients with sacroiliac
joint pain. Sci Rep. 2021 Mar 4;11(1):5189. doi:
10.1038/s41598-021-84737-1. PMID: 33664386;
PMCID: PMC7970840.
15. Doi T, Ohtomo N, Oguchi F, Tozawa K, Nakarai
H, Nakajima K, Sakamoto R, Okamoto N,
Nakamoto H, Kato S, Taniguchi Y, Matsubayashi
Y, Oka H, Matsudaira K, Tanaka S, Oshima Y.
Association Between Deep Posterior Cervical
Paraspinal Muscle Morphology and ClinicalFeatures in Patients With Cervical Ossification of
the Posterior Longitudinal Ligament. Global
Spine J. 2021 Jan 28:2192568221989655. doi:
10.1177/2192568221989655. Epub ahead of print.
PMID: 33504203.
16. Inanami H, Iwai H, Kato S, Takano Y, Yuzawa Y,
Yanagisawa K, Kaneko T, Segawa T, MatsudairaK, Oka H, Oshina M, Fukusima M, Saiki F,
Oshima Y. Partial Resection of Spinous Process
for the Elderly Patients with Thoraco-Lumbar
Kyphosis: Technical Report. Medicina (Kaunas).
2021 Jan 21;57(2):87. doi: 10.3390/medicina
57020087. PMID: 33494142; PMCID: PMC
7909842.
17. Kozaki T, Hashizume H, Nishiyama D, Iwasaki H,
Tsutsui S, Takami M, Yukawa Y, Minamide A,
Taniguchi T, Nagata K, Fukui D, Tamai H, Taiji
R, Murata S, Oka H, Yamada H. Adjacentsegment disease on hip joint as a complication of
spinal fusion surgery including sacroiliac joint
fixation. Eur Spine J. 2021 May;30(5):1314-1319.
doi: 10.1007/s00586-020-06700-4. Epub 2021
Jan 3. PMID: 33389138.
18. Oshima Y, Nagata K, Nakamoto H, Sakamoto R,
Takeshita Y, Ohtomo N, Kawamura N, Iizuka M,
Ono T, Nakajima K, Higashikawa A, Yoshimoto
T, Fujii T, Tanaka S, Oka H, Matsudaira K.
Validity of the Japanese core outcome measuresindex (COMI)-neck for cervical spine surgery: aprospective cohort study. Eur Spine J. 2021 Feb;
30(2):402-409. doi: 10.1007/s00586-020-066574. Epub 2020 Nov 19. PMID: 33211189.
19. Mera Y, Teraguchi M, Hashizume H, Oka H,
Muraki S, Akune T, Kawaguchi H, Nakamura K,

382

Tamai H, Tanaka S, Yoshida M, Yoshimura N,
Yamada H. Association between types of Modicchanges in the lumbar region and low back pain
in a large cohort: the Wakayama spine study. Eur
Spine J. 2021 Apr;30(4):1011-1017. doi: 10.
1007/s00586-020-06618-x. Epub 2020 Oct 9.
PMID: 33037486.
20. Jinnouchi H, Matsudaira K, Kitamura A,
Kakihana H, Oka H, Hayama-Terada M,
Yamagishi K, Kiyama M, Iso H; CIRCS
Investigators. Effects of brief self- exercise
education on the management of chronic low
back pain: A community- based, randomized,
parallel-group pragmatic trial. Mod Rheumatol.
2021 Jul;31(4):890-898. doi: 10.1080/14397595.
2020.1823603. Epub 2020 Oct 9. PMID:
32930621.
21. Ono K, Ohashi S, Oka H, Kadono Y, Yasui T,
Matsumoto T, Omata Y, Tanaka S. Evaluations ofdaily teriparatide using finite-element analysis
over 12 months in rheumatoid arthritis patients. J
Bone Miner Metab. 2021 Mar;39(2):270-277.
doi: 10.1007/s00774-020-01146-6. Epub 2020
Sep 4. PMID: 32886175.

383

Department of Osteoimmunology
Project Associate Professor
Kazuo Okamoto, Ph.D.

Project Assistant Professor
Asuka Terashima, Ph.D.

Homepage

http://www.osteoimmunology.com/kifu.html

Introduction and Organization
Bone is a key component of the skeletal-locomotor
system and serves as a calcium reservoir regulated by
the endocrine system in vertebrates. Bone also acts
as the “primary lymphoid organ” that harbors andmobilizes hematopoietic stem cells (HSCs) andimmune progenitor cells. Furthermore, the bone andimmune systems are closely related through a numberof shared regulatory molecules including cytokines,
receptors and signaling molecules.
Osteoimmunology is an interdisciplinary research field thatinvestigates the shared mechanisms and crosstalks
between the bone and the immune systems. Studies
on bone destruction associated rheumatoid arthritis(RA) have highlighted regulation of bone by the
immune cells and promoted this field. As seen in theclinical benefits of anti-TNF antibody, anti-IL-6
antibody and CTLA4-Ig on inflammation andosteoclast differentiation for the treatment of RA, theosteoimmunological insight is now of growing
importance in clinical applications. It is necessary tocomprehensively understand the interplay betweenbone and immune systems for elucidation of themolecular mechanisms underlying the pathogenesis ofvarious bone diseases (osteoporosis, osteoarthritis,
periodontal disease etc.) and immune diseases(autoimmune diseases, infectious diseases etc.).
Osteoimmunology is now emphasized by not only
the academic but also clinical sides, and theinternational competition has intensified in both basic
and pharmaceutical researches. This department was
founded as a new department focusing on the osteo-

immunology in May 2016. and now is supported by
AYUMI
Pharmaceutical
Corporation,
ChugaiPharmaceutical, MIKI HOUSE and Noevir. We aim
to understand the mechanisms underlying the pathogenesis of various skeletal and immune diseases, andto provide the molecular basis for novel drug
discovery in the field. Project Assistant Professor
Terashima left on September 30, 2021.

Teaching activities
As for under-graduate education, our department takes
a part in systemic lectures. We train post-doctoral
fellows, graduate and post-graduate students in
Department of Immunology, Graduate School of
Medicine and Faculty of Medicine, The University ofTokyo.

Research activities
By extending the concept of osteoimmunology tovarious skeletal and immune diseases, we aim tocomprehensively elucidate the crosstalks between thebone and immune systems involved in the pathogenesis of the diseases, and provide the molecularbasis for novel therapeutic strategies. Our achievement would help to improve the welfare and raise thelevel of medical treatment in the world.
Main research achievements
RANKL in bone, immunity and cancer
Bone is a dynamic organ that continuously
undergoes a process involving resorption andformation (bone remodeling), which are mediated by384

osteoclasts and osteoblasts, respectively.
An
imbalance of bone resorption and formation is often
central to metabolic bone diseases, including bone
destruction in RA, postmenopausal osteoporosis, bonetumors and osteopetrosis. Osteoclasts are large,
multinucleated cells formed by the fusion of precursor
cells of monocyte/macrophage lineage.
Matureosteoclasts degrade bone matrix proteins by secreting
proteolytic enzymes and decalcify the inorganic
components of bone by releasing hydrochloric acid.
RANKL is an essential cytokine for osteoclastdifferentiation. RANKL, which are produced by the
supporting mesenchymal cells including osteoblasts,
osteocytes and synovial fibroblasts, binds to its
receptor RANK expressed on osteoclast precursor
cells. Mice with a disruption of either Rank or Rankl
exhibit severe osteopetrosis accompanied by a tooth
eruption defect resulting from a complete lack ofosteoclasts. Mutations in the RANK and RANKL
genes have been identified in human patients withbone disorders such as autosomal recessive osteopetrosis. These genetic findings clearly demonstratethat RANK/RANKL signaling is essential for
osteoclastogenesis in vivo. We aim to elucidate themolecular mechanism underlying RANKL-induced
osteoclast differentiation, in order to develop thenovel therapeutic strategies for the treatment ofvarious bone diseases such as RA and osteoporosis(Tsukasaki et al, J Bone Miner Res, 2016; Okamoto etal, Physiol Rev, 2017). Recently, we have elucidated
the mechanism of osteoclastogenesis at the single celllevel by single-cell RNA sequencing analysis.
Osteoclast differentiation pathway can be divided into
multi stages, and we identified a number of genes that
determine each differentiation stage. We found thatthe transcriptional regulator Cited2 regulates theterminal differentiation step by promoting cell cycle
arrest. The single-cell analysis data covering all
pathways of osteoclast differentiation would be auseful resource for the development of therapeutic
treatments targeting osteoclasts (Tsukasaki et al, Nat
Metab, 2020).
RANKL plays crucial roles in not only osteoclastdifferentiation but also the immune system, including
lymph node development, thymic epithelial celldifferentiation and M cell differentiation in gut.
Thus, RANKL is one of the most important factors

explicitly linking the skeletal and immune systems.
RANKL is synthesized as a membrane-boundmolecule, which is cleaved into the soluble form byproteases. Both forms function as agonistic ligands
for RANK.
However, the functional difference
between the membrane-bound and soluble forms of
RANKL had been poorly understood in vivo. Thus,
we tried to elucidate the physiological andpathological significances of soluble RANKL bygenerating mice that selectively lack soluble RANKL.
Soluble RANKL-deficient mice did not show any
discernible osteopetrotic phenotype. In addition,soluble RANKL made no contribution to ovariectomyinduced osteoporosis.
Thus, membrane-boundRANKL mainly functions in osteoclast differentiationin vivo.
Furthermore, unlike RANKL-null mice,soluble RANKL-deficient mice had normal
development of the immune organs, including lymph
node development, thymic medullary epithelial celldifferentiation and M cell differentiation. Collectively,
we demonstrated that soluble RANKL is dispensablefor physiological regulation of bone and immune
systems (Asano et al, Nat Metab, 2019).
RANKL also deeply contributes to the pathogenesisof bone metastasis. In bone, tumor cells induce theRANKL expression in osteoblasts through the
production of PTHrP and IL-6. RANKL promotes
osteoclastic bone resorption, which provides space fortumor expansion and releases certain growth factors
from the degraded bone matrices to stimulate tumor
growth, forming a vicious cycle. In addition, RANK
is expressed at high levels on many different epithelial
tumor cells that preferentially metastasize to bone.
RANKL acts directly on RANK-expressing tumor
cells to increase tumor migration to bone. Notably,soluble RANKL contributes to bone metastasis byexerting a chemotactic activity in tumor cells
expressing RANK. Soluble RANKL deficiency inmice markedly suppressed the metastasis of murine
melanoma cell line B16F10 and breast cancer cell line
EO771, both of which express RANK, to bone
（Asano et al, Nat Metab, 2019; Okamoto, J Bone
Miner Metab, 2021）. Interestingly, the recent humanstudy indicates that breast cancer patients with highlevels of serum RANKL had an increased risk ofdeveloping bone metastases. Thus, to measure theserum RANKL level may help identify the patients

385

who have a high risk of development of bonemetastasis.
The RANKL decoy receptor osteoprotegerin (OPG)
regulates bone metabolism and the immune organ
development as an inhibitor of RANKL signal. OPG
is a soluble protein, which also circulates in the blood.
By analyzing osteoblast-specific, thymic epithelial
cell-specific and intestinal epithelial cell-specific
OPG-deficient mice, we showed that bone metabolism,
thymic epithelial cell differentiation and M celldifferentiation is controlled by OPG locally produced
in bone, thymus and intestine, respectively, but not bycirculating OPG. The findings further revealed theimportance of local regulation of the RANKL/RANK
system (Tsukasaki et al, Cell Rep, 2020).
Recently, a fully human anti-RANKL neutralizing
antibody has been introduced for the treatment of
osteoporosis and skeletal-related events by bonetumors. We have evaluated the efficacy of the novel
small molecule inhibitor against RANKL signaling
using mouse disease models (Guerrini et al, Immunity,2015). Using the mouse models of bone metastasis,
we have demonstrated that oral administration of thesmall-molecule RANKL inhibitor against RANKL
suppressed the metastasis of human breast cancer cellline and murine melanoma cell line to bone (Nakai etal, Bone Res, 2019).
Roles of T cells in bone destruction associated with
inflammation
The bone destruction in RA is the result of theenhanced osteoclast activity due to the inflammatory
responses triggered by the activation of pathogenic
helper T cells. We previously reported using amouse model of autoimmune arthritis that a subset of
Foxp3+ T cells loses Foxp3 expression under arthritic
conditions and converts into IL-17-prodcing T cells(called exFoxp3Th17 cells).
exFoxp3Th17 cells
display a greater capacity for inducing both synovitis
and osteoclastic bone resorption (Komatsu et al, Nat
Med, 2014). The conversion of Foxp3+ T cells into
effector T cells has also been observed in various
diseases such as diabetes and multiple sclerosis. We
have recently demonstrated that exFoxp3Th17 cells
also act as osteoclastogenic T cells in alveolar bone
destruction in periodontitis.
exFoxp3Th17 cells
accumulate in periodontitis tissues in response to oral

bacteria, and stimulate mesenchymal cells including
osteoblastic cells and periodontal ligament cells to
induce RANKL. We found that exFoxp3Th17 cells
protect against bacteria by evoking mucosal immune
responses as well as removing the tooth (Tsukasaki etal, Nat Commun, 2018). Our findings introduce a
new concept that bone destruction contributes to thehost defense against oral bacteria in periodontitis.
In recent years, Jak inhibitors have attracted
attention as potential agents for the autoimmune
diseases such as rheumatoid arthritis. We haverecently found that protein arginine methylation, a
post-translational modification, is critically involvedin the regulation of the Jak signaling pathway. T
cell-specific deficiency of the arginine methyltransferase PRMT5 led to a decrease in the number of
peripheral CD4, CD8 and regulatory T cells, and analmost complete loss of iNKT cells.
PRMT5mediated arginine methylation was essential for the
expression of the cytokine-signal-transducing components, the common cytokine receptor γ-chain (γc)
and JAK3, which are required for the development of
iNKT cells and the proliferation and survival of
peripheral T cells. PRMT5 induced the arginine
methylation of the spliceosomal component SmD3
that promoted the splicing of pre-mRNA encoding γc
and JAK3 (Inoue et al, Nature Immunol, 2018). This
study presented a novel regulatory mechanism
governing γc family cytokine-Jak3 signaling in T
cells.
Immune regulation by osteoblast in the bone marrow
HSCs have the capacity to differentiate into all
immune cells, and their activities require extrinsic
signals from the microenvironments (niches) in thebone marrow. Various cell types including CXCL12abundant reticular (CAR) cells, leptin receptorexpressing perivascular stromal cells, Nestin+
perivascular cells and neural cells have been shown to
be important for HSC maintenance. Although osteoblasts were first reported to function as the HSC nichein the early 2000s, the significance of the osteoblastic
niche had remained unclear. In order to clarify therole of osteoblasts in the hematopoiesis in the bonemarrow, we generated an inducible deletion system ofosteoblasts in adult mice. We found that inducible
ablation of osteoblast had no effect on the HSCs but

386

reduced the number of both common lymphoidprogenitors in the bone marrow and lymphocytes in
the periphery. Osteoblast-derived IL-7 is requiredfor development of common lymphoid progenitors inthe bone marrow (Terashima et al, Immunity, 2016).
Moreover, we showed that sepsis reduces theosteoblast number, which induces lymphopenia
through IL-7 downregulation. Our study identified anovel mechanism by which bone cells regulate theimmune system.

References
1.

2.

3.

Mikhail M Kostik, Maria A Makhova, Alexei S
Maletin, Shamai M Magomedova, Lybov S
Sorokina, Masayuki Tsukasaki, Kazuo Okamoto,
Hiroshi Takayanagi, Dmitriy S Vasiliev, Darya I
Kozlova, Alexander Yu Mushkin. Cytokine
profile in patients with chronic non-bacterial
osteomyelitis, juvenile idiopathic arthritis, andinsulin-dependent diabetes mellitus. Cytokine,
143: 155521, 2021
Komatsu N, Win S, Yan M, Huynh N C-N, Sawa
S, Tsukasaki M, Terashima A, Pluemsakunthai W,
Kollias G, Nakashima T, Takayanagi H. Plasma
cells promote osteoclastogenesis and periarticularbone loss in autoimmune arthritis. J Clin Invest.
131: e143060, 2021
Kazuo Okamoto. Role of RANKL in cancer
development and metastasis. Journal of Bone andMineral Metabolism, 39: 71-81, 2021

387

Department of Computational
Diagnostic Radiology andPreventive Medicine
Project Professor
Naoto Hayashi, M.D.,Ph.D.

Project Associate Professor
Takeharu Yoshikawa, M.D.,Ph.D.

Project Assistant Professor
Yukihiro Nomura, Ph.D., R.T.

Project Research Associate
Kensuke Asaba, M.D.,Ph.D., Eriko Maeda, M.D.,Ph.D., Soichiro Miki, M.D., Ph.D.,
Katsuhiro Koyama, M.D., Ph.D., Takayuki Fujiwara, M.D., Ph.D., Takahiro Nakao, M.D.,
Ph.D., Kanna Fujita, M.D., Ph.D., Mai Shimbo, M.D., Ph.D. Saori Koshino, M.D., Ph.D.

Project researcher
Masaya Akiyama, M.S., Hisaichi Shibata, Ph.D., Tomomi Takenaga, Ph.D., R.T.

Homepage

http://www.ut-radiology.umin.jp/division/cdrpm.html

Introduction and Organization

Clinical Activities

The Department of Computational Diagnostic
Radiology and Preventive Medicine (CDRPM) wasestablished in May 2005. It is under the supervision of
the Department of Radiology.
The aim of our research project is as follows: (1)to create a large database of health screening clinicaldata including medical images, (2) to develop methods
to analyze large volumes of medical images and to
search for algorithms to detect subtle abnormal
findings in these images, and (3) to evaluate theclinical usefulness of such image processing methods
and to apply the system in clinical settings.
The department comprises twelve professors andthree project researchers, along with a medical staff ofapproximately 70 employees in the health-screening
center.

CDRPM is responsible for the clinical activities in
the CDRPM Health Screening Center. The following
diagnostic imaging modalities are installed tofacilitate high level of diagnostic accuracy: positronemission computed tomography (PET), 3-teslamagnetic resonance imaging (3T-MRI) system, multidetector CT (MDCT), ultrasound imaging system, anddigital mammography.

Teaching Activities
At present, CDRPM does not accept students.
However, CDRPM participates in the education of
students and residents in the Department of Radiology.
CDRPM endeavors to help students whose research
themes include image analysis such as computerassisted detection, or epidemiologic studies employing

388

health-screening data.

Research Activities
1) Health screening database
We have developed a unique health screening information system to facilitate daily management of thehealth screening activities and to input healthscreening data. This information system is still underconstant revision. The medical images acquired in thehealth screenings are stored in the hospital picturearchiving and communication system (PACS) for
clinical use. Medical images used solely for research
purposes are stored in an independent PACS installedinside the CDRPM department.
2) Image processing software development
We have structured an integrated software developing
system to facilitate the production of image processing
software. The system is divided into the clinical partand the research part, with the data in the latter being
anonymized. The clinical part consists of case entry
for software development, and clinical application of
the developed software. The research part consists ofan interface to obtain images of the representative
cases to develop the software, and an interface to test
the developed software with the accumulated cases.
3) Clinical evaluation, application of software, andepidemiological studies
Researches based on the health-screening database arecarried out in collaboration with other researchers ofvarious specialties. Images are analyzed using thedeveloped software.

References
1)

2)

Aoyama G, Zhao L, Zhao S, Xue X, Zhong Y,
Yamauchi H, Tsukihara H, Maeda E, et al.
Automatic Aortic Valve Cusps Segmentationfrom CT Images Based on the Cascading
Multiple Deep Neural Networks. Journal of
Imaging 2022;8(1):11.
Fujiwara T, Takeda N, Hara H, Ishii S, Numata
G, Tokiwa H, et al. Three-Dimensional Visualization of Hypoxia-Induced Pulmonary Vascular
Remodeling in Mice. Circulation 2021;144(17):1452-1455.

3)

Goo HW, Siripornpitak S, Chen SJ, Lilyasari O,
Zhong YM, Latiff HA, Maeda E, et al. Pediatric
Cardiothoracic CT Guideline Provided by the
Asian Society of Cardiovascular Imaging
Congenital Heart Disease Study Group: Part 2.
Contemporary Clinical Applications. Korean J
Radiol 2021 Aug;22(8):1397-1415.
4) Goto K, Minatsuki S, Fujita K, Takeda N, Hatano
M, Komuro I. Two Siblings With Peripheral
Pulmonary
Arterial
Stenosis:
Pulmonary
Angiography of Advanced and Early Stages.
Chest 2022;161(2):e75-e80.
5) Han C, Rundo L, Murao K, Noguchi T,
Shimahara Y, Milacski ZÁ, Koshino S, et al.
MADGAN: Unsupervised medical anomaly
detection GAN using multiple adjacent brain
MRI slice reconstruction. BMC Bioinformatics
2021;22(2):1-20.
6) Hatano M, Jimba T, Fujiwara T, Tsuji M, Bujo C,
Ishida J, et al. Late-onset right ventricular failure
after continuous-flow left ventricular assist
device implantation: case presentation and reviewof the literature. J Cardiol 2021.
7) Hiroyuki KMT, Masaatsu A, Cristiano B, Rosa C,
Jon G, Naoto H, et al. First results of undersea
muography with the Tokyo-Bay Seafloor HyperKilometric Submarine Deep Detector. Scientificreports 2021;11(1):1-13.
8) Ishizuka M, Harada M, Nomura S, Ko T, Ikeda Y,
Guo J, Bujo S, Yanagisawa-Murakami H, Satoho
M, Yamada S, Kumaga H, Motozawa Y, Hara H,
Fujiwara T, et al. Author Correction: CXCR7
ameliorates myocardial infarction as a β-arrestinbiased receptor. Scientific Reports 2021;11(1):1-3.
9) Kamio S, Kubo T, Koshino S, Abe O. Successfultranscatheter arterial embolization for pseudoaneurysm of the deep femoral artery in a patientwith presumptive ACTA2-related vasculopathy.
Radiology Case Reports 2021;16(12):3652-3654.
10) Ko T, Nomura S, Fujita K, Yamada S, Zhang B,
Hatsuse S, et al. Cardiac Fibroblasts Are
Critically Involved in the Development of Heart
Failure by Inducing Cardiomyocyte Senescence.
Circulation 2021;144(Suppl_1):A9339-A9339.
11) Miki S, Nakao T, Nomura Y, Okimoto N,
Nyunoya K, Nakamura Y, et al. Computer-aided

389

detection of cerebral aneurysms with magnetic
resonance angiography: usefulness of volume
rendering to display lesion candidates. Japanese
Journal of Radiology 2021;39(7):652-658.
12) Miki S, Nomura Y, Hayashi N, Hanaoka S,
Maeda E, Yoshikawa T, et al. Prospective studyof spatial distribution of missed lung nodules byreaders in CT lung screening using computerassisted detection. Acad Radiol 2021;28(5):647654.
13) Nakamura Y, Hanaoka S, Nomura Y, Nakao T,
Miki S, Watadani T, et al. Automatic detection ofactionable radiology reports using bidirectional
encoder representations from transformers. BMC
Medical Informatics and Decision Making 2021;
21(1):1-19.
14) Nakao T, Hanaoka S, Nomura Y, Murata M,
Takenaga T, Miki S, et al. Unsupervised deep
anomaly detection in chest radiographs. J Digital
Imaging 2021;34(2):418-427.
15) Nakayama A, Kodera S, Morita H, Fujiwara T,
Takeda N, Komuro I. Cost-Effectiveness ofManagement for Hospitalized Patients GenderDifference Between Female and Male Cardiologists. International Heart Journal 2022;63(2):264-270.
16) Nomura Y, Hanaoka S, Nakao T, Hayashi N,
Yoshikawa T, Miki S, et al. Performance changes
due to differences in training data for cerebral
aneurysm detection in head MR angiography
images. Japanese Journal of Radiology 2021;
39(11):1039-1048.
17) Nomura Y, Hanaoka S, Takenaga T, Nakao T,
Shibata H, Miki S, et al. Preliminary study ofgeneralized semiautomatic segmentation for 3D
voxel labeling of lesions based on deep learning.
International Journal of Computer Assisted
Radiology and Surgery 2021;16(11):1901-1913.
18) Shibata H, Hanaoka S, Nomura Y, Nakao T, Sato
I, Sato D, et al. Versatile anomaly detection
method for medical images with semi-supervised
flow-based generative models. International
Journal of Computer Assisted Radiology andSurgery 2021;16(12):2261-2267.
19) Shohji T, Kuriyama K, Yanano N, Maeda E,
Katoh Y. Simple Method of Measuring SSDE for
Head CT: Facilitating PRE-CT Scan Dose

Calculation Using Specialized Head Scan Band.
Radiat Prot Dosimet 2021;197(1):1-11.
20) Suto A, Ueha R, Ogura T, Maeda E, Tatebayashi
M, Shimada D, et al. Swallowing computed
tomography and virtual reality as novel imaging
modalities for the diagnosis of clicking larynx:
Two case reports. Auris Nasus Larynx 2022.
21) Suzuki T, Hirose K, Tabei F, Sugishita Y, Oka T,
Ishii S, Fujiwara T, et al. An Autopsy Case of
Pulmonary Veno-Occlusive Disease Complicatedwith Chronic Obstructive Pulmonary Disease andSevere Pulmonary Hypertension. International
Heart Journal 2021;62(5):1186-1190.
22) Suzuki K, Otsuka Y, Nomura Y, Kumamaru KK,
Kuwatsuru R, Aoki S. Development andValidation of a Modified Three-Dimensional
U-Net Deep-Learning Model for AutomatedDetection of Lung Nodules on Chest CT Images
From the Lung Image Database Consortium andJapanese Datasets. Acad Radiol 2022 February2022;29:S11-S17.
23) Takenaga T, Hanaoka S, Nomura Y, Nakao T,
Shibata H, Miki S, et al. Multichannel
three-dimensional fully convolutional residual
network-based focal liver lesion detection andclassification in Gd-EOB-DTPA-enhanced MRI.
International journal of computer assisted
radiology and surgery 2021;16(9):1527-1536.
24) Yamada S, Ko T, Hatsuse S, Nomura S, Zhang B,
Dai Z, Inoue S, Kubota M, Sawami K, Yamada T,
Sassa T, Katagiri M, Fujita K. Spatiotemporal
single-cell analysis reveals critical roles ofmechano-sensing genes at the border zone inremodeling after myocardial infarction. 2021.
25) Yoshikawa M, Asaba K, Nakayama T. Causal
effect of atrial fibrillation/flutter on chronic
kidney disease: A bidirectional two-sample
Mendelian randomization study. PloS one 2021;
16(12):e0261020.
26) Yoshikawa M, Asaba K. Educational attainment
decreases the risk of COVID-19 severity in theEuropean population: A two-sample Mendelianrandomization study. Frontiers in public health2021:510.
27) Yoshikawa M, Asaba K, Nakayama T.
Estimating causal effects of atherogenic
lipid-related traits on COVID-19 susceptibility

390

and severity using a two-sample Mendelianrandomization approach. BMC medical genomics
2021;14(1):1-9.

391

Department of Cell Therapy inRegenerative Medicine
Specially Appointed Associate Professor
Dehua Chang, M.D., Ph.D

Researcher and Associate
Junfeng Xuan, M.D., Ph.D., Masaki Kobayashi, Ph.D., Katsuhiko Kida,
Jian Zhang, M.D., Ph.D., and Noriko Kajiwara

Department Outline
The Department of Cell Therapy in Regenerative
Medicine was established in 2021 to promote practicaltechnologies for regenerative medicine, such as thedevelopment of mass culture of 3D mesenchymal stem
cells (MSCs) and diagnostic imaging related to MSCs.
MSCs are stem cells derived from the mesoderm, a typeof somatic stem cells found in vivo, and candifferentiate into bone, cartilage, and cardiomyocytes,
etc. MSC culture methods are classified into two types:
adherent cells (2D) and floating cells (3D), with 3D
culture reported to be superior to 2D culture. Our
department aims to develop technology for the massculture of high-quality MSCs using Cellhesion®, ascaffold material developed by Nissan Chemical
Corporation.
In recent years, cell quality evaluation has become
necessary to ensure reproducibility, reliability, andaccuracy in drug discovery research using cultured
cells. MSCs are defined as cells expressing marker
genes, such as CD105, CD73, CD90, etc. However,since it is impossible to determine the quality of MSCs,
such as whether they are proliferating cells or not, even
if these markers are expressed, it is important to have amethod to evaluate the quality of MSCs. In addition,
because the nature of MSCs vary among tissues oforigin, donors, and other factors, even MSCs with alow number of passages may not proliferate and cannot
be passaged. At present, it is left to the operator todecide at what stage to discontinue the culture. Our

department will use Nikon Corporation's cell imaging
technology to evaluate the cell quality during MSC 3D
mass culture.

Research Content
Another important role of our department is to train
many technicians who have mastered special
techniques through research and development toward
the practical application of high-quality 3D massculture of MSCs and diagnostic imaging technology.
MSCs cultured with FCeM Cellhesion-MS, a scaffold
material for MSC culture developed by Nissan
Chemical for the regenerative medicine field, show
approximately seven times more anti-inflammatory
effects than conventional 2D cultured MSCs; and are
expected to be applied for the treatment of various
diseases. In FY2021, we measured the proliferative
potential of 2D and 3D cultured MSCs and analyzed
secreted factors related to angiogenesis and otherfactors. The cell proliferative capacity was higher in
2D than in 3D, but 3D cultures showed increased antiinflammatory
andangiogenic
factors.
The
differentiation ability was observed under both culture
conditions. In the future, the research and development
will be carried out toward the practical application ofcell imaging technology in 3D cell culture, and theeffects of in vivo 3D cultured MSC transplantation will
be evaluated.

392

Future Outlook
Based on the clinical research of 3D mass culture of
MSCs and 3D-related diagnostic imaging technology,
we would like to pursue the research and developmentof world-class and advanced regenerative medicine;and to engage in activities to globally deploy
regenerative medicine technology originating fromJapan.

8.

9.

References
1.

2.

3.

4.

5.

6.

7.

Campagnoli C, Roberts IA, Kumar S, Bennett PR,
Bellantuono I, Fisk NM. Identification ofmesenchymal stem/progenitor cells in humanfirst-trimester fetal blood, liver, and bone marrow.
Blood. 2001 Oct; 98: 2396-2402.
Zuk PA, Zhu M, Ashjian P, Ugarte DA, Huang JI,
Mizuno H, Alfonso ZC, Fraser JK, Benhaim P,
Hedrick MH. Human adipose tissue is a source ofmultipotent stem cells. Mol Biol Cell. 2002 Dec;
13(12): 4279-4295
Olmar REI, Beroud J, Stoltz J-F, Menu P, Velot E,
Decot V. Umbilical cord mesenchymal stem cells:
The new gold standard for mesenchymal stem
cell-based therapies? Tissue Eng Part B rev. 2014
Oct; 20(5): 523-544.
Anthony J Kanelidis, Courtney Premer, Juan
Lopez, Wayne Balkan, Joshua M Hare. Route of
Delivery Modulates the Efficacy of Mesenchymal
Stem Cell Therapy for Myocardial Infarction: A
Meta-Analysis of Preclinical Studies and Clinical
Trials. Circ Res. 2017 Mar 31;120(7):1139-1150.
Li-Tzu Wang, Chiao-Hsuan Ting, Men-Luh Yen,
Ko-Jiunn Liu, Huey-Kang Sytwu, Kenneth K Wu,
B Linju Yen. Human mesenchymal stem cells(MSCs) for treatment towards immune- andinflammation-mediated diseases: review ofcurrent clinical trials. J Biomed Sci. 2016 Nov 4;23(1):76.
Katsuda T, Kosaka N, Takeshita F, Ochiya T. The
therapeutic potencial of mesenchymal stem cellderived extracellular vesecles. Proteomics. 2013
May; 13 (10-11): 1637-1653.
Jun Zhang, Xiaowen Huang, Haijun Wang,
Xiaoyan Liu, Tao Zhang, Yunchuan Wang, Dahai
Hu. The challenges and promises of allogeneic

10.

11.

12.

13.

14.

15.

16.

mesenchymal stem cells for use as a cell-based
therapy. Stem Cell Res Ther. 2015 Dec1; 6:234
Chen K, Wang D, Du WT, Han Z-B, Ren H, Chi Y,
Yang SG, Zhu D, Bayard F, Han ZC. Humanumbilical cord mesenchymal stem cells hUCMSCs exert immunosuppressive activities
through a PGE2-dependent mechanism. Clin
Immunol. 2010 Mar.; 135: 448-458.
Zhou Y, Chan H, Li H, Wu Y. 3D culture increases
pluripotent gene expression mesenchymal stem
cells through relaxation of cytoskeleton tension.
J Cell Mol Med. 2017 Jun; 21(6): 1073–1084.
Sethe S, Scutt A, Stolzing A. Aging of
mesenchymal stem cells. Ageing Res Rev. 2006
Feb; 5(1): 91-116.
Ksiazek K. A comprehensive review on
mesenchymal stem cell growth and senescence.
Rejuvenation Res. 2009 Apr; 12 (2): 105-116.
Feng J, Yang S, Xu L, Tian H, Sun L, Tang X. Roleof caspase-3 inhibitor in induced anoikis ofmesenchymal stem cells in vitro. J Huazhong
Univ Sci Technolog Med Sci. 2007 Apr;27(2):183-5.
Eun Seo Kim, Katsuhiko Kida, Jongsoo Mok,
Yeonwoo Seong, Seo Yeon Jo, Tatsuro Kanaki,
Masato Horikawa, Kyung-Hee Kim, Tae Min Kim,
Tae Sub Park, Joonghoon Park. Cellhesion VP
enhances the immunomodulating potential of
human mesenchymal stem cell-derived extracellular vesicles. Biomaterials. 2021 Apr; 271:
120742.
Rangasamy
Jayakumar,
Krishna
PrasadChennazhi, Sowmya Srinivasan, Shantikumar V
Nair, Tetsuya Furuike, Hiroshi Tamura. Chitin
scaffolds in tissue engineering. Int J Mol Sci.
2011;12(3):1876-87.
Hung-Jen Shao, Yu-Tsang Lee, Chiang-Sang Chen,
Jyh-Horng Wang, Tai-Horng Young. Modulationof gene expression and collagen production ofanterior cruciate ligament cells through cell shapechanges on polycaprolactone/chitosan blends.
Biomaterials. 2010 Jun;31(17):4695-705.
Guo-Shiang Huang, Lien-Guo Dai, Betty L Yen,
Shan-hui
Hsu.
Spheroid
formationofmesenchymal stem cells on chitosan and chitosanhyaluronan membranes. Biomaterials. 2011 Oct;32(29):6929-45.

393

17. Yuriy Petrenko, Eva Syková, Šárka Kubinová.
The therapeutic potential of three-dimensional
multipotent mesenchymal stromal cell spheroids.
Stem Cell Res Ther. 2017 Apr 26;8(1):94.
18. Auletta JJ, Eid SK, Wuttisarnwattana P, Silva I,
Metheny L, Keller MD, Guardia-Wolff R, Liu C,
Wang F, Bowen T, Lee Z, Solchaga LA, Ganguly
S, Tyler M, Wilson DL, Cooke KR. Human
Mesenchymal Stromal Cells Attenuate GraftVersus-Host Disease and Maintain Graft-VersusLeukemia Activity Following Experimental
Allogeneic Bone Marrow Transplantation. StemCells. 2015 Feb;33(2):601-14.
19. Kota DJ, Prabhakara KS, Toledano-Furman N,
Bhattarai D, Chen Q, DiCarlo B, Smith P, Triolo
F, Wenzel PL, Cox CS Jr, Olson SD. Prostaglandin
E2 Indicates Therapeutic Efficacy of Mesenchymal Stem Cells in Experimental Traumatic Brain
Injury. Stem Cells. 2017 May;35(5):1416-1430.
20. Song WJ, Li Q, Ryu MO, Ahn JO, Ha Bhang D,
Chan Jung Y, Youn HY. TSG-6 Secreted by
Human Adipose Tissue-derived Mesenchymal
Stem Cells Ameliorates DSS-induced colitis by
Inducing M2 Macrophage Polarization in Mice.
Sci Rep. 2017 Jul 12;7(1):5187.
21. He Z, Hua J, Qian D, Gong J, Lin S, Xu C, Wei G,
Meng H, Yang T, Zhou B, Song Z. Intravenous
hMSCs Ameliorate Acute Pancreatitis in Mice via
Secretion of Tumor Necrosis Factor-α Stimulated
Gene/Protein 6. Sci Rep. 2016 Dec 5; 6:38438.
22. Lee RH, Pulin AA, Seo MJ, et al. Intravenous
hMSCs improve myocardial infarction in mice
because cells embolized in lung are activated tosecrete the anti-inflammatory protein TSG-6. Cell
Stem Cell. 2009, 5:54–63.
23. Usha Nekanti, Lipsa Mohanty, Parvathy
Venugopal, Sudha Balasubramanian, Satish Totey,
Malancha Ta. Optimization and scale-up of
Wharton's jelly-derived mesenchymal stem cells
for clinical applications. Stem Cell Res. 2010
Nov;5(3):244-54.
24. Roberta Tasso, Massimiliano Gaetani, Erica Molino,
Angela Cattaneo, Massimiliano Monticone, Angela
Bachi, Ranieri Cancedda. The role of bFGF on theability of MSC to activate endogenous regenerative mechanisms in an ectopic boneformation model. Biomaterials. 2012 Mar;33(7):2086-96.
25. Shiro Imagama, Ryoko Ogino, Shinya Ueno,
Norihito Murayama, Naohiro Takemoto, Yoshiari
Shimmyo, Taisuke Kadoshima, Shigeki Tamura,Mariko Kuroda, Yukihiro Matsuyama, Kenji
Kadomatsu, Yasuhiro Morita, Teruyoshi Inoue,
Naoki Ishiguro. Systemic treatment with a novel
basic fibroblast growth factor mimics smallmolecule compound boosts functional recovery
after spinal cord injury. PLoS One. 2020 Jul 17;
15(7): e0236050.

394

Department of Home Care
Medicine
Project Associate Professor
Takashi Yamanaka, M.D., Ph.D.

Project Lecturer
Jiro Okochi, M.D., Ph.D.

Project Research Associate
Kiwami Kidana, M.D., Ph.D., Shota Hamada, R.Ph., Dr.P.H.

Project Researcher
Shigemasa Katayama, M.D., Ph.D., Tatsuya Kurokawa, M.D., Ph.D.,
Maiko Mizuki, MPH.

Homepage

http://chcm.umin.jp/

Introduction and Organization
Department of Home Care Medicine was establishedin 2018 at the 22nd Century Medical and ResearchCenter in the University of Tokyo Hospital based upon
contributions by Mr. Kazuteru Noguchi, JSH Co., Ltd.,
Japan Home Medical Care Inc., Towa Pharmaceutical
Co. Ltd., Sawai Pharmaceutical Co. Ltd., and Ain
Pharmaciez. Our department collaborates with
Department of Geriatric Medicine. We have takenover educational activities and research activities fromCenter for Home Care Medicine, Faculty of Medicine.
With the increase in the elderly population, home care
medicine is more needed compared with the past. We
teach home care medicine to medical students andtrainee doctors along with studying the topics of homecare medicine to systematize it.

Education
Clinical education of home care medicine is provided
for fifth and sixth year medical students. We create apersonalized mandatory program of home care
medicine and give an orientation of the program. Then
medical students learn about home care medicine withphysicians, nurses, medical social workers or caremanagers in the community.
We also create a program of home care medicine fortrainee doctors who wish to learn about it.

Research
The main themes of our study were as follows.
1) Educational program development of home care
medicine and studying the educational effectiveness of the program2) Building a case registry system of home medicalcare3) Follow-up study on QOL or prognosis of patients
who receive home medical care and their caregivers4) Drug treatment in home medical care5) Skills of medical therapeutics and care in homecare medicine

Publications
1.

Yamanaka T, Kidana K, Mizuki M, Akishita M.
Comparison of regular home visits received by

395

2.

3.

4.

5.

older male and female patients from physicians.
Geriatr Gerontol Int 2021;21:1148–1150.
Son BK, Akishita M, Yamanaka T, Toyoshima K,
Tanaka T, Suthutvoravut U, Iijima K. Association
between inflammatory potential of the diet andsarcopenia/its components in communitydwelling older Japanese men. Arch Gerontol
Geriatr 2021;97:104481.
Yao N, Mutter JB, Berry JD, Yamanaka T,
Mohess DT, Cornwell T. In Traditional Medicare,
Modest Growth In The Home Care Workforce
Largely Driven By Nurse Practitioners. Health
Aff (Millwood) 2021;40(3):478-486.
Hirakawa Y, Hirahara S, Yamaguchi Y, Yamanaka
T, Arai H, Miura H. Improving the quality ofcommunity primary palliative care in COPD: A
qualitative study of health-care providers. Home
Health Care Serv Q 2021;40(1):39-53.
Kikuchi K, Tatebe T, Sudo Y, Yokoyama M,
Kidana K, Chiu YW, Takatori S, Arita M, Hori Y,
Tomita T. GPR120 signaling controls amyloid-βdegrading activity of matrix metalloproteinases. J
Neurosci 2021;41(28):6173–85.

396

Department of
Therapeutic Strategy forHeart Failure
Research Associate Professor
Masaru Hatano, M.D., Ph.D (-2021/10/31)
Eisuke Amiya, M.D., Ph.D (2021/11/1-)

Research Assistant Professor
Seitaro Nomura, M.D., Ph.D
Toshiyuki Ko, M.D., Ph.D (2021/11/1-)

Project Researcher
Naoko Kato, Ph.D
Yumiko Hosoya, M.D., Ph.D.

Homepage

http://plaza.umin.ac.jp/~heart-f/

Introduction and Organization
The Department of Therapeutic Strategy for Heart
Failure (TSHF) in the University of Tokyo Hospital
was established by the support of the Department of
Cardiac Surgery and the Department of Cardiovascular
Medicine of the University of Tokyo Hospital in May
2008. The purpose to establish the department of TSHF
is to promote surgical and medical innovative treatment
for end-stage heart failure in the University of Tokyo
Hospital, which includes heart transplant, pediatricheart transplant, ventricular assist device, andregenerative therapy. The Department has been also
supported by eight companies.
Recently, right heart failure (RHF) gains recognition
as well as left heart failure (LHF). RHF developed after
left ventricular assist devise (LVAD) is a critical issue
which remains to be elucidated. Pulmonary hypertension (PH) is also an important cause of RHF. Now a
lot of patients with severe PH are referred to our
hospital because the University of Tokyo Hospital has
been approved as a lung transplantation center since2014. We pursue optimal treatment strategy for not
only LHF but also RHF.

Clinical Activities
1. Heart Transplant (HTx)Patients who performed heart transplant in our
hospital or in abroad transferred from our hospital arefollowed up once a month in the out-patient clinic, andundergo repeated myocardial biopsy regularly. Whensome symptom or findings which suggest rejection aredetected, patients will undergo to intensify immunosuppressive regimen in-hospital treatment.
2. Ventricular Assist Device (VAD) Therapy
We recently implant not only extracorporeal
pulsatile but also implantable ventricular assist device(VAD). All candidates fell into end-stage heart failure
before VAD implantation, and a significant number ofthem were rescued with heart transplantation or bridge
to recovery. We implant centrifugal VAD (EVAHEART,
HVAD and HeartMate3) or axial VAD (HeartMate II

397

and Jarvik 2000) considering patients’ physics andclinical status). We also started the “Destination
therapy”, which means the implantation of VAD
without heart transplantation.
3. Treatment of PH
Although pulmonary arterial hypertension (PAH)
was a disease of poor prognosis, the treatment outcomeof PAH significantly improved in this decade attributed
to a number of newly approved drugs. Now we can use
ten agents for PAH including oral, inhaled, subcutaneous and intravenous drugs. Combination therapyof these drugs is increasingly prevalent for the management of PAH. We join the nationwide PH registry toestablish optimal treatment strategy for PAH .

Teaching Activities
We have the chair of systematic review of cardiovascular surgery in the spring term at the 2nd grade of
medical course. We also take charge in clinical practiceon diagnosis of cardiovascular disease in the autumn
term at the 2nd grade. We expose the students to dailyclinical works as well as research works during thecourse of “Free Quarter” and “Research Lab Visit”,
which are scheduled in the summer and springvacations at 1st and 2nd grade. Joint lectures with the
Cardiology Department are scheduled 3rd through 4th
grades. Each student is assigned one or two
cardiovascular surgical cases in the Bed Side Learning,in which he/she is required to learn preoperative patient
evaluation and management, surgical treatment andpostoperative care, based on participatory practice.
There are also twelve small key-lectures on
cardiovascular surgery. Hands-on practice is provided
during the “Clinical clerkship” one-month course in thelast months of 3rd grade.
We take charge in core surgical curriculum in the“Super-rotation” postgraduate training. We offer a
program in which each resident can learn basic
knowledge of cardiovascular disease and surgery, andhemodynamic and respiratory evaluation as well asbasic surgical techniques and patient management.
Residents who take the course of cardiovascularsurgery are required three-year general surgicaltraining for General Surgery Board certification. We
have well-developed specialty/ subspecialty training

programs to allow the residents to pass Cardiovascular
Board Examination by 10th postgraduate year.

Research Activities
In order to achieve excellent clinical results and toseek for new possibilities of surgical treatments forheart failure, it is essential for our department of the
University to have active research programs in clinicaland basic subjects related to assisted circulations andheart transplantation. We created highly active research
programs in every field of medical and surgical heart
failure treatment, and played an internationally leadingrole and contributed to its development. A researchmeeting is held every Saturday on a research projectwith Department of Cardiothoracic Surgery.
Basic and/or clinical research activities are focusedon 1) development of new driving method of rotary
blood pump, 2) basic and clinical research on
regenerative therapy, 3) establishment of social support
system for patients with implantable LVAD.

References
1:

2:

3:

4:

Amiya E. Link between hyperuricemia, renal
dysfunction, and hypertension. J Clin Hypertens(Greenwich). 2021 Dec;23(12):2078-2079.
Bujo C, Amiya E, Hatano M, Ishida J, Tsuji M,
Kakuda N, Narita K, Saito A, Yagi H, Ando M,
Shimada S, Kimura M, Kinoshita O, Ono M,
Komuro I. Long-Term renal function after
implantation of continuous-flow left ventricularassist devices: A single center study. Int J Cardiol
Heart Vasc. 2021 Nov 1;37:100907.
Itoh H, Amiya E, Narita K, Shimbo M, Taya M,
Komuro I, Hasegawa T, Makita S, Kimura Y.
Efficacy and Safety of Remote Cardiac Rehabilitation in the Recovery Phase of Cardiovascular
Diseases: Protocol for a Multicenter, Nonrandomized, Single-Arm, Interventional Trial.
JMIR Res Protoc. 2021 Oct 4;10(10):e30725.
Ishiwata J, Daimon M, Nakanishi K, Sugimoto T,
Kawata T, Shinozaki T, Nakao T, Hirokawa M,
Sawada N, Yoshida Y, Amiya E, Hatano M,
Morita H, Yatomi Y, Komuro I. Combined
evaluation of right ventricular function using
echocardiography in non-ischaemic dilated

398

cardiomyopathy. ESC Heart Fail. 2021 Oct;8(5):3947-3956.
5: Narita K, Amiya E. Is branched-chain amino acidnutritional
supplementation
beneficial
or
detrimental in heart failure? World J Cardiol. 2021
26;13(6):163-169.
6: Narita K, Amiya E. Social and environmental
risks as contributors to the clinical course of heart
failure. Heart Fail Rev. 2022 Jul;27(4):1001-1016.
7: Dai Z, Uehara M, Amiya E, Hatano M, Komuro I.
Acute cellular rejection after heart transplantationand its remission visualized by cardiac magnetic
resonance. Eur Heart J Case Rep. 2021 Feb 28;
5(3):ytab085.
8: Kakuda N, Amiya E, Hatano M, Maki H, Bujo C,
Tsuji M, Narita K, Fujita K, Ishida J, Ono M,
Komuro I. Case Report: A Case of Acute Cellular
Rejection Due to Atopic Dermatitis Exacerbation
3 Years After Heart Transplantation. Front
Immunol. 2021 Feb 22;12:630051.
9: Tsuji M, Amiya E, Bujo C, Hara T, Saito A,
Minatsuki S, Maki H, Ishida J, Hosoya Y, Hatano
M, Imai H, Nemoto M, Kagami Y, Endo M,
Kimura M, Ando M, Shimada S, Kinoshita O, Ono
M, Komuro I. Carbon Monoxide Diffusing
Capacity Predicts Cardiac Readmission in Patients
Undergoing Left Ventricular Assist Device
Implantation in Japan. ASAIO J. 2021 Oct 1;
67(10):1111-1118
10: Bujo C, Amiya E, Hatano M, Tsuji M, Maki H,
Ishida J, Ishii S, Narita K, Endo M, Ando M,
Shimada S, Kinoshita O, Ono M, Komuro I.
Association between infectious event and de novo
malignancy after heart transplantation. Heart
Vessels. 2021 Apr;36(4):499-508.
11: Yasunaga M, Yasuda Y, Honda A, Maki H,
Toyama K, Masamoto Y, Bujo C, Amiya E,
Hatano M, Ono M, Komuro I, Kurokawa M.
Successful treatment of EBV-related lymphoproliferative disease after heart transplantation
with autologous hematopoietic stem celltransplantation despite transient heart failure
associated with engraftment syndrome. Ann
Hematol. 2021 Apr;100(4):1097-1100.

399

Department of Biostatistics andBioinformatics
Project Professor
Daisuke Koide, R.Ph., HIM, Ph.D.

Project Lecturer
Shogo Nomura, Ph.D.

Project Assistant Professor
Shotaro Aso, MD, Ph.D .

Homepage

http://biostatistics.m.u-tokyo.ac.jp/

Introduction and Organization
Biostatistics is an applied statistics in the fields of
medical and health sciences and contributes to thesefields through developments of statistical methodologies for clinical trials and epidemiological researches.
Biostatisticians who work at an organization for
conducting and coordinating clinical researches (e.g.,
academic research organization) in hospitals andinstitutions are few in Japan. To this end, the Japanfunding agency, Agency for Medical Research andDevelopment (AMED), started the Support Programfor Biostatisticians from 2016.
The AMED selected the Graduate School of the
University of Tokyo and the Graduate school of the
Kyoto University, as 2 centers for training biostatisticians, which function as core facilities, respectively.
Each graduate school establishes a new biostatistics
course, forms a training center upon collaboration
with a hospital, and performs on-the-job training.
This program improves the environment that leads
to higher quality in clinical research and trials, withthe collaboration of industry, academia, and thegovernment, based upon the donations from drug
companies and national research funding. Collaborative projects of industry, academia, and the government through the flow of funds in this program, arethe first of their kind in Japan.
On March 1, 2017, the Department of Biostatistics

and Bioinformation was established in the Graduate
School of Medicine. In the Graduate School ofInterdisciplinary Information Studies in the Universityof Tokyo, the Biostatistics and Bioinformatics course
also started on April 1, 2018. This course provides
specialized education to acquire not only statisticalmethodologies, but also practical skills (e.g., design
and analysis of clinical research, programming,
reporting) for conducting clinical research. We train
biostatisticians with high communication skill andethics that can promote high quality research incollaboration with health care professionals byteaching and on-the-job -training (OJT). AMED has
renewed this project for more 5years since FY2021.

Teaching activities
1) Education in the Biostatistics and Bioinformatics
courseIn the Biostatistics and Bioinformatics course,
through the following teachings, we educate a wide
range of knowledge and skills required to biostatisticians. Its curriculum is made up of 28 subjects
including 42 credits. For students who have taken over
38 credits, we issue a certificate along with the Master
degree.
Biostatistics
Statistical inference,

categorical

data

analysis,

400

survival analysis, longitudinal data analysis, Bayesianstatistics, multiple comparison procedure, multivariate
analysis, causal inference, missing data analysis,
stochastic process and time series analysis, pharmacometrics, statistical programming, genomic data
analysis
Clinical research and epidemiology
Clinical trial methodology, design and analysis of
epidemiological research, research ethics andguidelines, medical research and CDISC standards,
general clinical medicine, regulatory science, medical
writing, medical technology evaluation exercises
In addition, the students receive the OJT at
University of Tokyo Hospital and the National Cancer
Center. The OJT programs are developed by thebiostatisticians of each institution. In the first year of
master's program, the students learn the basic practiceof biostatistician through the training at the Universityof Tokyo Hospital. In the second year, at the National
Cancer Research Center, students receive advanced
training in how to plan the design and analysis ofclinical researches.
2) Seminars and symposiums for the healthcare
professionals and biostatisticians
We give seminars about clinical trial methodologies
and biostatistics for physician, nurse, clinical researchcoordinator, monitor, and other healthcare professionals. We also hold symposia for biostatisticians inacademia and pharmaceutical companies in order toshare and discuss the “state-of-the-arts” of statisticalmethodologies.

Research activities
In the department of biostatistics and bioinformatics,
the main research areas are as follows:
1) Statistical methodology and design of clinical trials
and epidemiology
We study on the statistical methodologies and design
for streamlining clinical trial and estimating treatment
effect precisely. The research area includes Bayesian
design in oncology, clinical trial design using
biomarkers, adaptive design, study on the use ofBayesian statistics in clinical trials, causal inference,and multiple comparison method.
2) Epidemiological methodology
Epidemiology deals with health or disease related
incidence quantitatively in large populations,evaluates cause and effective factors, and ultimately
finds the measures of prevention. It starts fromepidemics (such as infectious diseases) and now its
focus is on lifestyle related diseases, such as cardiovascular disorders. Also, several kinds of medical
databases are developed rapidly in Japan. It is
important to conduct epidemiological, pharmacoepidemiological and clinical epidemiological studies
using such databases.
3) Pharmacoepidemiology
Pharmacoepidemiology is a study to investigate drug
use and its effects in a population. We are engaged inresearch on effectiveness, risk, and cost using dataobtained from hospital information system andelectronic medical record.
4) Clinical Epidemiology
Clinical epidemiology is the application of theprinciples and methods of epidemiology to conductclinical research studies focusing on prevention,
diagnosis, prognosis, and treatment of disease. As thebasic science of Evidence-based Medicine, the importance of clinical epidemiology has been increasing.
5) Medical informatics
Medical informatics is a science of studying how to
use data, information and knowledge in the all
medical fields, such as clinical, medical studies,
education and government. Recently, the area of
medical informatics is much expanding because of the
progress of genomic studies or bioinformatics, andintroduction of new technologies, such as virtual
reality and artificial intelligence (AI).
6) Algebraic statistics
The focus of research is on developing and applying
methods of algebraic statistics to specific statisticalproblems. In statistical inference, the computation ofcomplicated integrals or summation sometimes makes
the problem intractable. When a statistical model

401

has algebraic structure, techniques from algebraic
statistics are useful. I currently work on the topics
related to Groebner basis theory and the holonomic
gradient method.

References
1.

2.

3.

4.

5.

Yokosu K, Tanabe H, Nomura S, Ozone H, Saito M,
Takano H and Okamoto A. Total parietal
peritonectomy in primary debulking surgery foradvanced ovarian cancer. Gynecologic Oncology
Reports. 37:100805, 2021. (available online)
Nakamura Y, Okamoto W, Kato T, Esaki T, Kato K,
Komatsu Y, Yuki S, Masuishi T, Nishina T, Ebi H,
Sawada K, Taniguchi H, Fuse N, Nomura S, Fukui
M, Matsuda S, Sakamoto Y, Uchigata H, Kitajima
K, Kuramoto N, Asakawa T, Olsen S, Odegaard J I,
Sato A, Fujii S, Ohtsu A and Yoshino T. Circulatingtumor DNA-guided treatment with pertuzumab plus
trastuzumab for HER2-amplified metastatic
colorectal cancer: a phase 2 trial. Nat Med. 1-5,
2021.
Kobayashi S, Takahashi S, Nomura S, Kojima M,
Kudo M, Sugimoto M, Konishi M, Gotohda N,
Taniguchi H and Yoshino T. BRAF V600E
potentially determines "Oncological Resectability"for "Technically Resectable" colorectal liver
metastases. Cancer Medicine: 10(20). 6998-7011,
2021.
Sakai T, Udagawa H, Kirita K, Nomura S, Itotani R,
Tamiya Y, Sugimoto A, Ota T, Naito T and Izumi H.
Comparison of the efficiency of endobronchialultrasound-guided transbronchial needle aspiration
using a 22G needle versus 25G needle for the
diagnosis of lymph node metastasis in patients withlung cancer: a prospective randomized, crossoverstudy. Translational Lung Cancer Research: 10(9).
3745, 2021.
Nishizawa Y, Nishigori H, Tsukada Y, Sasaki T,
Tsukamoto S, Kanemitsu Y, Nakano D, Yamaguchi
T, Otsuka K, Nakamura T, Shiomi A, Iwasaki N,
Tamura H, Wakabayashi M, Nomura S and Ito M. A
multicentre confirmatory single-arm trial of thesafety and efficacy of a transanal drain forprevention of anastomotic leakage after surgery forrectal cancer. Colorectal Dis: 2021.

6.

Shiraishi Y, Hakozaki T, Nomura S, Kataoka T,
Tanaka K, Miura S, Sekino Y, Ando M, Horinouchi
H and Ohe Y. A Multicenter, Randomized Phase III
Study
Comparing
Platinum
Combination
Chemotherapy plus Pembrolizumab with Platinum
Combination Chemotherapy plus Nivolumab andIpilimumab for Treatment-Naive Advanced
Non-Small Cell Lung Cancer Without Driver Gene
Alterations: JCOG2007 (NIPPON Study). Clinical
Lung Cancer: 2021.
7. Uemura Y, Shinozaki T, Nomura S and Shibata T.
Comment on "Biostatistical Considerations When
Using RWD and RWE in Clinical Studies forRegulatory Purposes: A Landscape Assessment".
Statistics in Biopharmaceutical Research. 1-3,
2021.
8. Mamishin K, Naito Y, Nomura S, Ogawa G,
Niguma K, Baba K, Sakaeda S, Nakajima H,
Kusuhara S and Funasaka C. Comparison ofTreatment Completion Rate Between Conventionaland Dose-dense Doxorubicin and Cyclophosphamide (AC) Followed by a Taxane inPatients With Breast Cancer: A Propensity Scorematched Analysis. Anticancer Research: 41(12).
6217-6224, 2021.
9. Hasegawa S, Okada A, Aso S, et al. Association
Between Diabetes and Major Bleeding Complications of Renal Biopsy. Kidney Int Rep. 2021;7(2):232-240. Published 2021 Nov 25. doi:10.1016/j.ekir.
11.013, 2021
10. Umeoka A, Aso S. Delayed Metastasis of Renal
Cell Carcinoma [published online ahead of print,
2021 Dec 4]. Intern Med. 2021; 10.2169/internal
medicine.8549-21. doi:10.2169/internalmedicine.
8549-21
11. Hattori Y, Tahara S, Aso S, et al. Prophylactic
steroid administration and complications after
transsphenoidal pituitary surgery: a nationwide
inpatient database study in Japan. Br J Anaesth.
2021; 127(2): e41-e43. doi:10.1016/j.bja.2021.04.
006
12. Kondo Y, Ohbe H, Aso S, et al. Efficacy ofProphylactic Antibiotics during Extracorporeal
Membrane Oxygenation: A Nationwide Cohort
Study. Ann Am Thorac Soc. 2021;18(11):18611867. doi:10.1513/AnnalsATS.202008-974OC

402

13. Aso S, Matsui H, Fushimi K, Yasunaga H.
Dexmedetomidine and Mortality From Sepsis
Requiring Mechanical Ventilation: A Japanese
Nationwide Retrospective Cohort Study. J Intensive
Care Med. 2021; 36(9): 1036-1043. doi:10.1177/
0885066620942154
14. Shigemi D, Isogai S, Uda K, et al. Association
between rehabilitation during hospitalization andperinatal outcomes among pregnant women withthreatened preterm birth. J Matern Fetal Neonatal
Med. 2021; 34(7): 1028-1033. doi:10.1080/
14767058.2019.1623197

403

Department of Advanced
Cardiology
Project Associate Professor
Katsuhito Fujiu, M.D., Ph.D.

Project Lecturer
Hidehiro Kaneko, M.D., Ph.D.

Project Assistant Professor
Ying Chen, M.D., Ph.D.

Homepagehttps://cardiovasc.m.u-tokyo.ac.jp/

Introduction and Organization
This course is an endowed chair established on April 1,
2018, under the donations of Medtronic Japan Co.,
Ltd., St. Jude Medical Co., Ltd., Boston ScientificJapan Co., Ltd., Fukuda Denshi Tokyo Central Sales
Co., Ltd and SIMPLEX QUANTUM Co., Ltd.
In conjunction with the department ofcardiovascular medicine, this course develops leadingedge medical care. It elucidates the pathogenesis ofunresolved heart failure and cardiovascular disease
and analyzes the pathological condition using cultured
cells, experimental animals, and patient specimens. Byclarifying the new disease pathogenesis mechanismand pathogenesis mechanism, it aims at elucidating
the fundamental pathophysiology of cardiovasculardisease and developing development prevention
methods, new diagnostic methods, and newtherapeutic methods.

Teaching activities
The above research results are presented at theuniversity and academic conferences, the importanceof this field is well known and widely presented bydissertation. Also, we are actively engaged in outreachactivities for society.

cooperation with organs throughout the body. The
failure of this cooperation is considered to cause theonset of heart failure and sudden death. The therapy
that improved cardiovascular death prognosis is a drugthat acts on the whole body, not on the heart alone,
except for cardiac resynchronization therapy andimplantable defibrillator. From this point of view, as a
research to improve the prognosis of cardiovasculardeath, we will proceed with the investigation,
considering that poor coordination among multiple
organs is involved in the onset of heart disease.
Furthermore, about half of the cells that make up theheart are cardiomyocytes. In contrast, the other half
are non-cardiomyocytes. In this study, we focus on
non-cardiomyocytes and how non-cardiomyocytesinteract with cardiomyocytes. The aim is to find newtherapeutic targets for heart disease by clarifying
whether it is acting, maintaining homeostasis of theheart, and elucidating the pathogenesis of heart failurethat is its failure.
Furthermore, the relationship between theheart and the brain has been examined in detail as astudy of inter-organ cooperation.

References
1.

Research activities
The heart and blood vessels maintain homeostasis in

2.

Tripartite Left Bundle Branch Area Pacing.
Hasumi E, Fujiu K. Int Heart J. 2021;62(1):1-3.
<2021.1>
Percutaneous Mitral Valve Intervention Using

404

3.

4.

5.

6.

7.

8.

MitraClip for Functional Mitral Regurgitationand Heart Failure. Kaneko H, Kiriyama H,
Kamon T, Itoh H, Kodera S, Fujiu K, Daimon M,
Morita H, Hatano M, Komuro I. Int Heart J.
2021;62(1):4-8. <2021.1>
Impact of hospital volume on clinical outcomesof hospitalized heart failure patients: analysis of anationwide database including 447,818 patientswith heart failure. Kaneko H, Itoh H, Yotsumoto
H, Kiriyama H, Kamon T, Fujiu K, Morita K,
Michihata N, Jo T, Takeda N, Morita H,
Yasunaga H, Komuro I. BMC Cardiovasc Disord.
2021 Jan 25;21(1):49.
Association between changes in body weight andlipid profile in the general population: acommunity-based cohort study. Kiriyama H,
Kaneko H, Itoh H, Kamon T, Mizuno Y, Fujiu K,
Morita H, Yamamichi N, Komuro I. Eur Heart J
Qual Care Clin Outcomes. 2021 Jan 25;7(1):109-110.
Subclinical hypothyroidism as an independent
determinant of left atrial dysfunction in thegeneral population. Nakanishi K, Daimon M,
Yoshida Y, Sawada N, Hirose K, Iwama K,
Yamamoto Y, Ishiwata J, Hirokawa M, Kaneko H,
Nakao T, Mizuno Y, Morita H, Di Tullio MR,
Homma S, Komuro I. J Clin Endocrinol Metab.
2021 Mar 25;106(4):e1859-e1867.
Fasting plasma glucose and subsequent cardiovascular disease among young adults: Analysis ofa nationwide epidemiological database. Kaneko
H, Itoh H, Kiriyama H, Kamon T, Fujiu K,
Morita K, Michihata N, Jo T, Takeda N, Morita H,
Yasunaga H, Komuro I. Atherosclerosis. 2021
Feb;319:35-41.
Lipid Profile and Subsequent Cardiovascular
Disease among Young Adults Aged < 50 Years.
Kaneko H, Itoh H, Kiriyama H, Kamon T, Fujiu
K, Morita K, Michihata N, Jo T, Takeda N,
Morita H, Yasunaga H, Komuro I. Am J Cardiol.
2021 Mar 1;142:59-65.
Reverse J-shaped relationship between bodymass index and in-hospital mortality of patients
hospitalized for heart failure in JapanItoh H,
Kaneko H, Kiriyama H, Kamon T, Fujiu K,
Morita K, Yotsumoto H, Michihata N, Jo T,
Takeda N, Morita H, Yasunaga H, Komuro I.

9.

10.

11.

12.

13.

14.

15.

Heart Vessels 2021 Mar;36(3):383-392.
Possible association between eating behaviors
and cardiovascular disease in the general
population: Analysis of a nationwide epidemiological database. Kaneko H, Itoh H, Kiriyama H,
Kamon T, Fujiu K, Morita K, Michihata N, Jo T,
Takeda N, Morita H, Yasunaga H, Komuro I.
Atherosclerosis. 2021 Mar;320:79-85.
Cardiac macrophages prevent sudden death
during heart stress. Sugita J, Fujiu K, Nakayama
Y, Matsubara T, Matsuda J, Oshima T, Liu Y,
Maru Y, Hasumi E, Kojima T, Seno H, Asano K,
Ishijima A, Tomii N, Yamazaki M, Kudo F,
Sakuma I, Nagai R, Manabe I, Komuro I. Nat
Commun. 2021 Mar 26;12(1):1910.
Application of a Thin-Film Transistor Array for
Cellular-Resolution
Electrophysiology
andElectrochemistry. Anne-Claire Eiler, Pierre-Marie
Faure, Sugita J, Ihida S, Dongchen Zhu, Sakai Y,
Fujiu K, Komori K, Toshiyoshi H, Agnès TixierMita IEEE Transactions on Electron Devices.
2021 Apr;68(4):2041-2048
Surgical treatment for infective endocarditis in
the ageing society: a nationwide retrospective
study in Japan. Kiriyama H, Kaneko H, Itoh H,
Kamon T, Morita K, Jo T, Fujiu K, Daimon M,
Takeda N, Morita H, Yasunaga H, Komuro I.
Open Heart. 2021 Apr;8(1):e001627.
Early Initiation of Feeding and In-Hospital
Outcomes in Patients Hospitalized for AcuteHeart Failure. Kaneko H, Itoh H, Morita K,
Sugimoto T, Konishi M, Kamiya K, Kiriyama H,
Kamon T, Fujiu K, Michihata N, Jo T, Takeda N,
Morita H, Yasunaga H, Komuro I. Am J Cardiol.
2021 Apr 15;145:85-90.
Relation of Body Mass Index to Adverse Right
Ventricular Mechanics. Nakanishi K, Daimon M,
Yoshida Y, Ishiwata J, Sawada N, Hirokawa M,
Kaneko H, Nakao T, Mizuno Y, Morita H, Di
Tullio MR, Homma S, Komuro I. Am J Cardiol.
2021 Apr 1;144:137-142.
Cardiovascular Health Metrics of 87,160
Couples: Analysis of a Nationwide Epidemiological Database Kaneko H, Itoh H, Yotsumoto H,
Kiriyama H, Kamon T, Fujiu K, Morita K,
Kashiwabara K, Michihata N, Jo T, Morita H,
Yasunaga H, and Komuro I. J Atheroscler

405

16.

17.

18.

19.

20.

21.

Thromb 2021 May 1;28(5):535-543
Metabolically Healthy Obesity and the Risk of
Cardiovascular Disease in the General Population- Analysis of a Nationwide Epidemiological
Database. Itoh H, Kaneko H, Kiriyama H, Kamon
T, Fujiu K, Morita K, Michihata N, Jo T, Takeda
N, Morita H, Yasunaga H, Komuro I. Circ J. 2021
May 25;85(6):914-920.
Association of Blood Pressure Classification
Using the 2017 American College of Cardiology/
American Heart Association Blood Pressure
Guideline With Risk of Heart Failure and Atrial
Fibrillation. Kaneko H, Yano Y, Itoh H, Morita K,
Kiriyama H, Kamon T, Fujiu K, Michihata N, Jo
T, Takeda N, Morita H, Node K, Carey RM, Lima
JAC, Oparil S, Yasunaga H, Komuro I.
Circulation. 2021 Jun 8;143(23):2244-2253.
Sex-specific difference in the association
between arterial stiffness and subclinical left
ventricular dysfunction. Yoshida Y, Nakanishi K,
Daimon M, Ishiwata J, Sawada N, Hirokawa M,
Kaneko H, Nakao T, Mizuno Y, Morita H, Di
Tullio MR, Homma S, Komuro I. Eur Heart J
Cardiovasc Imaging. 2021 Jun 22;22(7):817-823.
Detection of significant antiviral drug effects on
COVID-19 with reasonable sample sizes in
randomized controlled trials: A modeling study.
Iwanami S, Ejima K, Kim KS, Noshita K, Fujita
Y, Miyazaki T, Kohno S, Miyazaki Y, Morimoto
S, Nakaoka S, Koizumi Y, Asai Y, Aihara K,
Watashi K, Thompson RN, Shibuya K, Fujiu K,
Perelson AS, Iwami S, Wakita T. PLoS Med.
2021 Jul 6;18(7):e1003660.
Correlation Between the Cohorts for Heart andAging Research in Genomic Epidemiology-Atrial
Fibrillation Risk Score and Left Atrial
Remodeling in the General Population. Hirose K,
Nakanishi K, Daimon M, Sawada N, Yoshida Y,
Ishiwata J, Hirokawa M, Koyama K, Nakao T,
Fujiu K, Morita H, Di Tullio MR, Homma S,
Komuro I. Circ Arrhythm Electrophysiol. 2021
Jul;14(7):e009826.
Association of Body Mass Index with Ischemicand Hemorrhagic Stroke. Shiozawa M, Kaneko H,
Itoh H, Morita K, Okada A, Matsuoka S,
Kiriyama H, Kamon T, Fujiu K, Michihata N, Jo
T, Takeda N, Morita H, Nakamura S, Node K,

22.

23.

24.

25.

26.

27.

28.

Yasunaga H, Komuro I. Nutrients. 2021 Jul 9;13(7):2343.
Uninterrupted Direct Oral Anticoagulants
Without a Change in Regimen for Catheter
Ablation for Atrial Fibrillation Is an Acceptable
Protocol. Oshima T, Fujiu K, Matsunaga H,
Matsuda J, Matsubara T, Saga A, Yoshida Y,
Shimizu Y, Hasumi E, Oguri G, Kojima T,
Komuro I. Circ Rep. 2021 Jul 30;3(9):481-487.
Possible Gender Difference in the Association
Between Abdominal Obesity, Chronic Inflammation, and Preclinical Atherosclerosis in the
General Population. Kamon T, Kaneko H, Itoh H,
Kiriyama H, Mizuno Y, Morita H, Takeda N,
Yamamichi N, Komuro I. Int Heart J. 2021;
62(4):837-842. <2021.7.30>
Relation of Serum Uric Acid and Cardiovascular
Events in Young Adults Aged 20-49 Years. Seki
H, Kaneko H, Morita H, Itoh H, Morita K,
Matsuoka S, Kiriyama H, Kamon T, Fujiu K,
Michihata N, Jo T, Takeda N, Yano Y, Nakamura
S, Node K, Yasunaga H, Komuro I. Am J Cardiol.
2021 Aug 1;152:150-157.
Pseudo-elevation of conduction system pacing
threshold through parallel connection of an
intracardiac electrogram recording system.
Yokota J, Fujiu K, Oshima T, Matsubara TJ,
Matsuda J, Shimizu Y, Hasumi E, Kojima T, Doi
K, Komuro I. J Cardiovasc Electrophysiol. 2021
Aug;32(8):2329-2332.
Automatic detection of vessel structure by deeplearning using intravascular ultrasound images of
the coronary arteries. Shinohara H, Kodera S,
Ninomiya K, Nakamoto M, Katsushika S, Saito A,
Minatsuki S, Kikuchi H, Kiyosue A, Higashikuni
Y, Takeda N, Fujiu K, Ando J, Akazawa H,
Morita H, Komuro I. PLoS One. 2021 Aug 5;
16(8):e0255577.
Promoting analysis of real-world data: Prospects
for preventive cardiology in Japan. Yotsumoto H,
Kaneko H, Itoh H, Kamon T, Kiriyama H, Fujiu
K, Takeda N, Morita H, Komuro I. Glob HealthMed. 2021 Aug 31;3(4):203-213.
Risk Factors and Lifestyles in the Developmentof Atrial Fibrillation Among Individuals Aged
20-39 Years. Itoh H, Kaneko H, Fujiu K,
Kiriyama H, Morita K, Kamon T, Michihata N,

406

29.

30.

31.

32.

33.

34.
35.

Jo T, Takeda N, Morita H, Yasunaga H, Komuro I.
Am J Cardiol. 2021 Sep 15;155:40-44.
Acute-phase initiation of cardiac rehabilitationand clinical outcomes in hospitalized patients for
acute heart failure. Kaneko H, Itoh H, Kamiya K,
Morita K, Sugimoto T, Konishi M, Kiriyama H,
Kamon T, Fujiu K, Michihata N, Jo T, Takeda N,
Morita H, Yasunaga H, Komuro I. Int J Cardiol.
2021 Oct 1;340:36-41.
Association Between Blood Pressure Classification Using the 2017 ACC/AHA Blood Pressure
Guideline and Retinal Atherosclerosis. Matsuoka
S, Kaneko H, Yano Y, Itoh H, Fukui A, Morita K,
Kiriyama H, Kamon T, Fujiu K, Seki H,
Michihata N, Jo T, Takeda N, Morita H,
Nakamura S, Yokoo T, Nishiyama A, Node K,
Yasunaga H, Komuro I. Am J Hypertens. 2021
Oct 27;34(10):1049-1056.
Relation of the Metabolic Syndrome to Incident
Colorectal Cancer in Young Adults Aged 20 to 49
Years. Jimba T, Kaneko H, Yano Y, Itoh H,
Yotsumoto H, Seki H, Morita K, Kiriyama H,
Kamon T, Fujiu K, Michihata N, Jo T, Takeda N,
Morita H, Nishiyama A, Node K, Yasunaga H,
Komuro I. Am J Cardiol. 2021 Nov 1;158:132138.
Corrigendum to: "Fasting plasma glucose andsubsequent cardiovascular disease among young
adults: Analysis of a nationwide epidemiological
database" [Atherosclerosis 319 (2021 Feb) 35-41].
Kaneko H, Itoh H, Kiriyama H, Kamon T, Fujiu
K, Morita K, Michihata N, Jo T, Takeda N,
MoritaH,
Yasunaga
H,
KomuroI.
Atherosclerosis. 2021 Nov;336:30-31.
Untreated
Hypertension
andSubsequent
Incidence of Colorectal Cancer: Analysis of a
Nationwide Epidemiological Database. Kaneko
H, Yano Y, Itoh H, Morita K, Kiriyama H,
Kamon T, Fujiu K, Michihata N, Jo T, Takeda N,
Morita H, Nishiyama A, Node K, Bakris G,
Miura K, Muntner P, Viera AJ, Oparil S,
Lloyd-Jones DM, Yasunaga H, Komuro I. J Am
Heart Assoc. 2021 Nov 16;10(22):e022479.
Electrical Storm. Kani K, Fujiu K. Int Heart J.
2021;62(6):1195-1198. ＜2021.11＞
The Effectiveness of a Deep Learning Model to
Detect Left Ventricular Systolic Dysfunction

from Electrocardiograms. Katsushika S, Kodera
S, Nakamoto M, Ninomiya K, Inoue S, Sawano S,
Kakuda N, Takiguchi H, Shinohara H, Matsuoka
R, Ieki H, Higashikuni Y, Nakanishi K, Nakao T,
Seki T, Takeda N, Fujiu K, Daimon M, Akazawa
H, Morita H, Komuro I. Int Heart J. 2021;
62(6):1332-1341. ＜2021.11＞
36. Deep Learning Algorithm to Detect Cardiac
Sarcoidosis From Echocardiographic Movies.
Katsushika S, Kodera S, Nakamoto M, Ninomiya
K, Kakuda N, Shinohara H, Matsuoka R, Ieki H,
Uehara M, Higashikuni Y, Nakanishi K, Nakao T,
Takeda N, Fujiu K, Daimon M, Ando J, Akazawa
H, Morita H, Komuro I. Circ J. 2021 Dec 24;
86(1):87-95.
37. Atrioventricular and Ventricular Functional
Interdependence in Individuals Without Overt
Cardiac Disease. Yoshida Y, Nakanishi K,
Daimon M, Ishiwata J, Sawada N, Hirokawa M,
Kaneko H, Nakao T, Mizuno Y, Morita H, Di
Tullio MR, Homma S, Komuro I. J Am Heart
Assoc. 2021 Dec 7;10(23):e021624.

407

Laboratory for Advanced Researchon Pathophysiology of Metabolic
Diseases
Project Associate Professor
Miki Okada-Iwabu, Ph.D.

Project Research Associate
Jun Hosoe, M.D., Ph.D.

Introduction and Organization
Laboratory for Advanced Research on Pathophysiology
of Metabolic Diseases was launched in 2017 topromote cutting-edge research aimed at unraveling theunderlying pathophysiology of diabetes and related
metabolic diseases thereby contributing to thedevelopment of effective preventive measures against
these diseases.
“Individuals at risk of diabetes”, i.e., thosestrongly suspected of having diabetes and those inwhom the possibility of diabetes cannot be denied, arecurrently estimated to account for 28.5% of males and21.4% of females in Japan, thus making it an urgent
task not only for metabolic science but for society atlarge to fully elucidate the underlying pathophysiology
of diabetes. Diabetes is defined as a hyperglycemic
condition resulting from decreased secretion and/or
action of insulin from the pancreas and encompasses awide disease spectrum from such rare conditions as
mitochondrial diabetes and lipoatrophic diabetes todiabetes mellitus as a common disease. Diabetes occurs
not only through genetic susceptibility to the disease
but due to disorderly living habits, such as overeating,lack of physical activity and obesity. Therefore, theLaboratory is intended to promote wide-ranging
research into human tissues from patients with diabetes
mellitus as a common disease but from those with rare
forms of diabetes by drawing on state-of-the-art
genomic, epigenomic, metabolomic, metagenomic and

iPS-cell technologies and to bring resulting research
insights to bear on the development of innovative
diagnostic, preventive and therapeutic modalities fordiabetes.
Within the research milieu that theLaboratory offers, therefore, the research currently
being promoted is expected to lead to the elucidation of
the pathophysiology of diabetes and related metabolic
diseases, where rare disease-derived tissue- and iPS
cell-based investigations are expected to provide
invaluable insights into the pathophysiology ofdiabetes as a common disease. Thus, the Laboratory is
devoted to promoting relevant research leading to thedevelopment of innovative diagnostic, preventive andtherapeutic modalities, thereby contributing to theeffective prevention and treatment of diabetes.

Teaching activities
Working in collaboration with its closely related
Laboratory, Departments of Diabetes and Metabolic
Disease, Division of Nephrology and Endocrinology,
the Laboratory aims to foster internationally-oriented
young talents in both an academic and social sense withthe focus on graduate students, through theLaboratory’s mentoring program for academic
dissertations and conference presentations to develop
and enhance their science capabilities and skills.
The Laboratory has also had an active role inthe clinical researcher development program by the408

University of Tokyo, the main aim of which is to impart
not only the importance of clinical research but the
rudiments of clinical thinking to medical students andclinical researchers in training. As part of Metabolism
Research Course on the clinical researcher
development program, the Course holds up and pursues,
as its research theme, exploration of key molecules
involved in the onset/progression of obesity/ type 2
diabetes, given that radical preventive/therapeuticmodalities remain yet to be established for the so-called
lifestyle-related diseases, which include the metabolic
syndrome, type 2 diabetes, obesity, dementia, andfrailty, as well as for age-related diseases, all of which
are known to occur and progress through interactions
between individuals’ genetic and environmental factors.
Thus, the aim of the program is to explore these key
molecules by drawing on the analysis of integrated
genomic, epigenomic, transcriptomic, metabolomic
and clinical data.
Metabolism Research Course is widely open
to medical students and clinicians in training alike toprovide support not only for designated themes but forthemes of interest to course participants and to foster
an infrastructure/environment that would facilitate thepresentation of research results at conferences in Japanand overseas as well as their publication as peerreviewed papers in a timely fashion.

Research themes also being pursued at theLaboratory include the onset/progression of chronic
diseases associated with aging and rare diseases, suchas mitochondrial diabetes and lipoatrophic diabetes, tofacilitate the development of innovative diagnostic,
preventive and therapeutic modalities for these diseases,
based on resulting research findings and insights.

References
1.

2.

3.

Research activities
Diabetes occurs due not only to genetic factors but tothe influence of environmental factors, such as
overeating, lack of physical activity, and obesity.
Therefore, while diabetes represents a disease
condition with a wide spectrum from inherited rare
forms of diabetes to diabetes as a common disease, its
pathophysiology remains yet to be fully elucidated.
The Laboratory thus focuses on the analysisof the physiological functions of organs and systems
that play a key role in the onset of diabetes, i.e.,pancreatic endocrine cells, liver, adipose tissue,
skeletal muscle, nervous system, immune system andintestinal tract, as well as diseases resulting from
disruption of their functions by drawing fully on stateof-the-art omic (genomic, epigenomic, metabolomic,
and metagenomic) and iPS-cell technologies andgenetic cell and animal engineering.

4.

5.

Iwabu M, Okada-Iwabu M, Tanabe H, Ohuchi N,
Miyata K, Kobori T, Odawara S, Kadowaki Y,
Yokoyama S, Yamauchi T, Kadowaki T. AdipoR
agonist increases insulin sensitivity and exercise
endurance in AdipoR-humanized mice. Commun
Biol. 4, 45, 2021
Ohn J, Been KW, Kim JY, Kim EJ, Park T, Yoon
HJ, Ji JS, Okada-Iwabu M, Iwabu M, Yamauchi T,
Kim YK, Seok C, Kwon O, Kim KH, Lee HH,
Chung JH. Discovery of a transdermallydeliverable pentapeptide for activating AdipoR1
to promote hair growth. EMBO Mol Med. 13,
e13790, 2021
Mizuno-Iijima S, Ayabe S, Kato K, Matoba S,
Ikeda Y, Dinh TTH, Le HT, Suzuki H, Nakashima
K, Hasegawa Y, Hamada Y, Tanimoto Y, Daitoku
Y, Iki N, Ishida M, Ibrahim EAE, Nakashiba T,
Hamada M, Murata K, Miwa Y, Okada-Iwabu M,
Iwabu M, Yagami KI, Ogura A, Obata Y,
Takahashi S, Mizuno S, Yoshiki A, Sugiyama F.
Efficient production of large deletion and genefragment knock-in mice mediated by genome
editing with Cas9-mouse Cdt1 in mouse zygotes.
Methods. 191, 23-31, 2021
Hosoe J, Suzuki K, Miya F, Kato T, Tsunoda T,
Okada Y, Horikoshi M, Shojima N, Yamauchi T,
Kadowaki T. Structural basis of ethnic-specificvariants of PAX4 associated with type 2 diabetes.
Hum Genome Var. 8, 25, 2021
Hosoe J, Kawashima-Sonoyama Y, Miya F,
Kadowaki H, Suzuki K, Kato T, Matsuzawa F,
Aikawa SI, Okada Y, Tsunoda T, Hanaki K,
Kanzaki S, Shojima N, Yamauchi T, Kadowaki T.
Genotype-Structure-Phenotype Correlations of
Disease-Associated
IGF1R
Variants
andSimilarities to Those of INSR Variants. Diabetes.
70, 1874-1884, 2021

409

Department of Advanced Clinical
Science and Therapeutics
Project Associate Professor
Mutsuo Harada, M.D., Ph.D.

Project Assistant Professor
Masamichi Ito, M.D., Ph.D.

Project Researcher
Yusuke Adachi, M.D., Ph.D.

Project Academic Support Staff
Kanako Ikeya,
Yuko Ishiyama

Homepage

http://square.umin.ac.jp/sentan/

Introduction and Organization
The Department of Advanced Clinical Science andTherapeutics, established at the University of Tokyo in
2004, aims to develop new clinical strategies andtherapy in cardiovascular medicine and other areas.
The laboratory location was moved to the brand new
research building called Clinical Research Center-A in
January 2020. This department hopes to develop not
only basic research, but also applications to devise
new clinical strategies.

Research activities
Followings are our recent basic and clinical research
activities.
• New strategies to regulate acute/chronic myocarditis.
• New strategies to regulate acute myocardial infarction and ischemia/reperfusion injury.
• New strategies to regulate atherosclerosis andaneurism.
• New strategies to regulate systolic/diastolic heart
failure.
• New strategies to regulate cardio-kidney syndrome.

• Development of gene therapies with AAV vectors(anti-inflammation etc.).
• Development of new growth factor treatments(hepatocyte growth factor, etc.).
• Development of new anti-adhesion molecule
treatments (anti-inflammation, etc.).
• Development of new anti-extracellular treatments(anti-inflammation, anti-oxidation, etc.).
• Development of new chemical compounds (antiinflammation, anti-coagulation, etc.).
• Development of drug screening for heart failureusing iPS cell-derived cardiomyocytes.
• Expanding the use of foods and natural extracts.
• Expanding the application of existing drugs anddevices.
• Analysis of angiogenesis using in situ hybridization.

References
1.

Ueda K, Fukuma N, Adachi Y, Numata G,
Tokiwa H, Toyoda M, Otani A, Hashimoto M,
Liu PY, Takimoto E. Sex Differences andRegulatory Actions of Estrogen in Cardiovascular

410

2.

3.

4.

5.

6.

7.

System. Front Physiol. 2021 Sep 28;12:738218.
doi:10.3389/fphys.2021.738218. PMID: 34650448;
PMCID: PMC8505986.
Adachi Y, Kiyosue A, Ando J, Kawahara T,
Kodera S, Minatsuki S, Kikuchi H, Inaba T,
Kiriyama H, Hirose K, Shinohara H, Saito A,
Fujiwara T, Hara H, Ueda K, Sakakura K, Hatano
M, Harada M, Takimoto E, Akazawa H, Morita H,
Momomura SI, Fujita H, Komuro I. Factors
associated with left ventricular reverse remodelling after percutaneous coronary intervention inpatients with left ventricular systolic dysfunction.
Sci Rep. 2021 Jan 8;11(1):239. doi: 10.1038/
s41598-020-80491-y. PMID: 33420237; PMCID:
PMC7794568.
Nakagama Y, Ito M. Towards Deeper
Phenotyping of the Dilated Cardiomyopathies inChildren - Where Are We Now, and Where Are
We Heading? Circ J. 2021 Dec 24;86(1):116-117.
doi:10.1253/circj.CJ-21-0802. Epub 2021 Oct 28.
Ito M, Morita H. Titin Truncation Variant in
Dilated Cardiomyopathy. Int Heart J. 2021;62(2):221-223. doi: 10.1536/ihj.21-053.
Sato T, Ito M. Fibroblast-Cardiomyocyte
Interaction in Pediatric Restrictive Cardiomyopathy. Circ J. 2021 Apr 23;85(5):687-689.
doi: 10.1253/circj.CJ-21-0100. Epub 2021 Mar 6.
Fujiwara T, Takeda N, Hara H, Ishii S, Numata G,
Tokiwa H, Maemura S, Suzuki T, Takiguchi H,
Kubota Y, Seo K, Sakata A, Nomura S, Hatano M,
Ueda K, Harada M, Toko H, Takimoto E,
Akazawa H, Nishimura S, Komuro I.
Three-Dimensional Visualization of HypoxiaInduced Pulmonary Vascular Remodeling in Mice.
Circulation. 2021 Oct 26;144(17):1452-1455.
doi: 10.1161/CIRCULATIONAHA.121.056219.
Epub 2021 Oct 25. PMID: 34694894
Ishizuka M, Harada M, Nomura S, Ko T, Ikeda Y,
Guo J, Bujo S, Yanagisawa-Murakami H, Satoh
M, Yamada S, Kumagai H, Motozawa Y, Hara H,
Fujiwara T, Sato T, Takeda N, Takeda N, Otsu K,
Morita H, Toko H, Komuro I. CXCR7
ameliorates myocardial infarction as a β-arrestinbiased receptor. Sci Rep. 2021 Feb 9;11(1):3426.
doi:10.1038/s41598-021-83022-5. PMID:33564089

411

Department of Comprehensive
Radiation Oncology
Project Professor
Keiichi Nakagawa, MD, Ph.D

Project Research Associate
Sho Ozaki, Ph.D

Homepage http://www.u-tokyo-rad.jp/staff/shuyougakukouza.html
Introduction and Organization
The endowed chair was launched on April 1, 2021. At
the time of its establishment, there were two members:
project professor Nakagawa and project associate
Ozaki. The purpose of the establishment of this course
is to: From the standpoint of clinical radiation oncology
and medical physics, (1) promote the development ofradiation therapy technology, (2) train medical
physicists with science and engineering backgrounds
and promote the precision of radiation therapy, (3)improve the public's literacy about cancer in generalwith a focus on radiation therapy (including medical
physics and the effects of radiation on the human body),and (4) "cancer education" described in the Course of
Study for junior high and high schools in particular. We
are supporting the promotion of the four of them. We
have received support from Elekta K.K. and Chiyoda
Technol Corporation.
Nakagawa is the former head of the Radiation Therapy
Division. While researching the development ofradiation therapy equipment and clinical applications,
he felt the importance of specialists in medical physics.
Currently, medical physicists are working at relatively
large hospitals that perform radiation therapy, but thedevelopment of bases for medical physicists has notprogressed. One of the primary goals of this course is
to contribute to the further development of medical
physics through the improvement of image quality
related to radiation therapy, the analysis of big data in
the field of radiation therapy, and the development of

human resources in collaboration with the Radiation
Therapy Division.
In addition, Nakagawa was involved in the launch of
the Basic Act on Cancer Control enacted in 2006 andserved as a member of the Council for the Promotionof Cancer Control for ten years. It has aimed to improve
public cancer education and Japanese people's healthliteracy by doing so. Improving health literacy usingcancer teaching materials leads to various benefits insociety, such as cancer prevention and early detection,
patient-centered decision-making when selecting
treatment methods, balancing cancer treatment andwork, and social understanding of the effects ofradiation on the human body. Our second goal is tobecome a base for these issues.

Clinical activities
Two LINACs, one Tomotherapy, one iridium
brachytherapy device, one gamma knife forstereotactic irradiation of the head, one CT imaging
device dedicated to treatment planning, and treatment
planning devices are equipped in the Department ofRadiation Oncology. The primary purpose of thiscourse is not clinical. Still, we assist in medical
treatment while examining cases with doctors in thetreatment department as appropriate.
In addition, feedback on issues recognized in clinicalpractice is received and linked to technologicaldevelopment.

412

Education
This course provides graduate school education to
students from the Graduate School of Medicine,
Faculty of Medicine, the University of Tokyo. The
Department also collaborates with the Graduate
Schools of Science and Engineering and accepts
students from science and engineering backgrounds
who wish to become medical physicists and research
students conducting medical physics research.
In 2021, we accepted a Ph.D. student who aimed to
become a medical physicist from the University ofTokushima. He belonged to Professor Akihiro Haga's
laboratory, a former Director of the Radiation
Management Office, The University of Tokyo Hospital.
We provided education about medical physics researchand clinical practice to the student. We plan to continue
to be involved in the education of physicists andradiation therapists in 2022 and beyond.

Research
Following the purpose of this course, we conduct
research on medical physics and cancer education. In
medical physics, we are developing new high-precision
radiation therapy technologies by researching "imageguided radiation irradiation methods" using images
related to radiation therapy and research on image
processing utilizing artificial intelligence and analysisof big data related to radiation therapy in collaboration
with related clinical departments.
For example, in the study on image quality
improvement, we presented a survey on improving theimage quality of MVCT using deep learning.
Megavoltage computed tomography (MVCT) is usedin helical Tomotherapy for image-guided radiotherapy(IGRT). For precise registration based on image
guidance, the quality of MVCT images must be
ensured. However, the image quality of MVCT isconsiderably lower than that of kilovoltage CT (kVCT)
and thereby limits the accuracy of IGRT. We developed
a deep-learning based model to improve the image
quality of MVCT. The image quality of the improved
MVCT image was quantitatively evaluated by several
image quality indices. As a clinical benefit, it wasobserved by medical doctors that the improved images
enhanced the precision of contouring. Furthermore, we
found that our deep-learning based model enables the

improvement of the image quality of MVCT while
reducing metal artifacts, which often appear in kVCT.
In addition, as a result of the joint research with theRadiation Oncology department, the treatment resultsof whole-body skin irradiation for Mycosis fungoides
using tomotherapy and SBRT in prostate cancer
patients with hydrospacer gel indwelling. The resultsof the phase 2 trial are reported.
Moreover, Dr. Masanari Minamitani, a fourth-year
graduate student who was involved in education in thiscourse, has been conducting cancer education in school
education, which is the purpose of this course. The
program is held at 20 junior high schools in ShinagawaKu and Hachioji City, Tokyo, and the number ofparticipants reaches about 2,000.
Research on determining the effectiveness of cancer
education was also initiated in collaboration with theJapan Cancer Society. In addition, as a study related todecision-making, we reported the results of a web
survey on satisfaction with surgery and radiation
therapy among cancer patients. In addition, in thesurvey report of prostate cancer patients, we alsopresent changes in income before and after treatment.
As cancer education for adults, Nakagawa andMinamitani have asked companies to take action topromote cancer control, a project commissioned by the
Ministry of Health, Labour and Welfare chaired by
Nakagawa Nakagawa and Minamitani have invitedcompanies to Lectures. In the future, research to verify
whether cancer education for adults like this will leadto correct preventive behavior against cancer and anincrease in cancer screening rate is also planned.
In February 2022, a joint research project with Daido
Life Insurance Co., Ltd. was started on "Cancer
Awareness in Small and Medium Enterprises andworking status of cancer patients." The content of theresearch is based on "insurance contract data of small
and medium-sized enterprises" held by Daido Life, etc.,
and Daido Life and the University of Tokyo Hospital
jointly analyze trends such as "awareness of cancer"
and "employment status of cancer patients" in small
and medium-sized enterprises. By utilizing the
research results in developing new insurance products
and services at Daido Life, etc., we will contribute to"the creation of a workplace environment where people
can work with peace of mind even if they have cancer."

413

As mentioned above, this course conducts various
research activities in medical physics and cancer
education. Together with human resource development,
we expect further evolution from the next fiscal year
onwards.

Publications
1:

2:

3:

4:

5:

6:

7:

Katano A, Yamashita H, Nakagawa K. Radical
radiotherapy for localized cutaneous angiosarcoma of the scalp. Mol Clin Oncol. 2021 Sep;
15(3):195.
Minamitani M, Mukai T, Ogita M, Yamashita H,
Katano A, Nakagawa K. Relationship between
Consulting for Second Medical Opinions,Radiotherapy, and Satisfaction with Therapy,
Analyzed by Structural Equation Modeling: A
Web-Based Survey. Asian Pac J Cancer Prev. 2021
Sep 1;22(9):2889-2896.
Minamitani M, Mukai T, Yamashita H, Katano A,
Nakagawa K. Effects on annual income changes
afterradicalradiotherapy
versusafter
prostatectomy in patients with localized prostatecancer with a specific employment status: A webbased pilot study. PLoS One. 2021 Sep 30;16(9):e0258116.
Enomoto A, Fukasawa T, Terunuma H, Nakagawa
K, Yoshizaki A, Sato S, Miyagawa K. Decrease in
MAP3Ks expression enhances the cell deathcaused by hyperthermia. Int J Hyperthermia.
2022;39(1):200-208.
Ozaki S, Kaji S, Nawa K, Imae T, Aoki A,
Nakamoto T, Ohta T, Nozawa Y, Yamashita H,
Haga A, Nakagawa K. Training of deep crossmodality conversion models with a small data set,
and their application in megavoltage CT tokilovoltage CT conversion. Med Phys. 2022 Jun;49(6):3769-3782.
Katano A, Takeuchi K, Yamashita H, Nakagawa K.
Stereotactic Body Radiotherapy for a Sacral
Metastasis Clarified by Diffusion-Weighted
Whole-Body Imaging With Background Body
Signal Suppression in a Patient With CastrationResistant Prostate Cancer. Cureus. 2022 Mar 10;
14(3):e23047.
Ogita M, Yamashita H, Nozawa Y, Ozaki S,
Sawayanagi S, Ohta T, Nakagawa K. Phase II

study of stereotactic body radiotherapy withhydrogel spacer for prostate cancer: acute toxicity
and propensity score-matched comparison. Radiat
Oncol. 2021 Jun 12;16(1):107.
8: Jinnouchi H, Yamashita H, Kiritoshi T, Miki Y,
Katano A, Nakagawa K, Abe O. Prognostic valueof pre-treatment maximum standardized uptake
value and CRP in radiotherapy of esophageal
cancer. Mol Clin Oncol. 2021 Jul;15(1):146.
9: Ogita M, Kawamori J, Yamashita H, Nakagawa K.
Palliative radiotherapy for gross hematuria inpatients with advanced cancer. Sci Rep. 2021 May
5;11(1):9533..
10: Katano A, Ishida A, Yamashita H, Nakagawa K.
Radiotherapy for symptom palliation of
splenomegaly in patients with haematologicalmalignancies. Mol Clin Oncol. 2021 Jun;14(6):114.
11: Kitaguchi M, Yamashita H, Takenaka R, Okuma
K, Nawa K, Nakagawa K. Helical Skin Radiation
Therapy Including Total Skin Radiation Therapy
Using Tomotherapy for Primary Cutaneous
Lymphoma With Bone Marrow Suppression as a
Related Adverse Event. Pract Radiat Oncol. 2021
May-Jun;11(3):e308-e321.

414

Department of Molecular Structure
and Dynamics
Project Professor
Nobutaka Hirokawa, M. D.

Home page

http://cb.m.u-tokyo.ac.jp/

Teaching activities
We are involved in teaching medical students andMaster course and Ph. D. course students in thefollowing lectures and laboratory courses together
with the Department of Cell Biology and Anatomy.
I.
1) Lecture on Cell Bilogy, Developmental Biology,
Histology and Neurocytology.
2) Lecture on Gross Anatomy and Neuroanatomy. to
medical students and students of other facultiesII.
1) Laboratory course of Gross Anatomy and
Neuroanatomy.
2) Laboratory course of Histology and Histology of
the Cenrtral Nervous System.
to medical students and students of other faculties.
In addition we offer a special training course (freequarter) of various kinds of molecular cell biology
techniques such as immunocytochemistry, electron
microscopy, biochemistry, molecular biology, biophysics, and cellular and molecular neurobiology
technique to medical students.
Especially we devote ourselves for the teaching of the
cutting edge approaches of new light microscopy suchas the Photoactivated Localization Microscopy (PALM),
cryo-electron microscopy and X-ray crystallography.

Research activities
Our laboratory studies molecular motors and rail
microtubules and the mechanisms of intracellulartransport. To study these molecular mechanisms we
use new molecular cell biological approaches
includingcuttingedge
light
microscopies,

cryoelectron microscopy of molecular resolution,
X-ray crystallography, biophysics, molecular biology
and molecular genetics. We aim to study the structureand dynamics of the molecular motors in vitro and invivo at the highest special and temporal resolution andon these bases try to elucidate functions of molecularmotors in vivo combining molecular genetics.

Reference
1. Yoshihara S., Jiang X., Morikawa Mo., Ogawa T.,
Ichinose S., Yabe H., Kakita A., Toyoshima M.,
Kunii Ya, Yoshikawa T., Tanaka Y., and N.
Hirokawa. Betaine ameliorates schizophrenic
traits by functionally compensating KIF3-based
CRMP2 transport. Cell Rep 35: 108971, April 13,
1-15,2021 https://doi.prg/10.1016/j. celrep.2021.
108971
2. Morikawa Ma, Jerath N. U., Ogawa T.,
Morikawa Mo, Tanaka Y., Shy M.E., Zuchner, S.,
and N. Hirokawa. KIF1A mutation of humanneurpathies hyperstabilizes the motor-neckinteraction in ATPase cycle. EMBO J. 2022
41:e108899 2021 https://doi.org/10.15252/embj.
2021108899
3. Wang S., Tanaka Y., Xu Y., Takeda S., and N.
Hirokawa. KIF3B promotes a PI3K signaling
gradient causing changes in a Shh protein
gradient and suppressing polydactyly in mice.
Dev Cell 57: 2273-2289, 2022 (Cover art)
https://doi.org/10.1016/j.devcel.2022.09.007
4. Wan Y., Morikawa Mo., Morikawa M., Iwata S.,
Naseer I., Caudhary A., Tanaka Y., and N.
Hirokawa. KIF4 regulates neuronal morphology

415

and seizure susceptibility via the PARP1
signaling pathway. J Cell Biol in press 2022

416

Department of
Immunotherapeutics
Project Professor
Kazuhiro Kakimi, M.D.,Ph.D.

Project Lecturer
Koji Nagaoka, Ph.D.

Project Researcher
Yukari Kobayashi

Technical Assistant
Mikiko Shibuya, Yaeko Furuhashi, Yuki Yoshikawa

Homepage https://immunotherapy-uth.jp/
Introduction and Organization

Teaching activities

The Department of Immunotherapeutics is locatedwithin the 22nd Century Medical and Research Center,established in 2004 within the University of Tokyo
Hospital as a base for industry-academia collaboration
and as an organization promoting translational
research. It was established to conduct clinicalresearch and clarify the role of this treatment
technology in cancer treatment.
In May 2019, MEDINET Co., Ltd. completed theendowed courses for three periods of 15 years, andfrom June, Takara Bio Co., Ltd. made a new start asendowed courses. The laboratory location has also
moved from the Central Clinical Building II to theMolecular Life Innovation Building. We conduct
several joint programs with many clinical departments
and engage in research on tumor immunology byanalyzing the obtained clinical specimens with
cutting-edge technology.
Our goal is to build a system that integrates a hugeamount of clinical data and provides optimal treatment
for each patient. In particular, we are focusing on
identifying neoantigens based on patient genome
information and developing TCR-T cell therapy using
neoantigen-specific TCRs.

Graduate students from the department of
Neurosurgery, Gastroesophageal Surgery, Respiratory
Surgery, and Urology joined our team for research. We
collected surgically resected tumors from each clinicaldepartment, cultured tumor-infiltrating lymphocytes,
extracted DNA/RNA from the tumors, and performed
NGS analysis. We are studying the effects of theintratumoral immune environment on anti-tumor
immune responses
In the laboratory, in addition to basic immunoassay
techniques using cell culture and flow cytometry, they
have mastered the handling of bioinformatics tools
necessary for genome analysis.
Graduate students who are actually in charge ofoutpatient care or endoscopies in their respective
clinical departments, or with the help of colleagues,
build cooperation with medical offices and affiliatedhospitals, collect specimens, and conduct research. I
believe that this experience will help them develop
new treatment methods and tackle unknown issues
when they become future clinical practice leaders.
Three graduate students who published papers on
research using valuable specimens before and after
treatment with immune checkpoint inhibitors,

417

searching for biomarkers that predict postoperative
prognosis, and researching neoantigen immunotherapy
using mouse models, successfully obtained a Ph.D.
degree.

Therefore, we constructed an innovative neoantigen
analysis platform that combines a neoantigen
prediction system and immunogenicity verification
using tumor-specific TCR-expressing cells. Our goal
is to realize TCR-T cell therapy targeting neoantigens.

Research activities
Immune checkpoint inhibitors have been approved forvarious cancer types, but many patients still do notrespond to these therapies or become resistant to themafter therapeutic effects have been shown. In order torationally judge the indications of immune checkpoint
inhibitors and clarify the points of resistance totreatment, we will clarify the molecular mechanismsthat determine the responsiveness to immune
checkpoint inhibitors in individual patients.
Accumulated clinical experience defines responsiveness to immune checkpoint inhibitors, including
tumor-specific factors, tumor microenvironment,
host-related factors, and dynamic changes associatedwith treatment. Furthermore, high-dimensional
analysis at the single-cell level becomes possible, and
it is possible and necessary to comprehensively
integrate detailed and enormous information forpredicting efficacy and searching for the key toovercoming treatment resistance.
We have studied current tumor immunology based on
detailed observations, accumulating hypotheses andtheir verification. On the other hand, in genomic
analysis, comprehensive information is searched foranswers without being bound by preconceptions using
bioinformatics and computer science. To haveconfidence in evaluating the anti-tumor immune
response, we should integrate conventional
immunology and genomic immunology. Therefore,
tumor immunology research conducted in our
department focuses on integrative analysis as cancer
immunogenomics.
NGS has allowed it to analyze neoantigens generated
from genomic abnormalities in individual patients,
enabling the development of cancer immunotherapy
targeting neoantigens.
Neoantigens are predicted based on genomic
information of individual patients by the high binding
ability to MHC molecules. Then, they are validated
for their reactivity to tumor-specific T cells.

References
1.

2.

3.

4.

5.

Masuda T, Tanaka N, Takamatsu K, Hakozaki K,
Takahashi R, Anno T, Kufukihara R, Shojo K,
Mikami S, Shinojima T, Kakimi K, Tsunoda T,
Aimono E, Nishihara H, Mizuno R, Oya M.
Unique characteristics of tertiary lymphoidstructures in kidney clear cell carcinoma:
prognostic outcome and comparison with bladdercancer. J Immunother Cancer. 2022 Mar;10(3):e003883.
Komura D, Kawabe A, Fukuta K, Sano K,
Umezaki T, Koda H, Suzuki R, Tominaga K,
Ochi M, Konishi H, Masakado F, Saito N, Sato Y,
Onoyama T, Nishida S, Furuya G, Katoh H,
Yamashita H, Kakimi K, Seto Y, Ushiku T,
Fukayama M, Ishikawa S. Universal encoding of
pan-cancer
histology
bydeep
texturerepresentations. Cell Rep. 2022 Mar 1;38(9):110424.
Kawanabe-Matsuda H, Takeda K, Nakamura M,
Makino S, Karasaki T, Kakimi K, Nishimukai M,
Ohno T, Omi J, Kano K, Uwamizu A, Yagita H,
Gomperts Boneca I, Eberl G, Aoki J, Smyth MJ,
Okumura K. Dietary Lactobacillus-derived
exopolysaccharide enhances immune checkpoint
blockade therapy. Cancer Discov. 2022 Feb 17:
candisc.0929.2021.
Sugawara T, Miya F, Ishikawa T, Lysenko A,
Nishino J, Kamatani T, Takemoto A,Boroevich
KA, Kakimi K, Kinugasa Y, Tanabe M, Tsunoda
T. Immune subtypes and neoantigen-related
immune evasion in advanced colorectal cancer.
iScience. 2022 Jan 6;25(2):103740.
Nagaoka K, Sun C, Kobayashi Y, Kanaseki T,
Tokita S, Komatsu T, Maejima K,Futami J,
Nomura S, Udaka K, Nakagawa H, Torigoe T,
Kakimi K. Identification of Neoantigens in Two
Murine Gastric Cancer Cell Lines Leading to the
Neoantigen-based
Immunotherapy.
Cancers(Basel). 2021 Dec 27;14(1):106.

418

6.

Saito T, Kurose K, Kojima T, Funakoshi T, Sato
E, Nishikawa H, Nakajima J,Seto Y, Kakimi K,
Iida S, Doki Y, Oka M, Ueda R, Wada H. Phase
Ib study on the humanized anti-CCR4 antibody,
KW-0761, in advanced solid tumors. Nagoya J
Med Sci. 2021 Nov;83(4):827-840.
7. Maeda Y, Wada H, Sugiyama D, Saito T, Irie T,
Itahashi K, Minoura K, Suzuki S, Kojima T,
Kakimi K, Nakajima J, Funakoshi T, Iida S, Oka
M, Shimamura T, Doi T, Doki Y, Nakayama E,
Ueda R, Nishikawa H. Depletion of central
memory CD8+T cells might impede the antitumor therapeutic effect of Mogamulizumab. Nat
Commun. 2021 Dec 14;12(1):7280.
8. Saito N, Kobayashi Y, Nagaoka K, Kushihara Y,
Sato Y, Wada I, Kakimi K, Seto Y. Two distinct
phenotypes of immunologically hot gastriccancer subtypes. Biochem Biophys Rep. 2021
Nov 3;28:101167.
9. Sun C, Nagaoka K, Kobayashi Y, Nakagawa H,
Kakimi K, Nakajima J. Neoantigen Dendritic
Cell Vaccination Combined with Anti-CD38 and
CpG Elicits Anti-Tumor Immunity against the
Immune Checkpoint Therapy-Resistant Murine
Lung Cancer Cell Line LLC1. Cancers (Basel).
2021 Nov 2;13(21):5508.
10. Takeuchi Y, Tanegashima T, Sato E, Irie T, Sai A,
Itahashi K, Kumagai S, Tada Y, Togashi Y,
Koyama S, Akbay EA, Karasaki T, Kataoka K,
Funaki S, Shintani Y, Nagatomo I, Kida H, Ishii
G, Miyoshi T, Aokage K, Kakimi K, Ogawa S,
Okumura M, Eto M, Kumanogoh A, Tsuboi M,
Nishikawa H. Highly immunogenic cancer cells
require activation of the WNT pathway for
immunological escape. Sci Immunol. 2021 Nov
12;6(65):eabc6424.
11. Ma L, Sakamoto Y, Ando K, Fujita H, Takahashi
A, Takeshima T, Otsuka H, Ebner DK, Kakimi K,
Imai T, Shimokawa T. Th balance related hostgenetic background affects the therapeutic effectsof combining carbon-ion radiotherapy withdendritic cell immunotherapy. Int J Radiat Oncol
Biol Phys. 2021 Nov 2:S0360-3016(21)03051-0.
12. Hakozaki K, Tanaka N, Takamatsu K, Takahashi
R, Yasumizu Y, Mikami S, Shinojima T, Kakimi
K, Kamatani T, Miya F, Tsunoda T, Aimono E,
Nishihara H, Mizuno R, Oya M. Landscape of

13.

14.

15.

16.

17.

prognostic signatures and immunogenomics of
the AXL/GAS6 axis in renal cell carcinoma. Br J
Cancer. 2021 Nov;125(11):1533-1543.
Takamatsu K, Tanaka N, Hakozaki K, Takahashi
R, Teranishi Y, Murakami T, Kufukihara R, Niwa
N, Mikami S, Shinojima T, Sasaki T, Sato Y,
Kume H, Ogawa S, Kakimi K, Kamatani T, Miya
F, Tsunoda T, Aimono E, Nishihara H, Sawada K,
Imamura T, Mizuno R, Oya M. Profiling theinhibitory receptors LAG-3, TIM-3, and TIGIT inrenal cell carcinoma reveals malignancy. Nat
Commun. 2021 Sep 20;12(1):5547.
Nishida M, Yamashita N, Ogawa T, Koseki K,
Warabi E, Ohue T, Komatsu M, Matsushita H,
Kakimi K, Kawakami E, Shiroguchi K, Udono H.
Mitochondrial reactive oxygen species trigger
metformin-dependent anti-tumor immunity via
activation of Nrf2/mTORC1/p62 axis in tumorinfiltrating CD8T lymphocytes. J Immunother
Cancer. 2021 Sep;9(9):e002954.
Morita M, Nishida N, Sakai K, Aoki T, Chishina
H, Takita M, Ida H, Hagiwara S, Minami Y,
Ueshima K, Nishio K, Kobayashi Y, Kakimi K,
Kudo M: Immunological Microenvironment
Predicts the Survival of the Patients with
Hepatocellular Carcinoma Treated with AntiPD-1 Antibody. Liver Cancer 2021.
Murakami T, Tanaka N, Takamatsu K, Hakozaki
K, Fukumoto K, Masuda T, Mikami S, Shinojima
T, Kakimi K, Tsunoda T, Sawada K, Imamura T,
Mizuno R, Oya M.Multiplexed single-cellpathology reveals the association of CD8 T-cellheterogeneity with prognostic outcomes in renal
cell carcinoma. Cancer Immunol Immunother.
2021 Jul 14.
Ahmadi H, Shogen K, Fujita K, Honjo T, Kakimi
K, Futami J. Unusual aggregation property ofrecombinantly expressed cancer-testis antigens inmammalian cells. J Biochem. 2021 Jul 10:
mvab081.

Social Cooperation Program420

Department ofAdvanced Nursing Technology
Project Associate Professor
Ryoko Murayama, Ph.D., R.N.M.

Project Assistant Professor
Mari Abe, MHS, R.N.

Visiting Researcher
Hidenori Tanabe, MS.

Homepage

http://ant.m.u-tokyo.ac.jp/index.html

Introduction and Organization
The Department of Advanced Nursing Technology
was established in December 2012 with the aim ofdeveloping new academic fields in order to create
advanced nursing technology based on clinicalevidences. The primary aim is to “Never let patientsendure suffering in healthcare;” therefore, our activities
aimed to directly assist patients to live longer and have
healthier lives.
To date, significant challenges in creating advanced
nursing technology have resulted in a gap between
academic research and clinical setting requirements.
Therefore, strategies of advanced nursing technology
have not been applied in hospitals due to its unsuitability in the clinical setting, despite being beneficial toacademic nursing researchers at universities.
In contrast, new nursing technologies are often
developed by nurses’ experiences in clinical settings;
however, they have certain limitations such as
unavailability of scientific processes. Furthermore,
systems to promote and support nurses who wish to
conduct research in the clinical setting are insufficient.
The Department of Advanced Nursing Technology
was established at the University of Tokyo Hospital(Tokyo, Japan), with the support of Terumo Corp.
(Tokyo, Japan), as a social cooperation program. The
social cooperation program at the University of Tokyo
was established to address the abovementioned

challenges and further development of nursing
technology. The Department of Advanced Nursing
Technology (since in March 2018) now comprises the
Department of Gerontological Nursing/Wound CareManagement, Department of Nursing, and Department
of Hematology and Oncology. This program aimed todevelop a new research model through a collaborative
research with the Departments of Nursing and Medical
Examination of the University of Tokyo Hospital andthe Division of Health Sciences and Nursing of the
University of Tokyo. In addition, this program aimed todisseminate advances in nursing technology based on
the needs of clinical practices worldwide.
The team included the following members fromvarious departments at the University of Tokyo: Ryoko
Murayama (Project Associate Professor) and Mari Abe(Project Assistant Professor), as well as Hidenori
Tanabe (Visiting Researcher; from Terumo Corp.).
Furthermore, the Global Nursing Research Center(GNRC), Graduate School of Medicine, the Universityof Tokyo, has been established in April 2017. We werein charge of the department of Clinical Nursing
Technology, Division of Care Innovation of GNRC,
and contributed to promote research on innovative
nursing science and to create an interdisciplinary
research and educational environment that fosters
young leaders in nursing research.

421

Teaching activities
This program guided Master’s and Ph.D. students
from the Department of Gerontological Nursing/
Wound Care management on matters concerning
research planning and practical work. Furthermore, wehave been involved in providing lectures on topics,
such as gerontological nursing and wound care nursing,for undergraduates, master’s and Ph.D. students within
the Department of Gerontological Nursing/Wound
Care management.
We were in charge of lectures on nursing
translational research at the seminar hosted by GNRC
for post-doctoral fellows and other researchers. (The 9th
Introduction seminar to Nursing Science andEngineering)Nursing and Medical Examination and School of
Health Science at the University of Tokyo Hospital.
2. Research fields and themes in 2021
 Understanding the mechanisms that lead toperipheral intravenous catheter failures: PIV-CF
 Evaluation of a new intravenous catheter to prevent
PIV-CF Development of a thermo-film for the early
detection of extravasation
 Development of a training program for the technicalimprovement of peripheral venous catheter
placement using ultrasonography

References
1.

Research activities
1. Activity policy
A new nursing research scheme aimed at identifying
clinical needs related to our primary belief will be
developed, i.e., “Never let patients endure suffering in
healthcare.” Solutions to clinical issues in nursing will
be determined using multidisciplinary studies andresearch. Regarding our scientific approach,epidemiologic surveys and genetic research conducted,
followed by evaluation of technologies/devices
developed in collaboration with companies,
endeavoring to provide epoch-making technologies
that meet clinical needs utilizing the Nursing
Translational Research system.
Several research projects were conducted in our
department, such as development of nursing technology for the early detection of extravasation, clarification of infiltration, identification of mechanisms,
development of a new intravenous catheter to prevent
catheter failures, and a proposal or new program on
infusion therapy management. These projects werebeing conducted in collaboration with nurses at the
University of Tokyo Hospital.
We offered lectures and consultations on researchmatters and provide guidance on article writing topromote nursing research in the clinical setting. We
were planning and running an annual symposium
known as “UTokyo nursing research” in order topromote joint research with the Departments of

2.

3.

4.

5.

Takahashi T, Shintani Y, Murayama R, Noguchi H,
Abe-Doi M, Koudounas S, et al., Ultrasonographic measurement of blood flow ofperipheral vein in the upper limb of healthy
participants: a pilot study. Journal of the JapaneseSociety of Wound, Ostomy, and ContinenceManagement. 2021; 25(3): 576-584.
Murayama R, Abe-Doi M, Kogure T, Takahashi T,
Kanno C, Ishigaki M, Sanada H. The influence of
peripheral intravenous catheterization on the sleep
quality of ophthalmic inpatients: An observational
study. Journal of Nursing Science and Engineering.
2021; 8: 134-142.
Abe-Doi M, Murayama R, Komiyama C, Tateishi
R, Sanada H. Effectiveness of ultrasonography for
peripheral catheter insertion and catheter failure
prevention in visible and palpable veins. Journalof Vascular Access. 2021; doi.org/10.1177/
11297298211022078
Abe-Doi M, Murayama R, Kawamoto A,
Komiyama C, Doorenbos A, Sanada H. Damage tosubcutaneous tissue at the catheterization site
during chemotherapy: A prospective observational
study using ultrasonography. Japan Journal of
Nursing Science. 2021; 18(4): e12436.
Takahashi T, Murayama R, Abe-Doi M, Miyahara
M, Kanno C, Nakagami G, et al., Catheter failurein the administration of hyperosmotic drugs
through a peripheral vein and vascular selection:
A retrospective cohort study. Drug Discoveries &Therapeutics. 2021; 15(5): 236-240

422

Department of Medical
Information Engineering
Project Associate Professor
Taichi Kin, M.D.,Ph.D.

Project Research Associate
Toki Saito, Ph.D.

Homepagehttps://medicalinfo-engneering.org

Introduction and Organization
Department of Medical Information Engineering waslaunched on November 2021, through the financial
support of SoftBank corporation, with assistance by
the Department of Neurosurgery. Two faculty staffs,
Taichi Kin as the Specially Appointed Associate
Professor and Toki Saito as the Specially Appointed
Assistant Professor started the research project.
The Department of Medical Information Engineering
aims at research and development of medical dataprocessing such as medical images by making full useof information and communication technology,
artificial intelligence technology, anonymous processing technology, and cloud technology. Specifically,
this includes medical image processing technologies
such as tissue segmentation, annotation, and virtual
reality surgical simulation, and anonymization,
information and communication technologies of
medical image data.

medical imaging. Our laboratory is engaged in thefollowing research activities:
1) medical image processing
3D reconstruction, segmentation, registration,
rendering, fluid dynamics
2) virtual reality surgical simulation
tissue deformation, using surgical instruments3) surgical support system
surgical navigation, XR technology4) information and communication technology
block chain, anonymization, cloud technology

References1.

2.

Teaching activities
Department of Medical Information Engineering was
involved in the education through research activities
of graduate students of the Graduate School of
Medicine.

Research activities
Our research covers the biomedical computer
applications that focus on medical data such as

3.

Takeda Y, Kin T, Sekine T, Hasegawa H, Suzuki
Y, Uchikawa H, Koike T, Kiyofuji S, Shinya Y,
Kawashima M, Saito N. Hemodynamic Analysis
of Cerebral Arteriovenous Malformations with 3Dimensional Phase-Contrast Magnetic ResonanceImaging. AJNR 42(12): 2138-2145, 2021
Koike T, Kin T, Tanaka S, Sato K Uchida T,
Takeda Y, Uchikawa H, Kiyofuji S, Saito T,
Takami H, Takayanagi S, Mukasa A, Oyama H,
Saito N. Development of new image-guideneuronavigation system: mixed-reality projection
mapping is accurate and feasible. Oper
Neurosurg 21(6): 549-557, 2021
Sugino T, Roth HR, Oda M, Kin T, Saito N,
Nakajima Y, Mori K. Performance improvementof weakly supervised fully convolutional
networks by skip connections for brain structure423

segmentation. Med Phys 48(11): 7215-7227,
2021
4. Sugino T, Kawase T, Onogi S, Kin T, Saito N,
Nakajima Y. Loss weightings for improving
imbalanced brain structures segmentation using
convolutional networks. Healthcase (Basel) 9(8):938, 2021
5. Ishigami D, Miyawaki S, Nakatomi H,
Takayanagi S, Teranishi Y, Ohara K, Hongo H,
Dofuku S, Kin T, Abe H, Mitsui J, Komura D,
Katoh H, Ishikawa S, Saito N. Brainstem
intraparenchymal schwannoma with genetic
analysis: a case report and literature review.
BMC Med Genomics 14(1): 205, 2021.
6. Yang X, Xia D, Kin T, Igarashi T. A two-stepsurface-based 3D deep learning pipeline forsegmentation of intracranial aneurysm. ElectricalEngineering and Systems Science, 2021.
7. Fang H, Yang X, Kin T, Igarashi T. Brain surface
reconstruction from MRI images based on
segmentation networks applying signed distancemaps. IEEE ISBI 2021: 1164-1168
8. Koike T, Kin T, Tanaka S, Takeda Y, Uchikawa H,
Shiode T, Saito T, Takami H, Takayanagi S,
Mukasa A, Oyama H, Saito N. Development ofinnovative neurosurgical operation support
method using mixed-reality computer graphics.
World Neurosurg X. 2021 Mar 13; 11: 100102.
doi: 10.1016/j.wnsx.2021.100102. eCollection
2021 Jul.
9. Uchida T, Kin T, Koike T, Kiyofuji S, Uchikawa
H, Takeda Y, Miyawaki S, Nakatomi H, Saito N.
Identification of the facial colliculus in
two-dimensional and three-dimensional images.
Neurol Med Chir (Tokyo) 61(6): 376-384, 2021.
10. Uchikawa H, Kin T, Takeda Y, Koike T, Kiyofuji
S, Koizumi S, Shiode T, Suzuki Y, Miyawaki S,
Nakatomi H, Mukasa A, Saito N. Correlation of
inflow velocity ratio detected by phase contrast
magnetic resonance angiography with the blebcolor of unruptured intracranial aneurysms.
World Neurosurg X. 2021 Jan 13; 10: 100098.
doi: 10.1016/j.wnsx.2021.100098. eCollection
2021 Apr.
11. Hasegawa H, Kin T, Shin M, Suzuki Y,
Kawashima M, Shinya Y, Shiode T, Nakatomi H,
Saito N. Possible association between rupture andintranidal microhemodynamics in arteriovenous
malformations:
phase-contrast
magnetic
resonance angiography-based flow quantification.
World Neurosurg 150: e427-e435, 2021.
12. Kiyofuji S, Kin T, Kakizawa Y, Doke T, Masuda
T, Nakatomi H, Morita A, Harada K, Saito N.
Development of integrated 3-dimensional
computer graphics human head model. Oper
Neurosurg 20(6): 565-574, 2021.
13. Sugino T, Suzuki Y, Kin T, Saito N, Onogi S,
Kawase T, Mori K, Nakajima Y. Label cleaningand propagation for improved segmentation
performance using fully convolutional networks.
Int J Comput Assist Radiol Surg 16(3): 349-361,
2021.
14. Nomura S, Kin T, Kunimatsu A, Shojima M,
Watanabe Y, Suzuki Y, Shono N, Imai H, Saito T,
Nakatomi H, Oyama H, Saito N. Registration
method between phase-contrast magnetic
resonance angiography and time-of-flightmagnetic resonance angiography – A preliminary
study. JMIHI 11(1): 33-39, 2021.

424

Department of Healthcare Quality
Assessment
Project Professor
Hiroaki Miyata, PhD

Project Associate Professor
Hiraku Kumamaru, MD, ScD

Project Assistant Professor
Naoaki Ichihara, MD, PhD, MPH

Project Researcher
Shun Kosaka, MD, PhD
Shiori Nishimura, MS
Hisateru Tachimori, PhD
Ryo Nakamaru, MD, PhD

Visiting Researcher
Norimichi Hirahara, PhD
Hiroyuki Yamamoto, MD, PhD, MPH
Arata Takahashi, HIM, PhD
Kan Nawata, MD, PhD
Eriko Fukuchi, MS
Hideki Endo, MD
Chieko Fujimura
Satoshi Shoji, MD
Shiyori Usune
Naoko Kinukawa
Daisuke Shinjo

Clerical Staff
Urara Isozumi, MS

Clerical Staff (Secretary)
Takayo Nakamura

Homepage

http://hqa.umin.jp/425

Introduction and Organization
The Department of Healthcare Quality Assessment(HQA) was established in 2006 and has been engaging
in research on healthcare quality improvement incollaboration with the Department of Cardiothoracic
Surgery in University of Tokyo.
The objective of providing healthcare is to provide
high quality healthcare services to all patients.
Institute of Medicine states that health care reform
should focus on improving the patients’ health as wellas health care values that they think are important.
In the 21st century, this viewpoint, together withinsight from health economics, has been the firstpriority in the field of medicine and healthcare.
“Quality improvement initiative,” therefore, needs toadjust the healthcare systems to accommodate thefee-for-service perspectives while improving theclinical environment for both patients and providers.

Education and Research
Department of Healthcare Quality Assessment (HQA)
has been actively collaborating with healthcare
professionals and various academic societies as theyplay key roles in the quality improvement initiatives
in the field. In such positive environment driven by
the patient-centered philosophy, the patients receive
more satisfying care, physicians are rewarded for their
excellence, and healthcare costs are sustained. To
accomplish this goal, there are 3 principles thatnavigate us through the journey: (a) the topmost value
should always be on that of patients, (b) all medical
practices should be organized around medical
conditions as well as the care cycles of the patients,and (c) the results---risk-adjusted outcomes andmedical costs spent---must be scientifically measured
and evaluated.
In April 2010, the Japan Society of Surgery and 10
related surgical societies founded the National
Clinical Database (NCD), which is an all-Japanendeavor that aims to build a large-scale,comprehensive clinical registry that utilize the “bigdata” to improve the quality of surgery as well as
surgical sciences in Japan. HQA has been playing
important academic roles in the project since its birth.
The actual data entry started from January 1st, 2011,
and since then NCD has been collecting approxi-

mately 95% of all surgical operations across Japan in
the collaboration with the clinical societies. NCD is
also connected with the participating societies’ boardof certification systems, which makes it unique among
other large-scale clinical registries in the world. Today(as of 2021) more than 5,400 hospitals and clinics are
participating in NCD with the accumulated data of 10
million cases (approximately 1.5 million each year).
HQA has developed risk models for different groupsof surgical procedures that help us implement several
practical tools aimed for medical professionals in the
joint research activity with Japan Cardiovascular
Surgery Database (JCVSD). One of those tools is
JapanSCORE, which allows a user to calculate apatient’s post-operative risk of mortality andmorbidities.
Another tool called RiskCalculator
returns a medical professional the calculated risk ofmortality and morbidity in a real-time manner afters/he inputs a minimum number of pre-operative risk
information. Both tools can be used in medical teammeetings as well as in sessions with patients to reachbetter informed consent. Just like JCVSD’s
JapanSCORE and RiskCalculator, feedback tools
based on the NCD data have been provided todifferent subspecialty areas. All of these activities
help Japan’s healthcare quality initiatives in various
places, and HQA is proud of being part of it.
HQA also has conducted evidence-based policy
analysis to help federal and local government todevelop better healthcare policy-making. It is anacademic activity that contributes in a different angle
to the endeavor of healthcare quality improvement
than those with healthcare professionals in the field,
described above. In 2012, HQA started participating
in a series of research to evaluate the validity ofJapan’s cancer control policy framework using various
stakeholders’ perspectives. Interview as well as
questionnaire studies were conducted in accordancewith the Basic Plan for Implementing Cancer Control
administered by the Japanese Government. Since
2014, HQA has been participating in the conducting
post marketing surveillance studies using nationwide
registries,incollaboration
with
PMDA
(Pharmaceuticals and Medical Devices Agency),
Academic societies and device manufacturers. Also,
starting in 2017, HQA has led a new initiative at NCDof collecting diagnosis procedure combination data426

and insurance claims data from participating facilities.
Data on the use of medical products as well as on
billings from these data are being used to supplement
the clinical information collected in the registries for
conducting clinical and health services research.
Future Directions
Clinical databases like NCD are the core componentsof quality improvement initiatives across the multiple
subspecialities. HQA supports NCD’s systematic
data collection, data management, data analyses, andthe development of useful feedback systems.
Non-surgical fields such as clinical oncology are also
joining NCD and this trend is becoming stronger. Our
benchmarking projects backed up by NCD’s big data
will keep driving the quality improvement activities inmany healthcare fields.
Increasing numbers of clinical research output has
been coming out of the detailed analyses on NCD datain collaboration with each specialty field. Besides
professional societies, medical device firms havestarted the operation of their post-marketingsurveillance studies in collaboration with NCD.
Working with NCD, the industry, PMDA, and therelated medical societies, HQA helps the project move
forward through academic support. Furthermore,
HQA has been involved in international collaborative
research work with database activities such as
American College of Surgeon’s NSQIP and Asian
Cardiac Database while contributing to the quality
improvement activities in different regions of theworld.

Publications (selected)
1. Hashimoto M, Yamamoto H, Endo S, Okada M,

2.

Miyata H, Hasegawa S, et al. Japanese Current
Status of Curative-Intent Surgery for Malignant
Pleural Mesothelioma. Ann Thorac Surg. 2022
Apr;113(4):1348–53.
Ban D, Tanabe M, Kumamaru H, Nitta H, Otsuka
Y, Miyata H, et al. Safe Dissemination of
Laparoscopic Liver Resection in 27,146 Cases
Between 2011 and 2017 From the National
Clinical Database of Japan. Ann Surg. 2021 Dec;
274(6):1043–50.

3.

Maeda H, Endo H, Ichihara N, Miyata H,
Hasegawa H, Kamiya K, et al. Association of dayof the week with mortality after elective righthemicolectomy for colon cancer: Case analysis
from the National Clinical Database. Ann
Gastroenterol Surg. 2021 May;5(3):331–7.
4. Arita J, Yamamoto H, Kokudo T, Hasegawa K,
Miyata H, Toh Y, et al. Impact of board
certification system and adherence to the clinicalpractice guidelines for liver cancer on posthepatectomy risk-adjusted mortality rate inJapan: A questionnaire survey of departments
registered with the National Clinical Database. J
Hepatobiliary Pancreat Sci. 2021 Oct;28(10):801–11.
5. Hörer J, Hirata Y, Tachimori H, Ono M, Vida V,
Herbst C, et al. Pediatric Cardiac Surgical
Patterns of Practice and Outcomes in Japan andEurope. World J Pediatr Congenit Heart Surg.
2021 May;12(3):312–9.
6. Matsuoka T, Ichihara N, Shinozaki H, Kobayashi
K, Lefor AK, Kimura T, et al. Antithrombotic
drugs have a minimal effect on intraoperative
blood loss during emergency surgery for
generalized peritonitis: a nationwide retrospective cohort study in Japan. World J Emerg
Surg. 2021 May;16(1):27.
7. Fujishiro J, Watanabe E, Hirahara N, Terui K,
Tomita H, Ishimaru T, et al. Laparoscopic Versus
Open Appendectomy for Acute Appendicitis inChildren: a Nationwide Retrospective Study on
Postoperative Outcomes. J Gastrointest Surg Off
J Soc Surg Aliment Tract. 2021 Apr;25(4):1036–44.
8. Fujishiro J, Fujiogi M, Hirahara N, Terui K,
Okamoto T, Watanabe E, et al. Abdominal
Drainage at Appendectomy for ComplicatedAppendicitis in Children: A Propensity-matchedComparative Study. Ann Surg. 2021 Dec;274(6):e599–604.
9. Ma M, Liu Y, Gotoh M, Takahashi A, Marubashi
S, Seto Y, et al. Validation study of the ACS
NSQIP surgical risk calculator for two
procedures in Japan. Am J Surg. 2021 Nov;
222(5):877–81.
10. Marubashi S, Takahashi A, Kakeji Y, Hasegawa
H, Ueno H, Eguchi S, et al. Surgical outcomes in427

gastroenterological surgery in Japan: Report of
the National Clinical Database 2011-2019. Ann
Gastroenterol Surg. 2021 Sep;5(5):639–58.
11. Hosaka A, Kumamaru H, Takahashi A, Azuma N,
Obara H, Miyata T, et al. Nationwide study ofsurgery for primary infected abdominal aortic
and common iliac artery aneurysms. Br J Surg.
2021 Apr;108(3):286–95.
12. Hosaka A, Kumamaru H, Usune S, Miyata H,
Goto H. Outcomes of Surgery for Endograft
Infection in the Abdominal Aorta and Iliac
Artery: A Nationwide Cohort Study. Ann Surg.
2021 Nov;

428

Department of Next-Generation
Locomotive Imaging System
Project Associate Professor
Yuki Taniguchi, M.D., Ph.D.

Project Lecturer
Toru Doi, M.D., Ph.D.

Introduction and Organization
The Department of Next Generation Locomotive
Imaging System is established to develop new
imaging system for scoliosis deformity in April 2020,
which is fully funded by ZOZO Corporation.
Screening examinations of scoliosis include theforward bending test and Moiré tomography. However,screening tests such as the forward bending test are
not considered accurate enough to detect scoliosis andMoiré tomography is no longer manufactured andcannot be used for school screening examinations.
Moreover, radiographic examinations for diagnosing
scoliosis requires radiation exposure. Therefore, it isnecessary to develop a new screening tool for detecting scoliosis. We aimed to develop a new screening
tool for detecting scoliosis using a 3-dimension (3D)
measurement bodysuit (ZOZOSUITⓇ).

shooting direction were set and the accuracy of the
3-D body surface data was further evaluated bycomparing it with that of a conventional 3-D scanner.
The results of validation study showed that a
relatively high accuracy of 3-D virtual body image
was obtained with a mean error of 3.7 mm. After the
improvement of bodysuit (ZOZOSUIT2Ⓡ), we started
to acquire the imaging data in scoliosis patients andhealthy controls. We completed the required numberof data and proceed the analysis of imaging data.
Further investigation on this new screening tool
enables us to detect scoliosis deformity more easily
and non-invasively.

References
1.

Research activities
Our research aim is to develop a new screening
imaging system for detecting scoliosis, using a unique
3D body measurement suit (ZOZOSUITⓇ), which wasdeveloped by ZOZO Co.. The development of thisnew-generation imaging system may detect scoliosis
deformity without radiation exposure.
We started the pilot study to establish a protocol for
creating a 3D virtual body image using ZOZOSUIT.
Specifically, we had the imaging data from subjects
with ZOZOSUIT using a smartphone equipped withthe application and verified the validity of theacquired body surface data. Shooting position and2.

Doi T, Ohtomo N, Oguchi F, Tozawa K, Nakarai
H, Nakajima K, Sakamoto R, Okamoto N,
Nakamoto H, Kato S, Taniguchi Y, Matsubayashi
Y, Oka H, Matsudaira K, Tanaka S, Oshima Y.
Association Between Deep Posterior Cervical
Paraspinal Muscle Morphology and ClinicalFeatures in Patients With Cervical Ossification of
the Posterior Longitudinal Ligament. Global
Spine J. 2021 Jan 28:2192568221989655. doi:
10.1177/2192568221989655. Online ahead ofprint. PMID: 33504203
Taniguchi Y, Matsubayashi Y, Kato S, Oguchi F,
Nohara A, Doi T, Oshima Y, Tanaka S. Tracheal
stenosis due to cervicothoracic hyperlordosis inpatients with cerebral palsy treated with posterior
spinal fusion: a report of the first two cases.

429

3.

BMC Musculoskelet Disord. 2021 Feb 23;22(1):217. doi: 10.1186/s12891-021-04094-y.PMID:
33622297
Sakai D, Tanaka M, Takahashi J, Taniguchi Y,
Schol J, Hiyama A, Misawa H, Kuraishi S, Oba
H, Matsubayashi Y, Kato S, Sugawara R, Sato M,
Watanabe M, Takeshita K. Cobalt-chromium

versus titanium alloy rods for correction ofadolescent idiopathic scoliosis based on
1-year follow-up: a multicenter randomized
controlled clinical trial. J Neurosurg Spine.

4.

5.

6.

7.

2021 Mar 19:1-10. doi: 10.3171/2020.9.SPINE
201486. Online ahead of print.PMID: 33740765
Nakajima K, Nakamoto H, Kato S, Doi T,
Matsubayashi Y, Taniguchi Y, Yoshida Y,
Kawamura N, Nakarai H, Higashikawa A,
Tozawa K, Takeshita Y, Fukushima M, Iizuka M,
Ono T, Shirokoshi T, Azuma S, Tanaka S,
Oshima Y. A Multicenter Observational Study on
the Postoperative Outcomes of C3 Laminectomy
in Cervical Double-door Laminoplasty. Clin
Spine Surg. 2021 May 1;34(4):146-152. doi: 10.
1097/BSD.0000000000001100.PMID: 33086255
Nagata K, Nakamoto H, Sumitani M, Kato S,
Yoshida Y, Kawamura N, Tozawa K, Takeshita Y,
Nakarai H, Higashikawa A, Iizuka M, Ono T,
Fukushima M, Sasaki K, Okazaki R, Ito Y, Hara
N, Doi T, Taniguchi Y, Matsubayashi Y, Tanaka S,
Oshima Y. Diabetes is associated with greater leg
pain and worse patient-reported outcomes at 1
year after lumbar spine surgery. Sci Rep. 2021
Apr 14;11(1):8142. doi: 10.1038/s41598-02187615-y.PMID: 33854161
Kato H, Koga M, Kinoshita Y, Taniguchi Y,
Kobayashi H, Fukumoto S, Nangaku M, Makita
N, Ito N. Incidence of Complications in 25 Adult
Patients With X-linked Hypophosphatemia.
Hajime Kato, Minae Koga, Yuka Kinoshita, Yuki
Taniguchi, Hiroshi Kobayashi, Seiji Fukumoto,
Masaomi Nangaku, Noriko Makita, Nobuaki Ito.
J Clin Endocrinol Metab. 2021 Aug 18;106(9):e3682-e3692. doi: 10.1210/clinem/dgab282.
PMID: 33912912
Otomo N, Lu HF, Koido M, Kou I, Takeda K,
Momozawa Y, Kubo M, Kamatani Y, Ogura Y,
Takahashi Y, Nakajima M, Minami S, Uno K,
Kawakami N, Ito M, Sato T, Watanabe K, Kaito T,

Yanagida H, Taneichi H, Harimaya K, Taniguchi
Y, Shigematsu H, Iida T, Demura S, Sugawara R,
Fujita N, Yagi M, Okada E, Hosogane N, Kono K,
Nakamura M, Chiba K, Kotani T, Sakuma T,
Akazawa T, Suzuki T, Nishida K, Kakutani K,
Tsuji T, Sudo H, Iwata A, Kaneko K, Inami S,
Kochi Y, Chang WC, Matsumoto M, Watanabe K,
Ikegawa S, Terao C. Polygenic Risk Score of
Adolescent Idiopathic Scoliosis for Potential
Clinical Use. J Bone Miner Res. 2021 Aug;36(8):1481-1491. doi: 10.1002/jbmr.4324. Epub
2021 Jun 22.PMID: 34159637
8. Takeda N, Inuzuka R, Yagi H, Morita H, Ando M,
Yamauchi H, Taniguchi Y, Porto KJ, Kanaya T,
Ishiura H, Mitsui J, Tsuji S, Toda T, Ono M,
Komuro I. Clinical Impact of Copy Number
Variation on the Genetic Diagnosis of Syndromic
Aortopathies. Circ Genom Precis Med. 2021
Aug;14(4):e003458. doi: 10.1161/CIRCGEN.121.
003458. Epub 2021 Jul 30.PMID: 34325513
9. Nakajima K, Nakamoto H, Nakarai H, Nagata K,
Kato S, Doi T, Matsubayashi Y, Taniguchi Y,
Kawamura N, Higashikawa A, Takeshita Y,
Fukushima M, Ono T, Hara N, Azuma S, Tanaka
S, Oshima Y. Risk factors for worsening sexualfunction after lumbar spine surgery andcharacteristics of non-responders to thequestionnaire of sex life. Eur Spine J. 2021 Sep;
30(9): 2661-2669. doi: 10.1007/s00586-02106867-4. Epub 2021 May 18.PMID: 34003382
10. Okamoto N, Kato S, Doi T, Matsubayashi Y,
Taniguchi Y, Yoshida Y, Kawamura N, Nakarai H,
Higashikawa A, Tozawa K, Takeshita Y, Yu J,
Hara N, Sasaki K, Azuma S, Tanaka S, Oshima Y.
Relative Risks and Benefits of Crossing the
Cervicothoracic Junction During Multilevel
Posterior Cervical Fusion: A Multicenter Cohort.
World Neurosurg. 2021 Sep;153:e265-e274. doi:
10.1016/j.wneu.2021.06.091. Epub 2021 Jun 25.
PMID: 34175484
11. Taniguchi Y, Matsubayashi Y, Kato S, Doi T,
Takeda N, Yagi H, Inuzuka R, Oshima Y,
Tanaka S. Predictive Physical Manifestations for
Progression of Scoliosis in Marfan Syndrome.
Spine (Phila Pa 1976). 2021 Aug 1;46(15):10201025. doi: 10.1097/BRS.0000000000003939.
PMID: 34228694

430

12. Okamoto N, Kato S, Doi T, Nakamoto H,
Matsubayashi Y, Taniguchi Y, Inanami H,
Higashikawa A, Kawamura N, Hara N, Azuma S,
Takeshita Y, Ono T, Fukushima M, Tanaka S,
OshimaY.
Influenceof
Perioperative
Antithrombic Agent Discontinuation in Elective
Posterior Spinal Surgery: A Propensity-ScoreMatched Analysis. World Neurosurg. 2022 Feb;
158:e362-e368. doi: 10.1016/j.wneu.2021.10.182.
Epub 2021 Nov 4.PMID: 34743017
13. Saiki F, Tanaka T, Tachibana N, Oshima H,
Kaneko T, Horii C, Nakamoto H, Kato S, Doi T,
Matsubayashi Y, Taniguchi Y, Tanaka S, Oshima
Y. Effect of Spinal Alignment Changes on Lower
Back Pain in Patients Treated with Total Hip
Arthroplasty for Hip Osteoarthritis. Medicina(Kaunas). 2021 Nov 9;57(11):1219. doi: 10.
3390/medicina57111219.PMID: 34833437
14. Taniguchi Y, Takeda N, Inuzuka R, Matsubayashi
Y, Kato S, Doi T, Yagi H, Yamauchi H, Ando M,
Oshima Y, Tanaka S. Impact of pathogenic FBN1
variant types on the development of severe
scoliosis in patients with Marfan syndrome. J
Med Genet. 2021 Dec 16:jmedgenet-2021108186. doi: 10.1136/jmedgenet-2021-108186.
Online ahead of print.PMID: 34916231
15. Ohtomo N, Nakamoto H, Miyahara J, Yoshida Y,
Nakarai H, Tozawa K, Fukushima M, Kato S, Doi
T, Taniguchi Y, Matsubayashi Y, Higashikawa A,
Takeshita Y, Kawamura N, Inanami H, Tanaka S,
Oshima Y. Comparison between microendoscopic
laminectomy and open posterior decompression
surgery for single-level lumbar spinal stenosis: amulticenter retrospective cohort study. BMC
Musculoskelet Disord. 2021 Dec 20;22(1):1053.
doi:10.1186/s12891-021-04963-6.PMID:34930238
16. Demura S, Hinoi E, Kawakami N, Handa M,
Yokogawa N, Hiraiwa M, Kato S, Shinmura K,
Shimizu T, Oku N, Annen R, Kobayashi M,
Yamada Y, Nagatani S, Iezaki T, Taniguchi Y,
Tsuchiya H. The L-type Amino Acid Transporter(LAT1) Expression in Patients with Scoliosis.
Spine Surg Relat Res. 2021 Dec 27;6(4):402-407.
doi: 10.22603/ssrr.2021-0189. eCollection 2022.
PMID: 36051676

431

Next-Generation Precision
Medicine Development
Laboratory
Project Associate Professor
Hidenori Kage, M.D., Ph.D.

Project Lecturer
Akiko Kunita, Ph.D.

Introduction and Organization
In June 2019, The University of Tokyo, National
Cancer Center Japan, and Konica Minolta, Inc. agreed
to develop Todai OncoPanel (TOP), a next-generation
comprehensive cancer genomic panel (CGP). TOP was
initially developed by Professor Aburatani, The
University Tokyo Research Center for Advanced
Science and Technology and Hiroyuki Mano, former
professor at The University of Tokyo and current Headof Cell Informatics, at National Cancer Center Japan.
The research collaboration combines the knowledge ofAmbry Genetics Corporation, a Konica Minolta
company, and its global gene diagnostic technology,
with the TOP technology to reinforce the informatics
foundation technology of the TOP and develop a nextgeneration CGP. The Department of Next-Generation
Precision Medicine Development Laboratory wasestablished in April 2021 as a Social Collaboration
Department within 22nd Century Medical andResearch Center of The University of Tokyo Hospital,collaborating with Konica Minolta, Inc.

Clinical activities
As a Social Collaboration Department within 22nd
Century Medical and Research Center, we do notdirectly engage in clinical activities. Dr. Kage isinvolved in cancer genomic medicine at The Universityof Tokyo Hospital through oversight of the Expert

Panel.

Teaching activities
As a Social Collaboration Department within 22nd
Century Medical and Research Center, we do notdirectly engage in teaching activities. When M4
medical students came to the Department of Clinical
Genomics for a one-month rotation in fiscal year 2021,
Dr. Kage gave lectures and participated in Expert
Panels with the students.

Research activities
TOP can detect a large number of gene mutations with
its DNA panel and gene fusions with its RNA panel. At
the Department of Next-Generation Precision Medicine
Development Laboratory, we focus on (1) optimizationof pathological specimens for CGP tests and (2)association of tumor mutational burden and immune
checkpoint efficacy using TOP.
(1) Best tissue processing practices for CGP tests with
RNA panel
Background: Formalin-fixed, paraffin-embedded(FFPE) samples are valuable resources routinely usedin pathology, and generally used for clinical CGP tests.
However, the preparation of these samples requires
multiple stages, that are far from standardised,especially for RNA sequencing. Since preanalytical

432

sample processing ultimately impacts sequencing
accuracy and reproducibility, its optimization isessential. RNA from FFPE tissues may be more prone
to being chemically modified, cross-linked anddegraded over time due to fixation and archiving
methods than DNA. Therefore, RNA sequencing may
be more difficult than DNA analysis, which has been
more standardized. We examined the best practice fortissue processing for extracting high-quality
DNA/RNA for CGP tests with RNA panels.
Methods: <1> Nucleic Acid Requirements; Fourteen
FFPE blocks from 6 tissue types were sectioned, andthe DNA and RNA were extracted either separately or
simultaneously.
<2>
Storage
DurationandTemperature; To validate the impact of storage durationand temperature of the FFPE sections, specimens were
preserved in a tube at room temperature, 4, -20, or -80
degrees Celsius for 1 week or 1 month. Subsequently,
the quality of DNA/RNA was evaluated.
Results: The type of extraction methods and storage
duration or temperature did not affect the DNA/RNA
purification efficiency. The average DNA/RNA yieldfrom all tissue types tested was comparable regardlessof the method.
Conclusions: The DNA/RNA yield and the quality ofvarious tissue types were comparable between
DNA/RNA extracted simultaneously from one sample
and DNA/RNA extracted in individual procedures. The
simultaneous purification method can maximize theuse of precious sample materials. Storage of thesections at room temperature for one week or one
month in a tube both met the sample requirement for
CGP tests.
(2) Tumor mutational burden (TMB) measurement
using TOP
Background: Tumors with a high number of mutationsin the genome, or tumor mutational burden (TMB), arepresumed to be more likely to respond to immune
checkpoint inhibitors. However, the optimal method to
calculate TMB using comprehensive genomic profilingassays is unknown. TOP DNA panel version 6 is an
improvement over version 3 with increased number oftargeted genes and limited targeting of intronic regions.
Methods: We calculated TMB using TOP and comparedthem with whole exosome sequencing (WES) TMB. In
addition, 16 lung cancer patients had their samples

analyzed with TOP and were treated with anti-PD-1 orPD-L1 antibody monotherapy.
Results: When compared with WES, TMB measured by
TOP resulted in correlation efficiency of 0.96-0.97.
When WES TMB of 10 or higher was considered TMBhigh, TOP TMB high showed sensitivity of 0.88-1.0
and specificity of 0.93. Patients with either partial
response or stable disease showed a trend towards
higher TMB and higher PD-L1 expression comparedwith patients with progressive disease.
Conclusions: Increase in targeted gene number andlimiting intronic regions improved TMB measurement
by TOP when compared with WES TMB.

Publications
1.

2.

3.

4.

5.

Ikushima H, Hiraishi Y, Toriumi K, Ando T,
Tamiya H, Ishida J, Amano Y, Kage H, Tanaka G,
Nagase T. Multiple cerebral infarctions in ROS1rearranged lung adenocarcinoma. Respirol Case
Rep 2021;9:e0831. PMID: 34471540
Kurokawa R, Inui S, Gonoi W, Nakai Y, Ishida M,
Watanabe Y, Kubo T, Amano Y, Okamoto K, Kage
H, Harada S, Tanaka G, Kawahara T, Nagase T,
Moriya K, Abe O. Standardized reporting systemsof chest computed tomography in a population
with low coronavirus disease 2019 prevalence: A
retrospective comparative study. Heliyon 2021;7:
e07743. PMID: 34395930
Ando T, Kage H, Matsumoto Y, Zokumasu K,
Nagase T. Lower dose of ethambutol may reduce
ocular toxicity without radiological deterioration
for Mycobacterium avium complex pulmonary
disease. Respir Investig 2021;59:777-782. PMID:
34389250
Manaka K, Sato J, Takeuchi M, Watanabe K, Kage
H, Kawai T, Sato Y, Miyagawa T, Yamada D,
Kume H, Sato S, Nagase T, Iiri T, Nangaku M,
Makita N. Immune checkpoint inhibitor combination therapies very frequently induce secondary
adrenal insufficiency. Sci Rep 2021;11:11617.
PMID: 34078988
Amano Y, Kage H, Tanaka G, Gonoi W, Nakai Y,
Kurokawa R, Inui S, Okamoto K, Harada S, Iwabu
M, Morizaki Y, Abe O, Moriya K, Nagase T.
Diagnostic prediction of COVID-19 based onclinical and radiological findings in a relatively

433

6.

7.

8.

low COVID-19 prevalence area. Respir Investig
2021;59:446-453. PMID: 33865743
Imai S, Ooki T, Murata-Kamiya N, Komura D,
Tahmina K, Wu W, Takahashi-Kanemitsu A,
Knight CT, Kunita A, Suzuki N, Del Valle AA,
Tsuboi M, Hata M, Hayakawa Y, Ohnishi N, Ueda.
Helicobacter pylori CagA elicits BRCAness to
induce genome instability that may underlie
bacterial gastric carcinogenesis. Cell Host
Microbe 2021;6:941-958. PMID: 33989515
Abe H, Kunita A, Otake Y, Kanda T, Kaneda A,
Ushiku T, Fukayama M. Virus-host interactions in
carcinogenesis of Epstein-Barr virus-associatedgastric carcinoma: Potential roles of lost ARID1A
expression in its early stage. PLoS One 2021;9:e0256440. PMID: 34469459
Iwasaki A, Shinozaki-Ushiku A, Kunita A,
Yamazawa S, Sato Y, Yamashita H, Fukayama M,
Seto Y, Ushiku T. Human Leukocyte Antigen Class
I Deficiency in Gastric Carcinoma: An Adaptive
Immune Evasion Strategy Most Common in
Microsatellite Instable Tumors. Am J Surg Pathol
2021;45:1213-1220. PMID: 34310369

434

Department of Tissue Stem Cells
and Life Dentistry
Project Professor
Makoto Komura, M.D., Ph.D.

Project Lecturer
Yukiyo Asawa, D.V.M., Ph.D.

Homepage http://plaza.umin.ac.jp/~tsc-lds/manage.html
Introduction and Organization
A social cooperation course, The Department of Tissue
Stem Cells and Life Dentistry was established on
November 1st, 2019, with the cooperation of
SheepMedical Co., Ltd. (formerly Dental Assist Co.,
Ltd.), Fukekai medical corporation Fuke Hospital,
Sankeikai medical corporation Sashiogi Hospital,
Kayuukai medical corporation Ikegami Home Clinic,
and Inotech Co., Ltd.
The research is currently based in University of Tokyo
Hospital Tissue Engineering Department, Departmentof Oral and Maxillofacial Surgery, and Department ofPediatric Surgery.
The goal of our department is to succeed intranslational research, from basic to clinical with thepromotion of technology development on tissue organ
regeneration. Specifically, using cells that constitutethe fibrillary connective tissue (BIOSHEET /BIOTUBE) that encapsulates around cells and tissues
such as dental pulp stem cells, adipose tissue-derived
stem cells or even a mold that is transplanted
subcutaneously. Furthermore, a research on thecorrelation between oral environment and systemic
diseases / intestinal environment is in preparation
process.
The department is currently headed by a Project
Professor, was formerly assisted by a Project Lecturer.

Teaching activities
We

sharedtheappealofbasic

researchtoundergraduates through laboratory tours.
With the cooperation of Department of PediatricSurgery, we are preparing to give lectures to master andPh.D. students. On December 21, 2021, We gave alecture on "Pediatric Surgery and Regenerative
Medicine" in the Department of Reproductive,
Developmental and Aging Sciences.
We also gave research guidance to master and Ph.D.
students majoring in pediatric surgery and oral andmaxillofacial surgery through practical training andexercises.

Research activities
In our study, we use somatic stem cell that exists in bio
tissue, and we try to stimulate the somatic cell. By
using dental pulp-derived stem cell, cartilage stem cell,and umbilical cord-derived stem cell, we are working
to make up for the functional and structural defects.
The target organs for this specific reproductions are,bone, cartilage, skin and muscle (including gingiva).
The following are the research topics of ourdepartment in 2020:

Self-regeneration mechanism identification ofskin mold encapsulation tissue
・ Structure analysis of skin-encapsulated tissue
・ Construction of regeneration model using skinencapsulated tissue
・ Factor examination of regeneration model Development of dental pulp stem cell culture435

method・ Development of human dental pulp stem cell
culture method
・ Analysis on human dental pulp cell・ Development of mouse dental pulp stem cell
culture method
・ Analysis on mouse dental pulp cell・ Evaluation of mouse dental pulp celldifferentiation
 Proliferation of cartilage stem cell・ Construction of tracheal cartilage anastomosis
site evaluation model・ Technical development of strengthened tracheal
anastomosis site・ Dynamic measurement of tracheal anastomosissite Bone differentiation culture technique of humanumbilical cord
・ Development of umbilical cord cell culture
method while maintaining undifferentiated form
・ Development of bone differentiation induction
methodReferences
1:

2:

3:

4:

Suzuki K, Komura M, Obana K, Komura H, Inaki
R, Fujishiro J, Suzuki K, Nakayama Y. A new
method of primary engineering of esophagus
using orthotopic in-body tissue architecture. J
Pediatr Surg. 2021 Jul;56(7):1186-1191.
Kanazawa S, Okada H, Hojo H, Ohba S, Iwata J,
Komura M, Hikita A, Hoshi K. Mesenchymal
stromal cells in the bone marrow niche consist ofmulti-populations with distinct transcriptional andepigenetic properties. Sci Rep. 2021 Aug 4;11(1):15811.
Miyamoto Y, Kubota K, Asawa Y, Hoshi K, Hikita
A. M1-like macrophage contributes to chondrogenesis in vitro. Sci Rep. 2021 Oct 29;11(1):21307.
Kanda K, Asawa Y, Inaki R, Fujihara Y, Hoshi K,
Hikita A. Requirement of direct contact betweenchondrocytes and macrophages for the maturationof regenerative cartilage. Sci Rep. 2021 Nov 18;
11(1):22476.

436

Department of Prevention of
Diabetes and Lifestyle-RelatedDiseases
Project Associate Professor
Satoko Yamaguchi, M.D.,Ph.D.

Project Assistant Professor
Akira Okada, M.D., Ph.D.

Homepage http://prev.umin.jp/
Introduction and Organization
The Department of Prevention of Diabetes andLifestyle-Related Diseases is a Social Cooperation
Program founded in April 2018, which is sponsoredby Asahi Mutual Life Insurance Company and iscooperating with the Department of Nephrology and
Endocrinology (Professor Masaomi Nangaku) and
Department of Diabetes and Metabolic Diseases(Professor Toshimasa Yamauchi).
The objective of our department is to undertake
research on preventing onset and progression ofdiabetes and other lifestyle-related diseases, throughanalyses of big data including medical databases andusage of information and communication technology(ICT), thereby making a contribution to improving
health of people in Japan.
Lifestyle-related diseases including diabetes
account for approximately 30% of medical expenses
and 60% of deaths. Moreover, Japan is facing an
unprecedented super aged society with aging rate of
28.1% in 2018, and an increasing number of people
require long-term care due to conditions caused bylifestyle-relateddiseases.
Analyzing
factors
associated with onset and progression of lifestylerelated diseases is expected to contribute topreventing lifestyle-related diseases and conditions
caused by them, decreasing the number of people
requiring long-term care, as well as optimizing

medical expenses.
Our department intends to conduct multidirectional
analyses of big data including medical databases andconstruct models predicting progression oflifestyle-related diseases.
We are receiving four collaborative researchers
from Asahi Mutual Life Insurance Company.

Research activities
The members of our department are working on thefollowing research topics.
1) Research on long-term care
An increasing number of people require long-termcare in recent years, and as of 2022, approximately 6.9
million people have been certified as being in need forlong-term care in Japan. However, factors anddiseases leading to conditions requiring long-termcare remain largely unknown. In order to identify
factors predicting conditions requiring long-term care,we obtained and have analyzed anonymized data ofComprehensive Survey of Living Conditions, anationwide survey containing household situation andhealth-related questions, from Ministry of Health,
Labor and Welfare.
2) Research on discontinuation of physician visit inpeople with diabetes

437

Discontinuation of diabetes care is associated withincreased rate of complications and mortality. We
analyzed JMDC database and showed thatguideline-recommended practices within the firstmonth of physician consultation for diabetes care candecrease subsequent discontinuation of physician
visits in patients with newly diagnosed diabetes.
Additionally, we developed a machine-learning model
for predicting people's failure to attend a follow-up
visit for diabetes care after recommendations from anational screening program.
3) Research on clinical characteristics of insulinoma
Little information on recent clinical practice inpatients with insulinoma is available. Using anationwide inpatient database, we identified clinicalcharacteristics of benign and malignant insulinoma inJapan.
4) Research on potassium replacement therapy fordiabetic ketoacidosis
Guidelines worldwide recommend potassium
replacement of 10 to 40 mmol/L in the initial fluid
therapy for patients with diabetic ketoacidosis.
However, evidence is lacking as to the association
between infused potassium concentration andmortality. Using a nationwide inpatient database, we
showed that patients receiving potassium replacement
at concentrations of 10 to 40 mmol/L had similar
in-hospitalmortality
rates,
whereaslower
concentrations were associated with higher mortality.
We performed research using DPC database and
JMDC database in collaboration with the Departmentof Clinical Epidemiology and Health Economics(Professor Hideo Yasunaga) and medical information
database of the University of Tokyo Hospital incollaboration with the Department of Biomedical
Informatics (Professor Kazuhiko Ohe).
In addition to moving these projects forward, we plan
to take on new projects using databases in the future.

References1.

Momose A, Yamaguchi S, Okada A,
Ikeda-Kurakawa K, Namiki D, Nannya Y, et al.

2.

3.

4.

5.

6.

Factors associated with long-term carecertification in older adults: a cross-sectional
study based on a nationally representative survey
in Japan. BMC Geriatr. 2021;21(1):374.
Kurakawa KI, Okada A, Manaka K, Konishi T, Jo
T, Ono S, et al. Clinical characteristics andincidences of benign and malignant insulinoma
using a national inpatient database in Japan. J
Clin Endocrinol Metab. 2021.
Okada A, Yamana H, Morita K, Sato Y,
Yamaguchi S, Kurakawa KI, et al. Potassium
concentration in initial fluid therapy andin-hospital mortality of patients with diabetic
ketoacidosis. J Clin Endocrinol Metab. 2021.
Okada A, Ono S, Yamaguchi S, Yamana H, Ikeda
Kurakawa K, Michihata N, et al. Association
between nutritional guidance or ophthalmologicalexamination and discontinuation of physician
visits in patients with newly diagnosed diabetes:
A retrospective cohort study using a nationwide
database. J Diabetes Investig. 2021;12(9):161931.
Okada A, Yamana H, Yamaguchi S, Kurakawa KI,
Michihata N, Matsui H, et al. Effect ofBranched-Chain Amino Acid Infusion on
In-Hospital Mortality of Patients With Hepatic
Encephalopathy and End-Stage Kidney Disease:
A Retrospective Cohort Study Using a National
Inpatient Database. J Ren Nutr. 2021.
Sato Y, Morita K, Okada A, Matsui H, Fushimi K,
Yasunaga H. Factors affecting in-hospitalmortality of diabetic ketoacidosis patients: A
retrospective cohort study. Diabetes Res Clin
Pract. 2021;171:108588.

438

Department of Pain and Palliative
Medical Sciences
Project Associate Professor
Maiko Hasegawa-Moriyama, M.D., Ph.D.

Project Assistant Professor
Mitsuru Konishi, M.D, Ph.D.

Homepage

N/A

History and outline of organization
About a half of the cancer patients die by cancer
though of the recent innovations of anti-cancer
treatments. It mainly depends on the efficacy of thefirst-line strategies whether cancer is curable or not.
Almost all the cancer patients whose initial treatment
was unsuccessful die after the distressing struggle
against their disease within several years. It is clear
for such patients that both sufficient anti-cancer
treatments and appropriate approaches to improvetheir quality of life (QOL) are simultaneously indispensable.
However, in our nation, most attention has been
entirely paid to the improvement of cure rate andsurvival time of cancer patients. On the other hand, we
have to consider that their QOL is scarcely
concentrated until quite recently.
Palliative care means the combination of active
therapeutic approach and total human care for thepatients no matter which their cancer does or does not
respond to anti-cancer treatments. Pain relief, othersymptom management, psychological, social andspiritual cares are as a top priority for these patients. It
is also emphasized that palliative care is necessary to
be applied in the cancer treatment even for patients inearly stage of their diseases as well as the progressiveor terminal phase of their clinical courses.
In Department of Pain and Palliative Medicine
Science, The University of Tokyo Hospital, weparticipate in pain and palliative care team and takes aleading role not only to control physical symptoms ofcancer patients but also to care for the mental andsocial support at the same time, and to improve theoverall QOL of patients.
Palliative care is described clearly in the law "Cancer
Control Act" approved by the National Diet on June
2006 that "The medical treatment to aim at relieving
many kinds of pain and problems of cancer patients is
applicable from the early course of the illness".
However, it is possible that the use of analgesic,
especially opioids are not sufficient for cancer pain in
Japan. Therefore, this department work on
development and distribution of pain screening tooland educational program. According to our recent
study, the nationwide adequacy of opioid availability
was approximately 75%, and the largest gaps inadequacy between prefectures were more than 65%,
suggesting that opioid might not be adequately
prescribed nationwide.
Therefore, we analyze the correlation between cancer
pain severity and opioid availability using medical big
data to reduce this regional disparity.
Based on these background and purpose, thedepartment was founded in May, 2021.

Consultation
In The University of Tokyo Hospital, we pain andpalliative care team are composed of many kinds ofspecialists containing three full-time staff doctors, twofull-time doctors, and two certificated cancer and439

hospice care nurses who take an initiative in thismultidisciplinary team. We visit to bedsides, consultation rooms and everywhere in the hospital, and offer
palliative care to cancer patients who have received
cancer care in cooperation with patients’ attending
doctors, ward staff, therapists of rehabilitation, social
workers and every kind of professionals.

Sciences have contributed to the progress of following
fields of investigations.
①

Education
In the Department of Pain and Palliative Medicine,junior residents of the first and second year can learn
the basic knowledge and practice of palliative care by
selecting an optional subject for one, two, four oreight months. And then they can participate in the pain
and palliative care team and attend the daily teamconference on weekdays.
Educational･ In the intensive course for the first-year residents,
we prepare lectures about:# pain management# diagnoses and management of delirium# Introduction of guidelines in the field of palliative
medicine and their use# Basic medication for palliative care
# Spirituality and whole person care for Japanesepatients facing death
Daily and weekly schedule･ Conference: Monday-Friday (every weekday);9:00-10:30am･ Consultation: Monday-Friday (every weekday);from the end of morning conference, up to the completion of all the requested consulting of the day.
･ The cancer registry: They input data in the ward
round with the HIS (Hospital information system)
terminal on each floor.

②

Publications
1.

2.

3.

Research
The clinical information accumulated from thepalliative care consultation and anesthesia for patients
undergoing cancer surgery is input to the concise
database simultaneously and utilized for various kindsof clinical researches to submit to the international
medical journal.
To date, we the Department of Palliative Mediccal

Opioid availability for the palliative care ofpatients with advanced cancer is increasing
globally. However, opioid consumption in Japanis still extremely low compared with that in othercountries. We investigated the current situationof pain control and opioid consumption inpatients with advanced cancer by a nationwide
questionnaire survey in Japan. Caregivers from2000 comprehensive support centres nationwide
answered the web-based questionnaire survey
asking for details about their assigned patients
who died of end-stage cancer. The survey
included the questionnaire of pain intensity andopioid prescription.
In clinical situation, the use of opioids frequently
induce delirium. As a result, the use of opioids
can be avoided although pain control is not
sufficient. Therefore, we investigate the methods
for diagnostic tool for delirium and its
mechanisms.

4.

5.

Mietani K, et al. Elevateed neuron-specificenolase level is associated with postoperativedelirium and detection of phosphorylated
neurofilament heavy subunit: A prospective
observational study. PLoS ONE 2021; 16:e0259217
The OSCIS investigators. Effect of early vsdelayed surgery on motor recovery in incomplete
cervical spinal cord injury with pre-existingcervical stenosis: a randomized clinical trial.
JAMA Network Open 2021; 4: e2133604
Inoue R, et al. Capecitabine-induced hand-footsyndrome does not emerge in the complex
regional pain syndrome-affected limb: Case
Report. Mol Clin Oncol 2021; 15: 254
Kato K, et al. Development of a severity
discrimination scale based on physical quality oflife for patients with chronic pain. J Orthop Sci
2021; 26: 1124-9
Osumi M, et al. Fear of movement-related pain
disturbs cortical preparatory activity after

440

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

becoming aware of motor intention. Behav Brain
Res 2021; 411: 113379
Osumi M, et al. Pain quality of thermal grill
illusion is similar to that of central neuropathic
pain rather than peripheral neuropathic pain.
Scand J Pain 2021; 22: 40-7
Tsuchida R, et al. Genetic polymorphisms oflysophosphatidic acid receptor 1 are associatedwith the onset of taxane-induced peripheral
neuropathy. Br J Anaesth 2021; 127: e43-6
Sumitani M. Time to act for reappraising the
educational system for universal access to opioid
analgesics, for quality palliative care andcancer-related pain relief in East Asian countries.
Lancet Regional Health – Western Pacific 2021;
16: 100270
Saita K, et al. Exponential correlations amongneuropathic components, pain intensity andcatastrophic
thoughts
inpatients
withmusculoskeletal pain disorder. Curr Med Res
Opin 2021; 37: 1341-8
Ikeda K, et al. Required research activities toovercome addiction problems in Japan. Taiwan J
Psychiatr 2021; 35: 6-11
Uranbileg B, et al. Inhibition of autotaxin activity
ameliorates neuropathic pain derived fromlumbar spinal stenosis. Scientific Reports 2021;
11: 3984
Ando M, et al. Tele virtual reality-based peer
support programme for cancer patients: apreliminary feasibility and acceptability study. Br
J Cancer Res 2021; 3: 443-8
Nagata K, et al. Diabetes is associated withgreater leg pain and worse patient-reported
outcomes at one year after lumbar spine surgery.
Scientific Reports 2021; 11: 8142
Owada H, et al. Peripheral nerve field stimulation
successfully manages axial pain after posteriorcervical spine surgery: case report. Ann Palliat
Med 2021; 10: 579-96
Nishi Y, et al. Kinematic change in goal-directedmovements in a fear-conditioning paradigm.
Scientific Reports 2021; 11: 11162
Kaizu M, Komatsu H, Yamauchi H, et al.
Characteristics of taste alterations in people
receiving taxane-based chemotherapy and theirassociation with appetite, weight and quality oflife. Supp Care Cancer 2021; 29: 5103-14(And, 18 Japanese articles)441

Department of Innovative
Dementia Prevention
Project Associate Professor
Tadafumi Hashimoto, Ph.D.

Project Assistant Professor
Tomoko Wakabayashi, Ph.D.

Homepage http://www.neuropathology.m.u-tokyo.ac.jp
Introduction and Organization

Education

Department of Innovative Dementia Prevention was
launched on July 2017, through the financial support of
Kobayashi Pharmaceuticals, with assistance by the
Department of Neuropathology. Two faculty staffs,
Tadafumi Hashimoto as the Project Associate Professor
and Ryoko Ihara as the Project Assistant Professor
started the research projects, with Dr. Daisuke Izawa of
Kobayashi as a collaborative researcher. From January
2019, Dr. Tomoko Wakabayashi joined in thedepartment in the replacement of Dr. Ryoko Ihara, andDr. Yutaro Ito of Kobayashi also joined in the research
project in the replacement of Dr. Izawa. Dr. Hashimoto
has moved out in September 2021, and Dr.
Wakabayashi has taken up the Project Associate
Professor in December 2021.
The aged society in Japan urges us to challenge thedementing disorders including Alzheimer’s disease(AD), although there have emerged no effective
therapeutic strategies against AD based on its
pathomechanism. Our laboratory will conduct basic
research on the molecular mechanism of dementia anddevelopment of clinical measures for evaluation ofefficacies of the therapeutic drugs in parallel, aiming at
identifying the novel targets for prevention and early
treatment of dementia and establish methods to preventor delay the progression of dementia by drugs andfunctional foods. We also will be actively involved in
the education and outreach activities of basic andclinical research on AD and dementia.

Department of Innovative Dementia Prevention was
involved in the education through research activities ofgraduate students of the Graduate School of Medicine
and medical student belonging to the Medical Scientist
Training Program. In addition, TH has given a lecture
on “Special Lecture Basic Pharmaceutical Science IV”
to students belonging to the Graduate School of
Pharmaceutical Sciences.

Research
Department of Innovative Dementia Prevention isconducting research in the following four directions,based on the amyloid hypothesis of AD, toward thegoal of developing strategies for prevention ofdementia and AD.
① Molecular mechanism of Aβ dynamics in the brain
Amyloid β peptide (Aβ), a causative protein for AD, isproduced from the amyloid precursor protein (APP)
through two-step proteolysis by β- and γ-secretases,
and then secreted into the extracellular space. Oncereleased outside the neurons, Aβ is readily cleared byproteolytic degradation or transported outside thebrains. However, Aβ that escaped from the clearance
starts to aggregate and deposit forming amyloid fibrils.
Thus, the elucidation of the Aβ dynamics in the brain,
comprised of the elementary processes of “production”,“secretion”, “aggregation” and “deposition”, is vital tothe clarification of the pathogenic mechanism of AD aswell as development of therapeutic and prevention

442

strategies against AD. However, to quantitatively
analyze each of the process, there is a compelling needfor accurate quantitation of Aβ that is present at
picomolar levels in brains.
We have adopted the microdialysis technique using
dialysis membrane of ~1,000 kDa cut-off that enables
the recovery of brain interstitial fluids and quantitationof the levels, rates of production and clearance of Aβ in
the hippocampus and other parts of the brains(Yamamoto K, et al., Cell Rep., 2015). In combination
with the in vivo seeding experiments injecting
aggregation seeds for Aβ and evaluate the following Aβ
deposition (Hori Y, et al., J. Biol. Chem., 2015), we
have identified a >200 kDa high molecular weight(HMW) Aβ oligomer species in the soluble fractions ofbrains of APP transgenic mice and AD brains(Hashimoto T, Soc for Neuroscience meeting 2017),
and found that oligomeric structure of HMW A isessential for the induction of -amyloidosis. We also
found that the level of HMW A oligomers in the brainsof amyloid angiopathy-rich AD cases weresignificantly higher than those of amyloid angiopathyminimal AD cases, suggesting that seed-competent
HMW Ab oligomers may accumulate in the amyloid
angiopathy in the brains of AD patients. We will further
identify Aβ species that are involved in the Aβ
dynamics in the brain, including those specificallyinvolved in deposition or toxicity of Aβ.
② Elucidation of the role of apolipoprotein E (apoE)in the pathogenesis of AD, and development of methodof AD prevention targeting apoE
Apolipoprotein E (apoE) is produced by astrocytes andcomprises the major lipoprotein in the central nervous
system. Human APOE gene has three genetic
polymorphisms (ε2, ε3, ε4), resulting in the productionof three protein isoforms (apoE2, apoE3, apoE4)
harboring different amino acids at two critical residues
at positions 112 and 158. The allele frequency of ApoE
ε4 allele is ~8-10% in normal population, whereas it iselevated to >30-40% in AD. Thus, ApoE ε4 is a strong
genetic risk factor of AD, although the mechanism
whereby ApoE ε4 accelerates AD pathophysiology hasremained elusive, without any effective therapeuticstrategies targeting apoE.
We have created a series of bigenic mice by crossing
knock-in (KI) mice expressing human apoE2, E3 or E4

with APP transgenic mice, and we are currently trying
to examine how each human isoform of apoE
influences on Aβ dynamics in the brain. This will lead
us to the intervention into the effect of apoE isoforms
on Aβ, toward the goal of AD prevention. We havefound a significant decrease in Aβ deposition in thebrains of human apoE3 KI/APP transgenic mice. Usingin vivo seeding technique, we have also found that
apoE3 suppressed the deposition of Aβ compared withmurine apoE, and that apoE4 was less able to suupress
the Ab deposition compared to apoE3. We further
found that deletion of the APOE gene in APP tg micemarkedly reduced A deposition, and that no Ab
deposition was induced by in vivo seeding experimentin the brain of APPtg/apoE KO mice. These datasuggested that apoE is an essential factor for A
deposition (Hashimoto T, Soc for Neuroscience
meeting 2021). In vivo microdialysis experiments, wefound that the Aβ levels in the interstitial fluids ofhuman apoE3 KI/APP transgenic mice are similar to
those in APP transgenic mice by method. We also haveestablished a method to monitor the interaction
between Aβ and apoE using a bi-molecularcomplementation assay. We will use this unique assay
system to identify small molecule drugs that modulate
the interaction of apoE and Aβ.
③ Establishment of a novel AD model using threedimensional culture system for the development ofprevention methods targeting brain Aβ metabolism.
To overcome the lack of experimental paradigms forthe evaluation of aggregation and deposition in vitro,
we adopted 3-dimensional culture system using
Matrigel for the neuronal differentiation of human
ReNcell-VM neuronal precursor cells, to observe theprocess of Aβ deposition and Aβ-dependentneurotoxicity reminiscent to that in AD brains. In 2018,
we found the phosphorylation of tau by the
overproduction of E22G mutant Aβ in the ReNcell-VM
neurons. We will use this system for the developmentof anti-dementia drugs targeting Aβ production anddeposition.
④ Clinical studies on the clinical and cognitive
measures in the early stages of AD.
We have set out to the systematic analysis of theclinical data on the natural course of the early stage of443

AD derived from Japanese Alzheimer’s Disease
Neuroimaging Initiative (J-ADNI), with a special focus
on the preclinical AD stage, where elderly individuals
are clinically and cognitively normal but positive foramyloid biomarkers. We have found that preclinical
AD individuals lack learning effects in the cognitive
tests, e.g., MMSE and logical memory, presumably
representing subtle cognitive deficits. We also aim atinternational harmonization and comparison of theevaluation of cognitive decline, using US-ADNI
database and other international datasets.
⑤ Molecular mechanisms linking type II diabetes
mellitus and Alzheimer’s disease
A number of epidemiological studies have reported thattype 2 diabetes increases the risk of developing
Alzheimer's disease (AD) by about twofold. Studies
using human autopsy brains, imaging analysis, andmouse models suggest that insulin resistance, a central
pathology of diabetes, may be correlated with amyloid
accumulation. In addition, analysis of Alzheimer's
patient brains has shown that insulin signaling may be
impaired in AD brains, suggesting that insulin
resistance may be a common pathology in both diseases.
Based on these findings, activation of insulin signaling
in the brain is being explored as a new target for AD
therapy. Therefore, we are investigating the effects ofmetabolic abnormalities such as diabetes or of genetic
suppression of insulin signaling on the formation ofamyloid pathology and its molecular mechanisms.
In order to elucidate the molecular mechanisms linking
type 2 diabetes and AD, especially the effects on
amyloid pathogenesis, we have been conducting
analyses using APP Tg mice (A7 strain), a mousemodel of Alzheimer's disease. In APP Tg mice, whichwere fed a high-fat diet (HFD) from 3 months of age
and developed a diabetic-like condition, there was adecrease in brain responsiveness to insulin stimulationin addition to systemic insulin resistance. In this mouse,
the amount of Aβ in the brain increased significantlywith age compared to the normal diet group, and theaccumulation of amyloid plaques was also accelerated
at 15 months of age. In vivo kinetic analysis showedthat this might be partly due to a decrease in Aβ
clearance in the brain caused by HFD feeding.
We then analyzed the contribution of IRS-1 and IRS-2,
substrates of insulin and IGF-1 receptors, to brain

signaling activity and found that IRS-2 is mainly
involved in brain insulin signaling. While loss of IRS1 did not affect the pathology of the APP Tg mousebrain, IRS-2 deficiency markedly suppressed amyloid
accumulation in the brain, even though it triggered
systemic insulin resistance and led to diabetes (Ochiai
et al., Neurobiol Dis 2021). By contrast, amyloid
accumulation was accelerated when IRS-2-deficient
APP Tg mice were fed with HFD. This suggests that
upstream factors, such as stress associated withmetabolic overload, rather than decreased insulin
signaling, may be responsible for accelerated amyloid
accumulation (Wakabayashi et al., Mol Neurodegener2019).
One of the factors contributing to insulin resistance isendoplasmic reticulum (ER) stress, which is altered bymetabolic stress. In HFD-fed and genetically obese
animals, ER stress in liver and adipose tissue isincreased and unfolded protein response (UPR)
signaling is elevated. Inhibiting ER stress has beenshown to improve insulin resistance. It has also beenreported that ER stress is elevated in the brains of
Alzheimer's disease patients, suggesting that it may bean aggravating factor in both diseases. Therefore, thechemical chaperone TUDCA was administered to theperiphery or brain of aging or HFD-fed APP Tg micewith metabolic abnormalities to analyze the effects ofreduced endoplasmic reticulum stress on Aβ
accumulation. The results showed that administration
of TUDCA to the periphery, but not to the brain,markedly suppressed amyloid accumulation in thebrain. This suggests that stress and inflammationinduced in peripheral tissues due to metabolic
abnormalities may directly regulate brain pathology(Ochiai et al., J Prev Alzheimer Dis 2021).
The mechanism by which IRS-2 deficiency has aprotective effect on Aβ accumulation has not yet been
elucidated. Deficiency of not only IRS-2 but also
insulin receptor and IGF-1 receptor suppresses Aβ
accumulation in AD mouse models, suggesting that
reduced insulin signaling may exert an anti-amyloid
effect. Using IRS-2 deficient mice, we are investigating
the molecular mechanism of this effect.

444

References
1. Matsukawa K, Kukharsky MS, Park SK, Park S,
Watanabe N, Iwatsubo T, Hashimoto T, Liebman
SW, Shelkovnikova TA. Long non-coding RNA
NEAT1_1 ameliorates TDP-43 toxicity in in vivo
models of TDP-43 proteinopathy. RNA Biol,
2021; 18(11): 1546–1554
2. Ochiai T, Nagayama T, Matsui K, Amano K, Sano
T, Wakabayashi T, Iwatsubo T. Tauroursodeoxycholic Acid Attenuates Diet-Induced and AgeRelated Peripheral Endoplasmic Reticulum Stress
and Cerebral Amyloid Pathology in a Mouse
Model of Alzheimer’s Disease. J Prev Alzheimer
Dis, 2021; 8(4):483-494
3. Ochiai T, Sano T, Nagayama T, Kubota N,
Kadowaki T, Wakabayashi T, Iwatsubo T.
Differential involvement of insulin receptor
substrate (IRS)-1 and IRS-2 in brain insulin
signaling is associated with the effects on amyloid
pathology in a mouse model of Alzheimer's
disease. Neurobiol Dis, 2021; 159:105510

445

Department of Health Services
Research
Project Associate Professor
Taisuke Jo, M.D.,Ph.D.

Project Lecturer/Project Assistant Professor
Hayato Yamana, M.D., PhD.
Project Assistant Professor
Nobuaki Michihata, M.D., PhD.

Homepage

http://webpark1902.sakura.ne.jp/wp/

Introduction and Organization
The Department of Health Services Research (HSR),
a Social Cooperation Program, was founded byProfessor Hideo Yasunaga, Department of Clinical
Epidemiology & Health Economics with the supportof Professor Takahide Nagase, Department ofRespiratory Medicine in April 2016. The program wasfunded by Tsumura & Co., Tokyo, Japan.
The objective of the Department of HSR was toconvey and develop HSR, which encompasses clinicalmedicine, clinical epidemiology and health economics,
to pursue the maintenance of health services
particularly in the ageing society in Japan. Educationand training of personnel to cultivate human resources
such as researchers and analysts in HSR is anotherimportant mission of this program.
The founding staff members were Taisuke Jo(Project Associate Professor), Nobuaki Michihata(Project Assistant Professor) and Yusuke Sasabuchi(Project Assistant Professor). Hayato Yamana (Project
Assistant Professor) started to take part in thisprogram in April 2018 with the two other staff
members, Taisuke Jo and Nobuaki Michihata. Hayato
Yamana was promoted to Project Lecturer in 2021.

Teaching activities
All the members of HSR participated in the lecturesof Clinical Epidemiology, a curriculum of School of
Public Health (SPH) in The University of Tokyo. The
members also contributed to the education andtraining of individual students of SPH as well as
students of the Graduate School of Medicine, The
University of Tokyo.
Taisuke Jo (Project Associate Professor)
participated in the series of clinical lectures in
Respiratory Medicine for students of Faculty of
Medicine, The University of Tokyo.

Research activities
Health Services Research covers a broadcross-disciplinary field involving studies of structures,processes and outcomes assessment in clinicalepidemiology and health services, studies evaluating
the quality of health care and analysis of healtheconomics, finance and allocation of medical
resources. Utilizing large databases, the members of
HSR were working to address the following issue.
1) Clinical and epidemiological research questions related to various diseases, including respiratory
disease.
2) Outcomes and cost-effectiveness in both western
medicine and eastern medicine in Japan.
3) Impact of super-ageing society on population
dynamics and demand for health services.
4) Efficient distribution of medical staff, medical

446

institutions and armamentarium.
The followings are examples of studies conducted
in 2020.
1) Sodium-containing versus sodium-trace preparations of IVIG for children with Kawasaki disease in
the acute phase. (Eur J Pediatr. 2021 Nov;180:
3279–86.)
Objective: Kawasaki disease (KD) is an acutesystemic vasculitis that most commonly causes
acquired cardiac disease in children in developed
countries. The most highly recommended treatment
for KD is 2 g/kg intravenous immunoglobulin (IVIG).
There are two types of IVIG, sodium-containing(high-Na) and sodium-trace (low-Na) preparations.
However, few studies have compared the effects ofthese two preparations for superiority. The purpose ofthis study was to compare outcomes between high andlow-Na IVIG preparations in KD children using anational inpatient database in Japan.
Methods: We used the Diagnostic Procedure
Combination database to identify KD patients treatedwith IVIG between 2010 and 2017. We identified
those receiving high and low-Na preparations of IVIG
as an initial treatment. Outcomes included proportionof coronary artery abnormalities (CAA), IVIG
resistance, adverse effects, length of stay, and medical
cost. Propensity score-matched analyses wereconducted to compare the outcomes between the twogroups. Instrumental variable analyses were
performed to confirm the results.
Results: We identified 42,345 patients with KD. There
were significant differences in proportions of CAA(2.8% vs. 3.2%; p = 0.031) and IVIG resistance (17%vs. 18%, p = 0.001) between the two groups. However,there were no significant differences in length of stayor medical cost. The instrumental variable analysis
confirmed the same results as the propensity scoreanalysis.
Conclusion: The present study suggests that high-Na
IVIG is potentially effective for reducing the
proportion of CAA in KD patients. Prospective studies
are warranted to confirm the effectiveness observed inthis study2) Association between maoto use and hospitalization
for seasonal influenza in a nonelderly cohort in Japan.
(Intern Med 2021;60:3401-8.)

Objective: Maoto is a traditional Japanese Kampo
formula used to treat influenza. However, clinicalevidence for maoto has been limited to small-scalestudies of its effect in alleviating symptoms. The
present study evaluated whether or not the addition of
maoto to a neuraminidase inhibitor was associatedwith a reduction in hospitalization following
influenza.
Methods: Using the JMDC Claims Database, we
identified outpatients <60 years old who werediagnosed with influenza by an antigen test from
September 2013 to August 2018. One-to-fivepropensity score matching was conducted between
patients who received maoto in addition to aneuraminidase inhibitor and those who received aneuraminidase inhibitor alone. Hospitalization withinseven days of the influenza diagnosis was compared in
the matched groups using the Mantel-Haenszel test.
Results: We identified 1.79 million cases of influenza
from the database in the 5-year study period. Maoto
was prescribed for 3.9% of the 1.67 million cases
receiving a neuraminidase inhibitor. In the 64,613
propensity score-matched groups of patients, the7-day hospitalization rate was 0.116% (n = 75) for
patients with maoto and 0.122% (n = 394) for patients
without maoto. The difference between thesetreatment groups was nonsignificant (common odds
ratio, 0.95; 95% confidence interval, 0.74 to 1.22; p =0.695).
Conclusion: The addition of maoto to a neuraminidase
inhibitor was not associated with a decrease in
hospitalization among nonelderly patients with
influenza. Further research is necessary to clarify theindication and efficacy of maoto.
3) Prognosis of patients with liver cirrhosis: a multicenter retrospective observational study. (Hepatol Res
2021;51:1196-206.)
Aim:Despite advances in the management of liverdiseases and changes in the etiology of cirrhosis, few
studies have updated the prognosis of cirrhosis. This
study aimed to clarify the recent prognosis of cirrhosis
and identify risk factors for death.
Methods: In this retrospective observational study by
the Hepatic Disease Network of the National Hospital
Organization in Japan, chart reviews were performed
to follow patients with cirrhosis beginning in 2011.

447

We conducted Kaplan–Meier survival time analyses
stratified by Child–Pugh classification and albuminbilirubin grade. Cox regression analysis was used to
identify risk factors for death.
Results: We identified 444 eligible patients from 25
hospitals, including 303 (68%), 110 (25%), and 31(7%) patients with Child–Pugh classes A, B, and C,
respectively. Hepatitis C virus infection was the causeof cirrhosis for 63% of the patients. The 1-year and5-year cumulative survival rates of patients withChild–Pugh classes A, B, and C were 90% and 61%,78% and 42%, and 65% and 25%, respectively. The
1-year and 5-year cumulative survival rates of patientswith albumin-bilirubin grades 1, 2, and 3 were 98%
and 80%, 91% and 56%, and 58% and 23%,
respectively. Cirrhosis classification (Child–Pugh andalbumin-bilirubin), age, liver cancer, and untreatedesophageal varices were associated with increased
hazard of death.
Conclusions: Little improvement was observed in the
prognosis of cirrhosis compared with previous reports,
and the prognosis of Child–Pugh class C cirrhosis
remained poor. Untreated esophageal varices wereidentified as a risk factor for death.
The members of HSR are further mounting an effort
to accomplish the task in cooperation with the Department of Clinical Epidemiology & Health Economics
and the Department of Respiratory Medicine.

References
1.

2.

3.

1. Ando T, Kawashima M, Jo T, Yasunaga H,
Nagase T. The authors reply. Crit Care Med
2021; 49: e466-e467.
Awano N, Jo T, Yasunaga H, Inomata M, Kuse N,
Tone M, Morita K, Matsui H, Fushimi K, Nagase
T, Izumo T. Body mass index and in-hospitalmortality in patients with acute exacerbation of
idiopathic pulmonary fibrosis. ERJ Open Res
2021; 7.
Fukui A, Kaneko H, Okada A, Yano Y, Itoh H,
Matsuoka S, Morita K, Kiriyama H, Kamon T,
Fujiu K, Michihata N, Jo T, Takeda N, Morita H,
Nakamura S, Nishiyama A, Node K, Yokoo T,
Nangaku M, Yasunaga H, Komuro I. Semiquantitative assessed proteinuria and risk of heart

failure: Analysis of a nationwide epidemiological
database. Nephrol Dial Transplant 2021.
4. Hashimoto Y, Michihata N, Yamana H, Shigemi
D, Morita K, Matsui H, Yasunaga H, Aihara M.
Intraocular pressure-lowering medications during
pregnancy and risk of neonatal adverse
outcomes: a propensity score analysis using alarge database. Br J Ophthalmol 2021;105:1390-4.
5. Hatachi T, Michihata N, Inata Y, Takeuchi M,
Matsui H, Fushimi K, Yasunaga H. Prognostic
Factors
AmongChildrenWith
Acute
Encephalitis/Encephalopathy Associated With
Viral and Other Pathogens. Clin Infect Dis. 2021
Jul 1;73:76–82.
6. Honda C, Naruse T, Yamana H, YamamotoMitani N. Infant injury prevention education for
pregnant women attending antenatal class: aquasi-experimental study. Int J Environ Res
Public Health 2021;18:9393.
7. Honda A, Michihata N, Iizuka Y, Mieda T,
Takasawa E, Ishiwata S, Matsui H, Fushimi K,
Yasunaga H, Chikuda H. Clinical features andearly post-operative complications of isolated C2
odontoid fractures: a retrospective analysis usinga national inpatient database in Japan. Eur Spine
J. 2021 May
8. Ikawa F, Isobe N, Michihata N, Oya S, Ohata K,
Saito K, Yoshida K, Fushimi K, Yasunaga H,
Tominaga T, Kurisu K. In-Hospital Complications After Surgery in Elderly Patients with
Asymptomatic or Minor Symptom Meningioma:
A Nationwide Registry Study. World Neurosurg.
2021 Apr;148:e459–70.
9. Isago H, Mitani A, Kohno S, Nagoshi S, Ishimori
T, Saito M, Tamiya H, Miyashita N, Ishii T,
Matsuzaki H, Yatomi Y, Nagase T, Jo T. The
Japanese Herbal (Kampo) Medicine Hochuekkito
Attenuates Lung Inflammation in Lung
Emphysema. Biol Pharm Bull 2021; 44: 39-45.
10. Itoh H, Kaneko H, Fujiu K, Kiriyama H, Morita
K, Kamon T, Michihata N, Jo T, Takeda N,
Morita H, Yasunaga H, Komuro I. Risk Factors
and Lifestyles in the Development of Atrial
Fibrillation Among Individuals Aged 20-39 Years.
Am J Cardiol 2021; 155: 40-44.

448

11. Itoh H, Kaneko H, Kiriyama H, Kamon T, Fujiu
K, Morita K, Michihata N, Jo T, Takeda N,
Morita H, Yasunaga H, Komuro I. Metabolically
Healthy Obesity and the Risk of Cardiovascular
Disease in the General Population- Analysis of a
Nationwide Epidemiological Database. Circ J
2021; 85: 914-920.
12. Itoh H, Kaneko H, Kiriyama H, Kamon T, Fujiu
K, Morita K, Yotsumoto H, Michihata N, Jo T,
Takeda N, Morita H, Yasunaga H, Komuro I.
Reverse J-shaped relationship between bodymass index and in-hospital mortality of patients
hospitalized for heart failure in Japan. Heart
Vessels 2021; 36: 383-392.
13. Itoh H, Kaneko H, Okada A, Yano Y, Morita K,
Seki H, Kiriyama H, Kamon T, Fujiu K,
Matsuoka S, Nakamura S, Michihata N, Jo T,
Takeda N, Morita H, Nishiyama A, Node K,
Yasunaga H, Komuro I. Fasting Plasma Glucose
and Incident Colorectal Cancer: Analysis of a
Nationwide Epidemiological Database. J Clin
Endocrinol Metab 2021.
14. Jimba T, Kaneko H, Yano Y, Itoh H, Yotsumoto H,
Seki H, Morita K, Kiriyama H, Kamon T, Fujiu K,
Michihata N, Jo T, Takeda N, Morita H,
Nishiyama A, Node K, Yasunaga H, Komuro I.
Relation of the Metabolic Syndrome to Incident
Colorectal Cancer in Young Adults Aged 20 to 49
Years. Am J Cardiol 2021; 158: 132-138.
15. Jo T, Michihata N, Yamana H, Morita K,
Ishimaru M, Yamauchci Y, Hasegawa W,
Urushiyama H, Uda K, Matsui H, Fushimi K,
Yasunaga H, Nagase T. Risk of drug-induced
interstitial lung disease in hospitalised patients: anested case–control study. Thorax 2021;76:1193-9.
16. Kamon T, Kaneko H, Itoh H, Okada A, Matsuoka
S, Kiriyama H, Fujiu K, Morita K, Michihata N,
Jo T, Takeda N, Morita H, Nakamura S, Node K,
Yasunaga H, Komuro I. Sex Difference in the
Association between Lipid Profile and Incident
Cardiovascular Disease among Young Adults. J
Atheroscler Thromb. 2022 Jan;
17. Kaneko H, Itoh H, Morita K, Sugimoto T,
Konishi M, Kamiya K, Kiriyama H, Kamon T,
Fujiu K, Michihata N, Jo T, Takeda N, Morita H,
Yasunaga H, Komuro I. Early Initiation of

18.

19.

20.

21.

22.

23.

Feeding and In-Hospital Outcomes in Patients
Hospitalized for Acute Heart Failure. Am J
Cardiol. 2021 Apr 15;145:85–90.
Kaneko H, Itoh H, Yotsumoto H, Kiriyama H,
Kamon T, Fujiu K, Morita K, Kashiwabara K,Michihata N, Jo T, Morita H, Yasunaga H,
Komuro I. Cardiovascular Health Metrics of
87,160 Couples: Analysis of a Nationwide
Epidemiological Database. J Atheroscler Thromb.
2021 May;28:535–43.
Kaneko H, Yano Y, Itoh H, Morita K, Kiriyama H,
Kamon T, Fujiu K, Michihata N, Jo T, Takeda N,
Morita H, Node K, Carey RM, Lima JAC, OparilS, Yasunaga H, Komuro I. Association of Blood
Pressure Classification Using the 2017 American
Collegeof
Cardiology/American
Heart
Association Blood Pressure Guideline With Risk
of Heart Failure and Atrial Fibrillation.
Circulation. 2021 Jun;143:2244–53.
Kaneko H, Yano Y, Itoh H, Morita K, Kiriyama H,
Kamon T, Fujiu K, Michihata N, Jo T, Takeda N,
Morita H, Nishiyama A, Node K, Bakris G,
Miura K, Muntner P, Viera AJ, Oparil S, LloydJones DM, Yasunaga H, Komuro I. UntreatedHypertension and Subsequent Incidence ofColorectal Cancer: Analysis of a Nationwide
Epidemiological Database. J Am Heart Assoc.
2021 Nov 16;10:e022479.
Katsuki R, Jo T, Yasunaga H, Ishimaru M,
Sakamoto T. Outcomes of self-expandable metal
stent as bridge to surgery versus emergency
surgery for left-sided obstructing colon cancer: A
retrospective cohort study. Am J Surg 2021; 221:168-173.
Kawata M, Jo T, Taketomi S, Inui H, Yamagami
R, Matsui H, Fushimi K, Yasunaga H, Tanaka S.
Type of bone graft and primary diagnosis wereassociated with nosocomial surgical site infection
after high tibial osteotomy: analysis of a national
database. Knee Surg Sports Traumatol Arthrosc
2021; 29: 429-436.
Kim H, Cheng SH, Yamana H, Lee S, Yoon NH,
Lin YC, Fushimi K, Yasunaga H. Variations in
hip fracture inpatient care in Japan, Korea, andTaiwan: an analysis of health administrative data.
BMC Health Serv Res 2021;21:694.

449

24. Kiriyama H, Kaneko H, Itoh H, Kamon T, Morita
K, Jo T, Fujiu K, Daimon M, Takeda N, Morita H,
Yasunaga H, Komuro I. Surgical treatment for
infective endocarditis in the ageing society: anationwide retrospective study in Japan. OpenHeart 2021; 8.
25. Kobayashi K, Jo T, Mimura W, Suzukawa M,
Ohshima N, Tanaka G, Akazawa M, Matsui H,
Fushimi K, Yasunaga H, Nagase T, Nagai H.
Interrupted time-series analyses of routine
vaccination program for elderly pneumonia
patients in Japan; an ecological study using
aggregated nationwide inpatient data. Hum
Vaccin Immunother 2021; 17: 2661-2669.
26. Konishi T, Fujiogi M, Michihata N, Kumazawa R,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Outcomes of Nonoperative
Treatment for Gastroduodenal Ulcer Perforation:a Nationwide Study of 14,918 Inpatients in Japan.
J Gastrointest Surg. 2021 Apr.
27. Konishi T, Fujiogi M, Michihata N, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Comparisons of postoperative
outcomes after breast cancer surgery in patientswith and without renal replacement therapy: amatched-pair cohort study using a Japanesenationwide inpatient database. Breast Cancer.
2021 Apr.
28. Konishi T, Fujiogi M, Michihata N, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Comparison of short-term surgicaloutcomes between men and women with breast
cancer: a retrospective study using nationwide
inpatient data in Japan. Breast Cancer Res Treat.
2021 Apr;186:731–9.
29. Konishi T, Fujiogi M, Michihata N, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga
H.
Comparingoutcomesofnonoperative treatment for adhesive small bowel
obstruction with and without antibiotics. J InfectChemother. 2021 May;27:690–5.
30. Konishi T, Fujiogi M, Michihata N, Niwa T,
Morita K, Matsui H, Fushimi K, Tanabe M, Seto
Y, Yasunaga H. Impact of body mass index on
short-term outcomes after differentiated thyroid
cancer surgery: a nationwide inpatient database

31.

32.

33.

34.

35.

36.

37.

study in Japan. Eur Thyroid J. 2022 Jan 1;11:e210081.
Kurakawa KI, Okada A, Manaka K, Konishi T, Jo
T, Ono S, Uda K, Michihata N, Matsui H,
Fushimi K, Yamaguchi S, Yamauchi T, Nangaku
M, Yasunaga H, Kadowaki T. Clinical
Characteristics and Incidences of Benign and
Malignant Insulinoma Using a National Inpatient
Database in Japan. J Clin Endocrinol Metab
2021; 106: 3477-3486.
Matsuda K, Ise M, Shimura A, Honda A,
Masamoto Y, Jo T, Yasunaga H, Kurokawa M.
Use of wide-spectrum antimicrobials with blood
culture tests during chemotherapy as an accurate
marker of febrile neutropenia in the DPC
database: A validation study. J Infect Chemother2021; 27: 1541-1542.
Matsuda K, Jo T, Miyauchi M, Toyama K,
Nakazaki K, Matsui H, Fushimi K, Yasunaga H,
Kurokawa M. Difference of preventing effects of
G-CSF according to age in patients withmalignant lymphoma: A nation-wide analysis inJapan. J Infect Chemother 2021; 27: 1151-1155.
Matsuda K, Jo T, Toyama K, Nakazaki K, Matsui
H, Fushimi K, Yasunaga H. Efficacy ofrecombinant human soluble thrombomodulin in
induction therapy for acute promyelocytic
leukemia. Thromb Res 2021; 202: 173-175.
Matsuda K, Jo T, Toyama K, Nakazaki K, Matsui
H, Fushimi K, Yasunaga H, Kurokawa M. Risk
factors for early in-hospital death in patients whodeveloped coagulopathy during induction therapy
for acute promyelocytic leukemia: a nationwide
analysis in Japan. Ann Hematol 2021; 100: 26132619.
Matsuoka S, Kaneko H, Yano Y, Itoh H, Fukui A,
Morita K, Kiriyama H, Kamon T, Fujiu K, Seki H,
Michihata N, Jo T, Takeda N, Morita H,
Nakamura S, Yokoo T, Nishiyama A, Node K,
Yasunaga H, Komuro I. Association Between
Blood Pressure Classification Using the 2017
ACC/AHA Blood Pressure Guideline and Retinal
Atherosclerosis. Am J Hypertens. 2021 May;
hpab074.
Matsuoka S, Kaneko H, Kamon T, Suzuki Y,
Yano Y, Okada A, Itoh H, Morita K, Fukui A,
Fujiu K, Michihata N, Jo T, Takeda N, Morita H,

450

38.

39.

40.

41.

42.

43.

Nakamura S, Yokoo T, Nishiyama A, Node K,
Yasunaga H, Komuro I. Incorporation of Retinal
Arteriolosclerosis into Risk Stratification of
Blood Pressure Category According to the 2017
ACC/AHA Blood Pressure Guideline. J
Atheroscler Thromb. 2021 Dec
Miyano S, Michihata N, Sada KE, Uda K, Matsui
H, Fushimi K, Nangaku M, Yasunaga H.
Comparison of fracture risk between proton
pump inhibitors and histamine-2 receptor
antagonists in ANCA-associated vasculitis
patients:anestedcase-control
study.
Rheumatology (Oxford). 2021 Apr 6;60:1717–23.
Mongkonchoo K, Yamana H, Aso S, Machida M,
Takasaki
Y,Jo
T,
Yasunaga
H,
ChongsuvivatwongV,
Liabsuetrakul
T.
Prediction of outpatient visits and expenditure
under the Universal Coverage Scheme in
Bangkok using subscriber’s attributes: a random
forest analysis. Public Health in Practice 2021;2:
100190.
Nomura O, Michihata N, Kaneko K, Yoshikawa T,
Ishiguro A, Japan Pediatric Society Steering
Committee for Board Examinations. Research
Publication Experience as a Requirement for
Board Examination Acceptance to Promote
Scholarly Activities of Pediatric Residents. JMA
J. 2022 Jan;5:93–8.
Ohbe H, Sasabuchi Y, Yamana H, Matsui H,
Yasunaga H. Intensive care unit versus
high-dependency care unit for mechanicallyventilated patients with pneumonia: a nationwide
comparative effectiveness study. The Lancet
Regional Health - Western Pacific 2021;13:
100185.
Ohbe H, Yamana H, Matsui H, Yasunaga H.
Development and validation of a procedure-basedorgan failure assessment model for patients in theintensive care unit: an administrative databasestudy. Acute Med Surg 2021;8:e719.
Okada A, Yamana H, Morita K, Sato Y,
Yamaguchi S, Kurakawa KI, Michihata N,
Matsui H, Fushimi K, Nangaku M, Yamauchi T,
Yasunaga
H,
KadowakiT.
Potassium
concentration in initial fluid therapy andin-hospital mortality of patients with diabetic

44.

45.

46.

47.

48.

49.

50.

51.

ketoacidosis. J Clin Endocrinol Metab 2021;105:
e2162-75.
Okada A, Ono S, Yamaguchi S, Yamana H,
Kurakawa KI, Michihata N, Matsui H, Nangaku
M, Yamauchi T, Yasunaga H, Kadowaki T.
Association between nutritional guidance or
ophthalmological examination and discontinuation of physician visits in patients with newly
diagnosed diabetes: a retrospective cohort study
using a nationwide database. J Diabetes Investig
2021;12:1619-31.
Okubo Y, Michihata N, Morisaki N, Yoshida K,
Matsui H, Fushimi K, Yasunaga H. Effects of
Glucocorticoids on Hospitalized Children With
Anaphylaxis. Pediatr Emerg Care. 2021 May;37:
255–9.
Ono S, Ishimaru M, Ida Y, Yamana H, Ono Y,
Hoshi K, Yasunaga H. Validity of diagnoses andprocedures in Japanese dental claims data. BMC
Health Serv Res 2021;21:1116.
Sakamoto Y, Yamauchi Y, Jo T, Michihata N,
Hasegawa W, Takeshima H, Matsui H, Fushimi K,
Yasunaga H, Nagase T. In-hospital mortality
associated with community-acquired pneumonia
due to methicillin-resistant Staphylococcus
aureus: a matched-pair cohort study. BMC Pulm
Med 2021; 21: 345.
Sawada R, Yamana H, Shinoda Y, Tsuda Y,
Matsui H, Fushimi K, Kobayashi H,
Matsubayashi Y, Yasunaga H, Tanaka S, Haga N.
Predictive factors of 30-day mortality after
surgery for spinal metastasis: Analysis of anationwide database. J Orthop Sci 2021;26:66671.
Seki H, Kaneko H, Morita H, Itoh H, Morita K,
Matsuoka S, Kiriyama H, Kamon T, Fujiu K,
Michihata N, Jo T, Takeda N, Yano Y, Nakamura
S, Node K, Yasunaga H, Komuro I. Relation ofSerum Uric Acid and Cardiovascular Events in
Young Adults Aged 20-49 Years. Am J Cardiol.
2021 Aug;152:150–7.
Shigemi D, Morishima T, Yamana H, Yasunaga H,
Miyashiro I. Validity of initial cancer diagnoses
in the Diagnosis Procedure Combination data inJapan. Cancer Epidemiol 2021;74:102016.
Shigemi D, Hashimoto Y, Michihata N, Yasunaga
H. Effect of Japanese herbal Kampo medicines

451

52.

53.

54.

55.

56.

57.

58.

59.

on live birth rate in women with recurrent
pregnancy loss. Int J Gynaecol Obstet. 2021 Jun;
153:489–95.
Shinozaki N, Morita K, Matsui H, Jo T, Yasunaga
H. Semisolid vs Liquid Nutrients and 30-Day
Readmission in Gastrostomy Tube-Fed Patients:
A Propensity-Matched Analysis. JPEN J
Parenter Enteral Nutr 2021; 45: 720-728.
Shiozawa M, Kaneko H, Itoh H, Morita K, Okada
A, Matsuoka S, Kiriyama H, Kamon T, Fujiu K,
Michihata N, Jo T, Takeda N, Morita H,
Nakamura S, Node K, Yasunaga H, Komuro I.
Association of Body Mass Index with Ischemicand Hemorrhagic Stroke. Nutrients 2021; 13.
Suzuki T, Michihata N, Aso S, Yoshikawa T,
Saito K, Matsui H, Fushimi K, Yasunaga H.
Sodium-containing
versussodium-trace
preparations of IVIG for children with Kawasaki
disease in the acute phase. Eur J Pediatr. 2021
Nov;180:3279–86.
Suzuki Y, Kaneko H, Okada A, Itoh H, Morita K,
Fujiu K, Michihata N, Jo T, Takeda N, Morita H,
Yamaguchi S, Kamiya K, Matsunaga A, Ako J,
Fukui A, Nishiyama A, Yokoo T, Node K,
Yamauchi T, Nangaku M, Yasunaga H, Komuro I.
Change in Cardiovascular Health Metrics andRisk for Proteinuria Development: Analysis of a
Nationwide Population-Based Database. Am J
Nephrol. 2022;53:240–8.
Takano A, Yamana H, Ono S, Matsui H,
Yasunaga H. Outpatient treatment following
alcohol screening at health checkups and change
in drinking patterns among excessive drinkers
with lifestyle-related diseases. Prev Med Rep
2021;24:101549.
Tamiya H, Mitani A, Isago H, Ishimori T, Saito
M, Jo T, Tanaka G, Yanagimoto S, Nagase T.
Measurement of chest wall motion using a
motion capture system with the one-pitch phaseanalysis method. Sci Rep 2021; 11: 21497.
Tanaka G, Jo T, Tamiya H, Sakamoto Y,
Hasegawa W, Matsui H, Fushimi K, Yasunaga H,
Nagase T. Factors affecting in-hospital mortalityof non-tuberculous mycobacterial pulmonary
disease. BMC Infect Dis 2021; 21: 698.
Urushiyama H, Jo T, Hasegawa W, Ando T,
Sakamoto Y, Uda K, Matsui H, Fushimi K,

60.

61.

62.

63.

64.

65.

66.

Yasunaga H, Nagase T. Preoperative use of
pirfenidone and reduced risk of postoperative
severe respiratory complications in patients with
idiopathic pulmonary fibrosis: Propensity scorematched analysis using a nationwide database inJapan. Respirology 2021; 26: 590-596.
Ueno K, Kamiya K, Kaneko H, Okada A, Itoh H,
Fujiu K, Takeda N, Morita H, Michihata N, Jo T,
Yasunaga H, Komuro I. Acute-Phase Initiation of
Cardiac Rehabilitation for Short-Term Improvement in Activities of Daily Living in Patients
Hospitalized for Acute Heart Failure. J
Cardiovasc Dev Dis. 2022 Mar;9:97.
Ugata Y, Michihata N, Matsui H, Fushimi K,
Yasunaga H. Impact of proton pump inhibitors on
mortality and severe esophageal injury after
catheter ablation for atrial fibrillation: anationwide retrospective study using propensity
score matching. Heart Vessels. 2021 Apr.
Yamana H, Iba A, Tomio J, Ono S, Jo T,
Yasunaga H. Treatment of latent tuberculosis
infection in patients receiving biologic agents. J
Infect Chemother 2021;27:243-9.
Yamana H, Ono S, Michihata N, Jo T, Yasunaga
H. Association between maoto use andhospitalization for seasonal influenza in anonelderly cohort in Japan. Intern Med 2021;60:
3401-8.
Yamana H, Imai S, Yamasaki K, Horiguchi H,
Ario K, Komatsu T, Sugimoto R, Katsushima S,
Naganuma A, Mano Y, Yamashita T, Kamitsukasa
H, Tsuruta S, Jo T, Yasunaga H, Fushimi K,
Yatsuhashi H. Prognosis of patients with livercirrhosis:amulti-center
retrospective
observational study. Hepatol Res 2021;51:1196206.
Yagi Y, Takahashi Y, Ogata Y, Yamana H,
Kumakura Y, Ichihashi K, Kasai K, Kondo S.
Oral corticosteroid dosage and clinicalpresentation of psychiatric conditions after
steroid use: a consultation-liaison psychiatry
service's experience. Neuropsychopharmacol Rep
2021;41:471-5.
Yasui H, Michihata N, Matsui H, Fushimi K,
Iwase S, Yoshiuchi K, Sakata Y, Yasunaga H.
Association between ambulance use and452

hospitalization costs among heart failure patients.
Heart Vessels. 2021 May;36:654–8.
67. Yokoyama A, Sakamoto Y, Jo T, Urushiyama H,
Tamiya H, Tanaka G, Matsui H, Fushimi K,
Yasunaga H, Nagase T. Pulmonary disease as arisk factor for transfusion-related acute lunginjury. ERJ Open Res 2021; 7.
68. Yoshii E, Yamana H, Ono S, Matsui H, Yasunaga
H. Association between allergic or autoimmune
diseases and incidence of endometriosis: a nested
case-control study using a health insurance
claims database. Am J Reprod Immunol 2021;86:
e13486.
69. Yoshihara S, Yamana H, Akahane M, Kishimoto
M, Nishioka Y, Noda T, Matsui H, Fushimi K,
Yasunaga H, Kasahara K, Imamura T.
Association between prophylactic antibiotic use
for transarterial chemoembolization and occurrence of liver abscess: a retrospective cohort
study. Clin Microbiol Infect 2021;27:1514.e5-10.
Books
1. Michihata N, Aso S, Fujiogi M. Medical
Statistics, a book to learn the basics using Stata
while analyzing data. Yodosha; 2021.

453

Division of Chronic Kidney Disease(CKD) Pathophysiology
Division Chief (Professor)
Reiko Inagi, Ph.D.

Assistant Professor
Sho Hasegawa, M.D., Ph.D.

PhD Students
Haruki Ouchi, M.D. (Division of Nephrology and Endocrinology)
Yuto Takenaka, M.D. (Division of Nephrology and Endocrinology)
Chigusa Kitayama, M.D. (Division of Nephrology and Endocrinology)
Li Qi, M.D. (Division of Nephrology and Endocrinology)

Lab Technician
Ikumi Okuaki, B.S.
Keiko Miyamoto, B.S.

Homepage

http://www.todai-ckd.com

Introduction and Organization
In Japan, more than 13 million people suffer fromchronic kidney disease (CKD), or roughly one inevery eight adults. Why has the number of CKD
patients increased so remarkably? One major cause is
the sharp increase in the number of people withdiabetic nephropathy, which is a complication ofdiabetes; since 1998, this has been the most importantcause among diseases which require incipient dialysis
in Japan. Additional causes include the aging ofsociety and other social factors. The kidney is called asilent organ, and CKD progresses without subjective
symptoms. It is now evident, however, thatasymptomatic CKD which progresses over time
carries a number of risks.
One risk is the possible progression of CKD to
end-stage renal disease (ESRD), which requires renal
replacement therapy. A second risk is the development

and progression of lifestyle-related diseases, such asheart attack and arteriosclerosis. The kidneys work
closely with the heart and other organs, and a decrease
in renal function causes dysfunction of the heart andblood vessels. This adverse impact of the progressionof CKD on other organs underlines the importance of
the kidneys in maintaining general health. Further,many researchers have also focused on the vicious
spiral of aging and CKD: aging worsens the
progression of CKD, while CKD accelerates aging.
With our modern lifestyles and the super-aging society,
CKD cannot be separated from lifestyle-relateddiseases, and senility cannot be separated from CKD.
Creating a healthy, long-lived society full of energy
and vigor requires that the quality of life (QOL) of theelderly be improved. In turn, total medical
expenditures will also be decreased. These are important issues requiring urgent solutions. Against thisbackground, the Division of CKD Pathophysiology

454

was newly established in November 2013 withsupport from Kyowa Hakko Kirin Co., Ltd. The aimof the Division is to aid and support the CKD control
and the creation of a healthy and long-lived society.
The Division takes an innovative approach toidentifying the pathophysiology of CKD and works todevelop more effective CKD preventive andtherapeutic strategies. Through these research
activities, our goal is to contribute to the creation of ahealthy, long-lived society in which the elderly canlive a happy and independent life.

Major Research Projects
The Division of CKD Pathophysiology works incollaboration with the Division of Nephrology and
Endocrinology, a part of The University of Tokyo
Graduate School of Medicine (Professor Masaomi
Nangaku) to conduct basic and clinical research on
CKD pathophysiology, including:1) Identifying the mechanism of destruction ofadaptive signals to various stresses (endoplasmic
reticulum stress, ischemia, glycative stress,
oxidative stress) in CKD; and using the findings
obtained to establish new CKD treatment
strategies.
2) Clarifying the mechanism of functional change inrenal erythropoietin (EPO)- producing cells, alongwith the mechanisms of CKD progression andidentification of the mechanism of development
and progress of renal anemia.
3) Clarifying the impact of kidney aging on CKD
progression in super-aging society4) Identifying factors in the exacerbation of CKD inpatients with diabetes, and developing diagnostic
and therapeutic drugs targeting such factors.
5) Pathophysiology of uremic toxins on organcrosstalk and impact of uremia management in
CKD6) Identifying a novel renoprotective mechanism
based on the molecular inflammatory axis in
kidney injury7) Pathophysiological role of organelle stress,
organelle crosstalk damage in renal injury

Research Funds (PI) Japan Society for the Promotion of Science, Grants-

in-Aid for Scientific Research
21H02824 (to Reiko Inagi, Novel tubular
homeostasis mechanism mediated by primary cilia),
21K9439 (to Reiko Inagi, Pathophysiological roleof organelle contact site in tubular homeostasis),
21K6159 (to Sho Hasegawa, Unraveling the roleof ER-mitochondria crosstalk in the pathogenesis of
diabetic kidney disease),
20K17243 (to Hiroshi Maekawa, The elucidationof pathophysiology of cGAS-STING pathway in
AKI-to-CKD transition).
 Japan Agency for Medical Research andDevelopment (AMED)CREST 20gm1410005s0101 (to Reiko Inagi,
Study on understanding of the molecularmechanisms of tissue-specific unfolded protein
responses for radical cure of human chronic
diseases) Nipro Co. Ltd, (to Reiko Inagi, Collaborative study
on metabolome of serum exosome in HD patients)
 Astellas Foundation for Research on Metabolic
Disorders, Research Grant, (to Reiko Inagi,
Pathophysiological role for organelle crosstalkbased on primary cilia)
 MSD Life Science Foundation, Public Interest
Incorporated Foundation, Research Grant (to Sho
Hasegawa,
Pathophysiologicalroleof
ER-mitochondria crosstalk in diabetic kidneydisease) The Cell Science Research Foundation (to Sho
Hasegawa, Elucidation of the pathogenesis of ERmitochondria crosstalk in diabetic kidney disease) Takeda Science Foundation, Medical Research
Grant (to Sho Hasegawa, Elucidation of thepathophysiological role of ER-mitochondria contact
site in diabetic kidney disease) The Ichiro Kanehara Foundation for the Promotionof Medical Sciences and Medical care (to Sho
Hasegawa, Study on the pathophysiological effectof peripheral nerve remodeling in chronic kidneydisease)AwardsProf. Reiko Inagi received the Kidney International
2020 Reviewer-Of-The-Year Award from theInternational Society of Nephrology.

455Prof. Reiko Inagi received the Kidney International
2021 Reviewer-Of-The-Year Award from theInternational Society of Nephrology.
Dr. Sho Hasegawa received the ISN-KI Early-Career
Researcher Award from the International Society ofNephrology.
Dr. Sho Hasegawa received the Best Abstract Awardat the 4th Annual Meeting of the Japanese Society ofUremic toxin Reserach.
Dr. Sho Hasegawa received the ISN-KI Editorial
Fellowship in Basic and Translational Nephrology in
the International Society of Medicine (2021-2023).
Dr. Kentaro Yoshioka received the President Awardat the 11th Annual Meeting of the Japanese Society of
Pathophysiology in Kidney Failure.

References
1.

2.

3.

4.

Okpechi IG, Caskey FJ, Gaipov A, Tannor EK,
Hamonic LN, Ashuntantang G, Donner JA,
Figueiredo A, Inagi R, Madero M, Malik C,
Moorthy M, Pecoits-Filho R, Tesar V, Levin A,
Jha V. Assessing the impact of screening, early
identification and intervention programmes forchronic kidney disease: protocol for a scoping
review. BMJ Open. 2021 Dec 16;11(12):e053857. doi: 10.1136/bmjopen-2021-053857.
Hasegawa S, Okada A, Aso S, Kumazawa R,
Matsui H, Fushimi K, Yasunaga H, Nangaku M.
Association Between Diabetes and Major
Bleeding Complications of Renal Biopsy.
Kidney Int Rep. 2021 Nov 25; 7(2): 232-240.
doi: 10.1016/j.ekir.2021.11.013.
Hasegawa S, Inagi R. The subtle long-lastingburden of mitochondrial DNA variants. Nat Rev
Nephrol. 2021 Oct 18. doi: 10.1038/s41581-02100500-9.
Fujii R, Hasegawa S, Maekawa H, Inoue T,
Yoshioka K, Uni R, Ikeda Y, Nangaku M, Inagi
R. Decreased IFT88 expression with primarycilia shortening causes mitochondrial dysfunction
in cisplatin-induced tubular injury. Am J Physiol

Renal Physiol. 2021 Sep 1;321(3):F278-F292.
doi: 10.1152/ajprenal.00673.2020.
5. Doi K, Kimura H, Wada T, Tanaka T, Hiromura
K, Saleem MA, Inagi R, Nangaku M, Fujii T. A
novel method for successful induction ofinterdigitating process formation in conditionallyimmortalized podocytes from mice, rats, andhumans. Biochem Biophys Res Commun. 2021
Sep 17; 570:47-52. doi: 10.1016/j.bbrc.2021.07.
029.
6. Sakashita M, Tanaka T, Inagi R. Metabolic
Changes and Oxidative Stress in Diabetic Kidney
Disease. Antioxidants (Basel). 2021 Jul 19;
10(7):1143. doi: 10.3390/antiox10071143.
7. Hasegawa S, Inagi R. Harnessing Metabolomics
to Describe the Pathophysiology Underlying
Progression in Diabetic Kidney Disease. Curr
Diab Rep. 2021 May 11;21(7):21. doi: 10.1007/
s11892-021-01390-8
8. Higashihara T, Nishi H, Takemura K, Watanabe
H, Maruyama T, Inagi R, Tanaka T, Nangaku M.
β2-adrenergic receptor agonist counteracts
skeletal muscle atrophy and oxidative stress inuremic mice. Sci Rep. 2021 Apr 28;11(1):9130.
doi:10.1038/s41598-021-88438-7.
9. Muso E, Sakai S, Ogura Y, Yukawa S, Nishizawa
Y, Yorioka N, Saito T, Mune M, Sugiyama S,
Iino Y, Hirano T, Hattori M, Watanabe T,
Yokoyama H, Sato H, Uchida S, Wada T, Shoji T,
Oda H, Mori K, Kimura H, Ito O, Nishiyama A,
Maruyama S, Inagi R, Fujimoto S, Tsukamoto T,
Suzuki Y, Honda H, Babazono T, Tsuruya K,
Yuzawa Y. Favorable therapeutic efficacy of
low-density lipoprotein apheresis for nephrotic
syndrome with impaired renal function. Ther
Apher Dial. 2022 Feb;26(1):220-228. doi: 10.
1111/1744-9987.13694.
10. Hasegawa S, Inoue T, Nakamura Y, Fukaya D,
Uni R, Wu CH, Fujii R, Peerapanyasut W,
Taguchi A, Kohro T, Yamada S, Katagiri M, Ko
T, Nomura S, Nakanishi Ozeki A, Susaki EA,
Ueda HR, Akimitsu N, Wada Y, Komuro I,
Nangaku M, Inagi R. Activation of Sympathetic
Signaling in Macrophages Blocks Systemic
Inflammation and Protects against Renal
Ischemia-Reperfusion Injury. J Am Soc Nephrol.

456

2021 Apr 19: ASN.2020121723. doi: 10.1681/
ASN.2020121723
11. Inagi R. Organelle stress and glycation in kidneydisease. Glycoconj J. 2021 Jun;38(3):341-346.
doi: 10.1007/s10719-021-09989-5.

457

Department of Retinal Biology andPathology
Project Professor
Sumiko Watanabe, Ph.D.

Project Assistant Professor
Toshiro Iwagawa, Ph.D

Introduction and Organization
We are focusing on analysis of retinal development
and basic mechanisms of retinal degenerative diseases
with ultimate goal to elucidate new targets for drug
design in ocular diseases. Our laboratory had been
established 2021 July and is supported by
Chugai-pharmaceutical co. The basis of our laboratory
is Department of Molecular and Developmental
Biology, which was in The Institute of Medical
Science. University of Tokyo (IMSUT) until 2021.
Major members of current laboratory including thefaculties were working on molecular basis of retinal
development especially focusing on transcriptional
mechanisms including epigenetics of retinal
development at this laboratory in IMSUT. Recent few
years, we had started to work on retinitis pigmentosa,
which is the inherited severe retinal degenerative
disease. Analysis of impact of the gene mutations,which was reported from patients genomic analysis,for maintenance of photoreceptor homeostasis was
main strategy of our research. However, we had
started analysis of roles of inflammation for onset andprogression of retinal degeneration, and how to build
the inflammatory environment within retina is an
important issue to be solved. There are several retinal
immunocompetent cells, and we have particularinterests with the microglia. In the new laboratory, we
expanded our focus from retina to retina and sclerawith particular interest with blood vessel. Therefore,
not only retinitis pigmentosa, various vessel relateddiseases such as ocular complications of diabetic

mellitus are our research targets. Microglia andinflammatory environment in retina must play pivotal
roles for the vessel related ocular disease, and weestablished several assay system related to this point
both in in vitro and in vivo.
The laboratory aimed to bridge the basic researchteam and the clinical team. We have regular discussion
occasion of our laboratory members andophthalmology department clinicians, and exchange
knowledge and techniques between two groups. Bysuch efforts, we aim to establish basic/clinicalcollaborative research group in ophthalmology field.

Teaching activities
The graduate students (2 Ph.D candidates, 4 mastercourse students) moved to Hongo campus fromIMSUT when our current laboratory started. All ofstudents have their own project, and in 2021, we
submitted two papers of the students projects toscientific journals. Group data discussion, laboratory
data discussion, journal club, and individual data
discussion are regularly hold by onsite as well as
online.
We also participate to train Ph.D candidate students of
the ophthalmology department by teaching principles
of experimental techniques and discussing researchdata.

Research activities
Summary of the research: Mouse and human iPS cells
are two major models used in our research.

458

Technically, we had been employing molecularbiology,and biochemistry, but introduced the LC-MS
based membrane lipid analysis and the proteome incollaboration with the experts. Ophthalmological
techniques also facilitate to make our research
activities deepen with broad spectrum. Details of someof specific projects are as follows.
＊Analysis of membrane phospholipid dynamism inhealthy and pathological retinas.
Membrane phospholipids play pivotal roles in various
cellular processes, and their levels are tightly
regulated. In the retina, phospholipids had been
scrutinized because of their distinct composition andrequirement in visual transduction. However, howlipid composition changes during retinal development
remains
unclear.
Here,
we
used
liquidchromatography-mass spectrometry (LC-MS) toassess the dynamic changes in the levels of two main
glycerophospholipids, phosphatidylcholine (PC) andphosphatidylethanolamine (PE), in the developing
mouse retina under physiological and pathologicalconditions. The total levels of PC and PE increased
during retinal development, and individual lipid
species exhibited distinct level changes. The amountof very-long-chain PC and PE increased dramaticallyin the late stages of retinal development. The mRNAlevels of Elovl2 and Elovl4, genes encoding enzymes
essential for the synthesis of very-long-chain
polyunsaturated fatty acids, increased in developing
photoreceptors. Cell sorting based on CD73
expression followed by LC-MS revealed distinct
changes in PC and PE levels in CD73-positive rod
photoreceptors and CD73-negative retinal cells.
Finally, using the NaIO3-induced photoreceptor
degeneration
model,
we
identified
photoreceptor-specific changes in PC and PE levels
from 1 day after NaIO3 administration, before theoutersegmentofphotoreceptors
displayedmorphological impairment. In conclusion, ourfindings provide insight into the dynamic changes in
PC and PE levels in the developing and adult mouse
retina under physiological and pathological conditions.
Furthermore, we provide evidence that cell sorting
followed by LC-MS is a promising approach forinvestigating the relevance of lipid homeostasis in thefunction of different retinal cell types.

＊Roles of histone H3K4 methyltranferase Sed1a forretinal development
During retinal development, retinal progenitor cells(RPCs) proliferate and differentiate into six types ofneurons and one type of glial cell. The temporal orderof the production of each retinal cell is known to behighly regulated and conserved among species. The
molecular mechanisms by which cell fate isdetermined and maturation is accomplished have been
intensively investigated, and much attention has been
paid to the roles of transcription factors in the retinal
development. Moreover, the contributions of
epigenetic modifications, such as DNA methylationand histone modifications, to the retinal development
are becoming more clear. We have been studying
epigenetic histone modifications during retinal
development and, with others, found that histone H3
methylation at lysine 4 (H3K4) and 27 (H3K27),
which facilitates transcriptional gene activation andrepression, respectively, was highly specific to retinal
cell type. Additionally, analyses of knockout mice
have revealed the functions of enzymes involved inthese processes, especially H3K27 methylation. At
least nine histone lysine methyltransferases and fivehistone lysine demethylases have been reported to be
involved in H3K4 methylation. We found high levelsof H3K4me3 in photoreceptor-related genes in rod
photoreceptor lineage. However, involvement of
H3K4 methylation in early retinal development is not
well-documented. This time, we focus on Setd1a,which is the methyltransferase specific to H3K4.
H3K4me3 has been reported to regulate rod
photoreceptor differentiation; however, the roles
H3K4me3 plays in retinal progenitor cell (RPC)
proliferation and differentiation during early retinal
development remain unclear. Using an in vitro retinal
explant culture system, we suppressed the expressionof Setd1a by introducing shSetd1a. We examined theexpression level and H3K4me3 level of genes by RNA
Sequencing and ChIP assay, respectively. We foundthat Setd1a depletion resulted in increased apoptosis
and proliferation failure in late RPCs. Expression of
wild-type SETD1A, but not SETD1A that lacked thecatalytic SET domain, reversed the shSetd1a-induced
phenotype.
RNA Sequencing
revealedthat
proliferation-related genes were downregulated upon
shSetd1a expression. Based on publicly available

459

H3K4me3-ChIP sequencing
dataof
retinaldevelopment, we identified Uhrf1 as a candidate target
gene of Setd1a. Uhrf1 is multi-functional gene andrecently paid attention since UHRF1 plays pivotal
roles for carcinogenesis and DNA damage repair. The
expression of shSetd1a led to a decrease in Uhrf1
transcript levels and reduced H3K4me3 levels at the
Uhrf1 locus. Increased apoptosis and the suppressionof proliferation in late RPCs were observed in retinal
explants expressing shUhrf1, similar to the outcomes
observed in shSetd1a-expressing retinas. The
overexpression of UHRF1 did not rescue
shSetd1a-induced apoptosis, but reversed the
suppression of proliferation. These results indicatethat Setd1a contributes to the survival andproliferation of retinal cells by regulating histone
methylation, Setd1a regulates Uhrf1 expression, andthese two molecules cooperate to regulate RPC
survival and proliferation.

References
1.

2.

3.

4.

5.

Kohno, H, Terauchi, R, Watanabe, S, Ichihara, K,
Watanabe, T, Nishijima, E, Watanabe, A, Nakano,T. Effect of lecithin-bound iodine treatmen on
inherited retinal degeneration in mice. TVST,
2021 10(13); 8Nakamura, N, Honjo,, H, Yamagishi, R, Kurano,
M, Yatomi, Y, Watanabe, S, Aihara, M.
Neuroprotective Role of sphingolipid rheostat in
Excitotoxic Retinal Ganglion Cell Death, Exp
Eye Res. 2021 208: 108623
Deng, X, Iwagawa, T, Fukushima, M, Suzuki, Y,
Watanabe, S. Setd1a plays pivotal roles for thesurvival and proliferation of retinal progenitors
via histone modifications of Uhrf1, Invest.
Ophthalmol. Vis. Sci. 2021 62(6), 1
Terauchi, R, Kohno, H, Watanabe, S. Saito, S,
Watanabe, A, Nakano, T. Ccr2 suppression by
minocycline in Cx3cr1/Ccr2-visualized inherited
retinal Degeneration, PlosOne 2021 16:
e0239108
Hamano, F, Kuribayashi, H, Iwagawa, T, Nagata,
K, Shimizu, T, Shindou, T, Watanabe, S,
Mapping of membrane lipids in the developing
and adult mouse retina under physiological andpathological conditions using mass spectrometry.
J. Biol. Chem. 2021 296, 100303

460

Department of Lipidomics
Professor
Yoshiya Oda, Ph.D.

Assistant Professor
Suzumi Tokuoka, Ph.D.

Homepage http://lipidomics.m.u-tokyo.ac.jp/index-e.html
Introduction and Organization
The Department of Lipidomics was established in
April 2011, funded by Shimadzu Corp. and Ono
Pharmaceutical Co., Ltd. The objective of the laboratory is to establish and improve mass spectrometrybased lipidomics methodologies, and its application tobiomedical studies including basic lipid biology as
well as clinical research.
The laboratory was started with three staff scientists,
Takao Shimizu (Professor), Yoshihiro Kita (Associate
Professor. He moved to Life Science Core Facility in
Dec. 2013), and Suzumi Tokuoka (Assistant Professor). In April, 2014, Fuyuki Tokumasu joined as an
Associate Professor (he moved to Nagasaki University
in April, 2019) and in May 2018, Yoshiya Oda joined
as a professor. In 2021, we have three guest
researchers and two technical assistants. This year
marks the 20th year since the launch of the former
donated laboratory for metabolomics.

Teaching activities
The department staffs gave several lectures forundergraduate and graduate students. For undergraduate students, Drs. Shimizu and Kita delivered
several lectures on biochemistry. Dr. Kita gave
lectures on “Proteome and metabolome” for master’s
students and “Principles and Applications of Mass
Spectrometry” for doctoral students.

Research activities
Our research interests cover following topics.

Methods for clinical samples
Studies using human specimens are more reflectiveof human diseases than experimental data using
laboratory animals and cell lines. However, lipidomics
analysis on human clinical specimens such as blood,urine, feces, and biopsy samples is not always
optimized for lipidomics analysis because of the large
variability of data depending on individual differencescompared to animal experiments. We are developing atechnique for handling clinical samples for lipidomics
analysis, and are working to create a highly practicallipidomics analysis method. Furthermore, in theclinical field, it is required to measure a large numberof samples to take into account individual differences.
Therefore, we are developing high-throughput andhighly reliable assays and applying them to clinicalpractice.
Lipid biomarker discovery
Lipid biomarker discovery by liquid chromatographymass spectrometry-based method requires a high-level
integration of chromatography and mass spectrometry,
which ensures lipid separation, semi-quantitative detection, and identification. We are collaborating withindustries to overcome known difficulties in lipid
chromatography, develop differential analyses andfeature-extraction methods, and establish an intelligent analytical system linked with lipid database.
Metabolic flux analysis of lipids
A simple lipidomics analysis provides large datasetsthat describe the amount-based profile of lipidome.
However, such a ‘snapshot’ analysis is not sufficientto understand the dynamics of lipid metabolic pathway,461

because changes in metabolic flux is not always
reflected to static amount of metabolites. To overcome
this situation, we are developing a flux-oriented
lipidomics analysis using stable-isotope tracers.
Lipid biomarker/lipid mediator discovery using
animal models
Appling the latest lipidomics technologies to theanalysis of specimens from the animal models forvarious diseases including metabolic disease, we aretrying to discover novel lipid biomarkers. We also
analyze various gene-deficient mice and transgenic
mice to seek important lipid markers, lipid mediators,
and lipid profiles.
Multiplex quantitation strategy for lipid mediators
Lipid mediators, including prostaglandins, leukotrienes, platelet-activating factor, and many otherbioactive lipid metabolites are attracting great
attention as disease-related or physiologically important molecules. Comprehensive analysis of known
lipid mediators is a useful, unbiased method in diseasemechanism studies, and the lipid mediator profile is a
useful parameter that characterizes disease status aswell. We have developed an original multiplex
quantification method for trace amounts of lipid
mediators using liquid chromatography-tandem mass
spectrometry (LC-MS/MS). We are developing moresensitive and rapid methods that cover more lipid
mediators, which meet the demands on various
large-scale studies and high-throughput screening
approaches.
Discovery of novel lipid mediator metabolizing
pathways
Although major biosynthetic and catabolic
pathways for classical lipid mediators have been well
documented so far, there are still possibilities for yet
unidentified lipid mediator metabolizing pathways invivo. We have obtained preliminary data for novel
lipid mediator-producing pathway using genedeficient mice. Using the latest lipidomics techniques
to the cell cultures and animal models, we will
elucidate a novel lipid mediator related pathway andits biological significance.
Expansion of proteomics based on immune-PCR
Until now, proteomics based on mass spectrometry
has been the mainstream method, but quantitative

analysis was poor and plasma proteomics could notdetect proteins such as cytokines, which are only
present in very small amounts. This is why weintroduced this method for the first time in Japan. We
have already found interesting biomarker candidates
in various diseases. We are also trying to integrate
lipidomics and proteomics.

References
1.

2.

3.

4.

5.

6.

7.

Kita Y, Tokuoka SM, Oda Y, Shimizu T. TRACES:
A lightweight browser for liquid chromatography–
multiple reaction monitoring–mass spectrometry
chromatograms. Metabolites, 12, 354 (2022)(Published: 15 April 2022).
Tokuoka SM, Kita Y, Sato M, Shimizu T, Yatomi Y,
Oda Y. Lipid profiles of human serum fractions
enhanced with CD9 antibody-immobilized
magnetic beads. Metabolites, 12, 230 (2022)(Published: 5 March 2022).
Hamano F, Tokuoka SM, Ishibashi M, Yokoi Y,
Tourlousse DM, Kita Y, Sekiguchi Y, Yasui H,
Shimizu T, Oda Y. Multi-omics analysis to generate
hypotheses for mild health problems in monkeys.
Metabolites, 11, 701 (2021) (Published: 13 October2021).
Tokuoka SM, Kita Y, Sato M, Shimizu T, Yatomi Y,
Oda Y. Development of Tandem Mass Tag Labeling
Method for Lipid Molecules Containing Carboxy
and Phosphate Groups, and Their Stability in
Human Serum. Metabolites. 2020 Dec 30;11(1):19.
Tokuoka SM, Yasumoto A, Kita Y, Shimizu T,
Yatomi Y, Oda Y. Limitations of deuterium-labeledinternal standards for quantitative electrosprayionization mass spectrometry analysis of fatty acidmetabolites. Rapid Commun Mass Spectrom. 2020
Jul 15;34(13):e8814.
Tokuoka SM, Kita Y, Shimizu T, Oda Y. Isobaric
mass tagging and triple quadrupole mass spectrometry to determine lipid biomarker candidates for
Alzheimer's disease. PLoS One. 2019 Dec 10;
14(12):e0226073.
Izumi Y, Matsuda F, Hirayama A, Ikeda K, Kita Y,
Horie K, Saigusa D, Saito K, Sawada Y, Nakanishi
H, Okahashi N, Takahashi M, Nakao M, Hata K,
Hoshi Y, Morihara M, Tanabe K, Bamba T, Oda Y.
Inter-Laboratory Comparison of Metabolite

462

8.

9.

10.

11.

12.

13.

14.

Measurements for Metabolomics Data Integration.
Metabolites, 9, 257 (2019) (Published Online:31
October 2019)
Tanaka TQ, Tokuoka SM, Nakatani D, Hamano F,
Kawazu S, Wellems TE, Kita K, Shimizu T,
Tokumasu F. Polyunsaturated fatty acids promote
Plasmodium falciparum gametocytogenesis. Biol.
Open, 8, bio042259 (2019) (Published Online:20
June 2019)
Kohira T, Kita Y, Tokuoka SM, Shiba M, Satake M,
Shimizu T. Characterization of supported liquid
extraction as a sample pretreatment method foreicosanoids and related metabolites in biologicalfluids. J Chrom B, 1124, 298-307 (2019) (Published
Online:12 Jun 2019)
Yoshida K, Kita Y, Tokuoka SM, Hamano F,
Yamazaki M, Sakimura K, Kano M, Shimizu T.
Monoacylglycerol lipase deficiency affects
diet-induced obesity, fat absorption, and feeding
behavior in CB1 cannabinoid receptor-deficientmice. FASEB J, 33, 2484-2497 (2019) (Published
Online:30 Jan 2019)
Yanagida K, Igarashi H, Yasuda D, Kobayashi D,
Ohto-Nakanishi T, Akahoshi N, Sekiba A, Toyoda T,
Ishijima T, Nakai Y, Shojima N, Kubota N, Abe K,
Kadowaki T, Ishii S, Shimizu T. The Gα12/13coupled receptor, LPA4 limits proper adipose tissue
expansion and remodeling in diet-induced obesity.
JCI Insight, 3, e97293 (2018) (First published
December 20, 2018)
Kita Y, Shiudou H, Shimizu T. Cytosolic
phospholipase A2 and lysophospholipid acyltransferases. Biochim Biophys Acta, 1864, 838-845(2019) (Available online 9 August 2018)
Hori T, Okuno T, Hirata K, Yamashita K, Kawano Y,
Yamamoto M, Hato M, Nakamura M, Shimizu T,
Yokomizo T, Miyano M, Yokoyama S.
Na+-mimicking ligands stabilize the inactive stateof leukotriene B4 receptor BLT1. Nat Chem Biol,14, 262–269 (2018)
Valentine WV, Tokuoka SM, Hishikawa D, Kita Y,
Shindou H, Shimizu T. Lysophosphatidic acidacyltransferase 3 incorporates docosahexaeneoic
acid into skeletal muscle cell membranes and isupregulated by PPARδ activation. J Lipid Res, 59,
184-194 (2018)

15. Tabe S, Hikiji H, Ariyoshi W, Hashidate-Yoshida T,
Shindou H, Shimizu T, Okinaga T, Seta Y,
Tominaga K, Nishihara T. Lysophosphatidylcholine
acyltransferase 4 is involved in chondrogenic
differentiation of ATDC5 cells. Sci Rep, 7,16701(2017)
16. Kimura H, Suzuki M, Konno S, Shindou H,
Shimizu T, Nagase T, Miyazaki T, Nishimura M.
Orchestrating role of apoptosis inhibitor ofmacrophage in the resolution of acute lung injury. J
Immunol, 199, 3870-3882 (2017)17. Iizuka-Hishikawa Y, Hishikawa D, Sasaki J, Takubo
K, Goto M, Nagata K, Nakanishi H, Shindou H,
Okamura T, Ito C, Toshimori K, Sasaki T, Shimizu
T. Lysophosphatidic acid acyltransferase 3 tunes themembrane status of germ cells by incorporating
docosahexaenoic acid during spermatogenesis. J
Biol Chem, 292, 12065-12076 (2017)18. Shindou H, Koso H, Sasaki J, Nakanishi H, Sagara
H, Nakagawa MK, Takahashi Y, Hishikawa D,
Iizuka-Hishikawa Y, Tokumasu F, Noguchi H,
Watanabe S, Sasaki T, Shimizu T. Docosahexaenoic
acid preserves visual function by maintaining
correct disc morphology in retinal photoreceptor
cells. J Biol Chem, 292, 12054-12064 (2017)19. Takeda T, Komiya Y, Koga T, Ishida T, Ishii Y,
Kikuta Y, Nakaya M, Kurose H, Yokomizo T,
Shimizu T, Uchi H, Furue M, Yamada H. Dioxininduced increase in leukotriene B4 biosynthesis
through the aryl hydrocarbon receptor and its
relevance to hepatotoxicity owing to neutrophil
infiltration. J Biol Chem, 292. 10586-10599 (2017)20. Shindou H, Shiraishi S, Tokuoka MS, Takahashi Y,
Harayama T, Abe T, Bando K, Miyano K, Kita Y,
Uezono Y, Shimizu T. Relief from neuropathic painby blocking of platelet-activating factor-pain loop.
FASEB J, 31, 2973-2980 (2017)21. Shimura M, Shindou H, Szyrwiel L, Tokuoka SM,
Hamano F, Matsuyama S, Okamoto M, Matsunaga
A, Kita Y, Ishizaka Y., Yamauchi K, Kohmura Y,
Lobinski R, Shimizu I, Shimizu T. Imaging of intracellular fatty acids by scanning X-ray fluorescencemicroscopy. FASEB J. 30, 4149-4158 (2016) Epub.
22. Kita Y, Yoshida K, Tokuoka MS, Hamano F,
Yamazaki M, Sakimura K, Kano M, Shimizu T.
Fever is mediated by conversion of endocannabi-

463

noid 2-arachidonoylglycerol to prostaglandin E2.
PLoS ONE, 10, e0133663 (2015)23. Harayama T, Shindou H, Kita Y, Otsubo E, Ikeda
K, Chiba S, Weaver T, Shimizu T. Establishment
of LC-MS method for the analysis ofpalmitoylated surfactant proteins. J. Lipid Res.,56, 1370-1379 (2015)24. Yamada M, Kita Y, Kohira T, Yoshida K, Hamano
F, Tokuoka SM, Shimizu T. A comprehensive
quantification method for eicosanoids and related
compounds by using liquid chromatography/mass
spectrometry with high speed continuous ionization polarity switching. J. Chrom. B, 995, 74-84(2015)

464

Department of Preventive Medicine
for Locomotive Organ Disorders
Project Professor
Noriko Yoshimura, M.D., Ph.D.

Project Research Associate
Toshiko Iidaka, M.D., Ph.D.

Homepage

http:// www.h.u-tokyo.ac.jp/research/center22/index.html

Introduction and Organization
The department of Preventive Medicine for
Locomotive Organ Disorders in 22nd Century
Medical and Research Center, The University ofTokyo Hospital, on April 1st, 2020, which is a social
collaboration department with NIPPON TELEGRAPH
AND TELEPHONE CORPORATION (NTT), Suntory
Wellness
Ltd.,
ASAHI
KASEI
PHARMA
CORPORATION, and Fujifilm Corporation, and inclose collaboration with departments of Orthopaedic
Surgery and Rehabilitation Medicine in the hospital.
Our department has been established to clarify the
epidemiological profiles of locomotive organ
disorders, such as, osteoarthritis (OA), osteoporosis(OP) and sarcopenia (SP). Further, we also try to
elucidate the frequencied and risk factors forlocomotive syndrome, which was defined by theJapanese Orthopaedic Association (JOA) in 2014.

bone mass and geometry, lifestyle, nutritional factors,
anthropometric and neuromuscular measures, and fall
propensity. In addition, the study’s aim was also to
determine how these diseases affect activities of dailyliving and quality of life in Japanese men and women.
We have completed the baseline study in 2005-2007,
then, 2nd, 3rd, 4th, and 5th follow-ups werecompleted in 2008-2010, 2012-2013, 2015-2016, and2018-2019 respectively. We have been conducting
further follow-up surveys.

References
1.

Research activities
Although locomotive organ disorders are major causesof disability and require support, little information isavailable regarding their epidemiology. The Research
on Osteoarthritis/Osteoporosis Against Disability(ROAD) study, which started in 2005-7, is a
prospective cohort study that aims to elucidate theenvironmental and genetic background for bone andjoint diseases. It was designed to examine the extent
to which risk factors for these diseases are related toclinical features, laboratory and radiographic findings,

2.

3.

Suzuki T, Nishita Y, Jeong S, Shimada H, Otsuka
R, Kondo K, Kim H, Fujiwara Y, Awata S,
Kitamura A, Obuchi S, Iijima K, Yoshimura N,
Watanabe S, Yamada M, Toba K, Makizako H:
Are Japanese older adults rejuvenating? Changes
in health-related measures among older
community dwellers in the last decade.
Rejuvenation Research 24(1), 37-46, 2021
Leyland KM, Gates LS, Nevitt M, Felson D,
Jones G, Jordan JM, Judge A, Sanchez-Santos
MT, Sheard S, Yoshimura N, Newton J, Cooper C,
Lin J, Liu Q, Collins G, Altman D, Arden NK,
and the PCCOA steering committee: Knee
osteoarthritis and time-to all-cause mortality in
six community-based cohorts: an international
analysis of individual participant-level data.
Aging Clin Exp Res 33(3), 529-545, 2021.
Makizako H, Nishita Y, Seungwon J, Otsuka R,

465

Shimada H, Iijima K, Obuchi S, Kim H,
Kitamura A, Ohara Y, Awata S, Yoshimura N,
Yamada M, Toba K, Suzuki T: Trends in theprevalence of frailty in Japan: A meta-analysis
from the ILSA-J. The Journal of Frailty & Aging
10(3): 211-218, 2021.
4. Taniguchi T, Harada T, Iidaka T, Hashizume H,
Taniguchi W, Oka H, Asai Y, Muraki S, Akune T,
Nakamura K, Kawaguchi H, Yoshida M, Tanaka
S, Yamada H, Yoshimura N: Prevalence andassociated factors of pistol grip deformity in a
Japanese population: The ROAD Study. Scic Rep
11(1), 6025, 2021.
5. Miyamoto K, Hirayama A, SatoY, Ikeda S,
Maruyama M, Soga T, Tomita M, Yoshimura N,
Miyamoto T: Metabolomic profile predictive of
new osteoporosis or sarcopenia development.
Metabolites 11(5), 278, 2021.
6. Otsuka Y, Iidaka T, Horii C, Muraki S, Oka H,
Nakamura K, Izumo T, Rogi T, Shibata H, Tanaka
S, Yoshimura N: Dietary intake of vitamin E andfats
associatedwithsarcopenia
incommunity-dwelling older Japanese people: Across-sectional study from the fifth survey of the
ROAD study. Nutrients 13(5), 1730, 2021.
7. Hira K, Nagata K, Hashizume H, Asai Y, Oka H,
Tsutsui S, Takami M, Iwasaki H, Muraki S,
Akune T, Iidaka T, Kawaguchi H, Nakamura K,
Yoshida M, Tanaka S, Yoshimura N, Yamada H:
Relationship of sagittal spinal alignment with low
back pain and physical performance in thegeneral population. Sci Rep 11(1): 20604, 2021.
8. Mera Y, Teraguchi M, Hashizume H, Oka H,
Muraki S, Akune T, Kawaguchi H, Nakamura K,
Tamai H, Tanaka S, Yoshida M, Yoshimura N,
Yamada H: Association between types of Modicchanges in the lumbar region and low back pain
in a large cohort: the Wakayama spine study. Eur
Spine J 30(4): 1011-1017, 2021.
9. Teraguchi M, Hashizume H, Oka H, Cheung JPY,
Samartzis D, Tamai H, Muraki S, Akune T,
Tanaka S, Yoshida M, Yoshimura N, Yamada H:
Detailed subphenotyping of lumbar modicchanges and their association with low back pain
in a large population-based study: The Wakayama
Spine Study. Pain Ther 11(1):57-71, 2022.
10. Horii C, Iidaka T, Muraki S, Oka H, Asai Y,

Tsutsui S, Hashizume H, Yamada H, Yoshida M,
Kawaguchi H, Nakamura K, Akune T, Oshima Y,
Tanaka S, Yoshimura N: The cumulative
incidence and risk factors for morphometricsevere vertebral fractures in Japanese men andwomen: the ROAD study third and fourth
surveys. Osteoporos Int 33:889-899, 2022.
11. Shoji A, Gao Z, Arai K, Yoshimura N: Trends inincidence of osteoporosis-related fractures inJapan over the past 30 years: A systematic review
and meta-analysis. J Bone Miner Metab
40(2):327-336, 2022.
12. Asai Y, Tsutsui S, Yoshimura N, Hashizume H,
Iidaka T, Horii C, Kawaguchi H, Nakamura K,
Tanaka S, Yoshida M, Yamada H.: Relationshipbetweenage-related
spinopelvic
sagittalalignment and low back pain in adults of
population-based cohorts: The ROAD Study. J
Pain Research 15:33-38, 2022.
13. Matsumoto T, Higuchi J, Maenohara Y, ChangSong Ho, Iidaka T, Horii C, Oka H, Muraki S,
Hashizume H, Yamada H, Yoshida M, Nakamura
K, Tanaka S, Yoshimura N: The discrepancy
betweenradiographically-assessedandself-recognized hallux valgus in a large
population-based cohort. BMC Musculoskeletal
Disorders 23(1):31, 2022.

University Hospital
Clinical Divisions

University Hospital
Central Clinical Facilities

468

Department of Clinical Laboratory
Professor
Yutaka Yatomi, M.D.

Associate Professor
Makoto Kurano, M.D.

Lecturer
Masao Daimon, M.D., Yuichiro Shirota, M.D.
Kosuke Watanabe, M.D., Masaya Sato, M.D.

Associate
Tomoko Nakao, M.D., Masako Nishikawa, M.D,
Hideaki Isago, M.D.

Chief Technologist
Yoshikazu Ono, M.T.

Homepage

http://lab-tky.umin.jp/

Introduction and Organization
Department of Clinical Laboratory consists of thefollowing sections, and the 3rd - generation
Laboratory Automation System is in full operation,and ordering of laboratory tests, the flow of samples,
operation of laboratory analyzers, quality control ofanalysis, and data reporting are all controlled by the
Laboratory Automation computer system.
Thissystem has greatly improved the quality, safety, andefficiency of the laboratory and contributed to bothpatients and doctors by providing rapid and highquality laboratory testing.
The 1st Section
This section deals mainly with the maintenance oflaboratory system, blood and urine sampling, andurinalysis.
In 2021, 219,932 outpatient blood
sampling were performed in this section. Furthermore,
256,874 urine samples were examined.
The 2nd Section
This section deals with clinical biochemistry andimmuno-serology tests. In 2021, 5,447,680 serum

enzyme tests (such as AST and ALT), and 572,737
immunological tests were performed.
The 3rd Section
This section deals with laboratory hematology anddiabetes-related tests, and gene analysis tests. In
2021, 1,164,555 samples were examined for complete
blood cell counts, cell surface marker analysis,
prothrombin time, fibrinogen, glucose, and HbA1C
tests.
The 4th Section
This section deals with physiological tests,
including circulatory, pulmonary, and neuromuscularfunction ones.
In 2021, 42,787 ECG, 18,193
pulmonary function tests, and 10,738 EEG were
performed.
The 5th Section
This section deals with ultrasonography. In 2021,
12,073 echocardiography tests, 13,816 abdominal
echography tests, and 12,170 other ultrasonography
tests were performed.

469

Teaching activities

References

Lectures are given to the fourth and sixth grade
medical students on clinical laboratory medicine
including hematology, chemistry, endocrinology,
immunology, bacteriology, cardiology, and pulmonary
function. The reversed CPC program is presented tothe sixth grade students. Clinical clerkship is provided
for the sixth year medical students, in small groups of
6-7 students for one-week duration. Elective clerkshipis provided for two sixth year medical students, who
selected to join the training on clinical laboratory
medicine, for four-week duration. In this course,
students learn clinical and practical knowledge andtechniques on various laboratory tests. The second,
third, and fourth grade medical students can join
research activities in our department (Free Quartercourse).
Students from professional schools also study
laboratory medicine under the guidance of members inClinical Laboratory Center. As educational facilities
for certified clinical laboratory physicians, we havebeen training up many physicians.

Original article:
1. Chou, S., Yasukawa, K., Fujino, Y., Ishibashi, M.,
Haraguchi, M., Sato, M., Ikeda, H., Nakamura, S.,
and Yatomi, Y. Non-mercaptalbumin issignificantly associated with the coronary plaqueburden and the severity of coronary artery disease.
Sci. Rep.11: 14242, 2021.
2. Hirose, K., Nakanishi, K., Daimon, M., Sawada, N.,
Yoshida, Y., Iwama, K., Yamamoto, Y., Ishiwata,J., Hirokawa, M., Koyama, K., Morita, H., Di,
Tullio, M.R., Homma, S., and Komuro I. Impact of
insulin resistance on subclinical left ventricular
dysfunction in normal weight and overweight/obesejapanese subjects in a general community.
Cardiovasc. Diabetol. 20: 22, 2021.
3. Honjo, M., Yamagishi, R., Igarashi, N., Ku, C.Y.,
Kurano, M., Yatomi, Y., Igarashi, K., and Aihara,
M. Effect of postoperative corticosteroids onsurgical outcome and aqueous autotaxin following
combined cataract and microhook ab interno
trabeculotomy. Sci. Rep. 11: 747, 2021.
4. Igarashi, N., Honjo, M., Asaoka, R., Kurano, M.,
Yatomi, Y., Igarashi, K., Miyata, K., Kaburaki, T.,
and Aihara, M. Aqueous autotaxin and TGF-βs arepromising diagnostic biomarkers for distinguishingopen-angle glaucoma subtypes. Sci. Rep. 11: 1408,
2021.
5. Igarashi, N., Honjo, M., Yamagishi, R., Kurano, M.,
Yatomi, Y., Igarashi, K., Kaburaki, T., and Aihara,
M. Crosstalk between transforming growth factor
beta-2 and Autotaxin in trabecular meshwork anddifferent subtypes of glaucoma. J. Biomed. Sci.28:
47, 2021.
6. Isago, H., Mitani, A., Kohno, S., Nagoshi, S.,
Ishimori, T., Saito, M., Tamiya, H., Miyashita, N.,
Ishii, T., Matsuzaki, H., Yatomi, Y., Nagase, T.,
and Jo, T. The Japanese Herbal (Kampo) Medicine
Hochuekkito Attenuates Lung Inflammation in
Lung Emphysema. Biol. Pharm. Bull. 44: 39-45,
2021.
7. Ishihara, Y., Okamoto, K., Shimosaka, H., Ono, Y.,
Kanno, Y., Ikeda, M., Harada, S., Kurano, M.,
Okugawa, S., Moriya, K., and Yatomi Y.
Prevalence and clinical characteristics of patientswith biologically false-positive reactions with

Research activities
The main goal of our research projects is thedevelopment of new and useful laboratory tests, andelucidation of pathophysiology of diseases throughlaboratory tests. The present main areas included are:i) (Patho)physiological roles of lysophospholipid
mediators and its application into laboratory medicine,ii) introduction of mass spectrometry into clinicallaboratory practice, iii) development of COVID-19associated biomarkers, iv) platelet biology, development of laboratory diagnosis in thrombosis andhemostasis, v) cancer genomic medicine using next
generation sequencing, vi) oxidized albumin as aredox marker, vii) echocardiographic studies of thepathophysiology of valvular heart disease and thehemodynamics, viii) neuroscience research using
magnetoencephalography and non-invasive brain
stimulation, and ix) promotion of medical-scienceengineering cooperation.

470

8.

9.

10.

11.

12.

13.

14.

serological syphilis testing in contemporary
practice: 10-year experience at a tertiary academic
hospital. Sex. Transm. Infect. 97: 397-401, 2021.
Iwata, Y., Kitajima, S., Yamahana, J., Shimomura,S., Yoneda-Nakagawa, S., Sakai, N., Furuichi, K.,
Ogura, H., Sato, K., Toyama, T., Yamamura, Y.,
Miyagawa, T., Hara, A., Shimizu, M., Ohkawa, R.,
Kurano, M., Yatomi, Y., and Wada, T. Higher
serum levels of autotaxin and phosphatidylserinespecific phospholipase A1 in patients with lupus
nephritis. Int. J. Rheum. Dis. 24: 231-239, 2021.
Kaneko, H., Kiriyama, H., Kamon, T., Itoh, H.,
Kodera, K., Fujiu, K., Daimon, M., Morita, H.,
Hatano, M., and Komuro, I. Percutaneous mitralvalve intervention using MitraClip for functional
mitral regurgitation and heart failure. Int. Heart J.
62: 4-8, 2021.
Kano, K., Matsumoto, H., Kono, N., Kurano, M.,
Yatomi, Y., and Aoki, J. Suppressing postcollection
lysophosphatidic acid metabolism improves theprecision of plasma LPA quantification. J. Lipid
Res. 62: 100029, 2021.
Kamon, T., Kaneko, H., Kiriyama, H., Itoh, H.,
Fujiu, K., Kumazawa, R., Morita, K., Michihata, N.,
Jo, T., Miura, M., Kodera, S., Uehara, M., Ando, J.,
Inoue, T., Kinoshita, O., Yamauchi, H., Mori, Y.,
Nakao, T., Daimon, M., Takeda, N., Morita, H.,
Ono, M., Yasunaga, H., and Komuro, I.
Transcatheter aortic valve implantation and surgicalaortic valve replacement for aortic stenosis inJapan; Analysis of a nationwide inpatient database.
Circ. Rep. 2: 753–758, 2021.
Kiriyama, H., Kaneko, H., Itoh, H., Kamon, T.,
Morita, K., Jo, T., Fujiu, K., Daimon, M., Takeda,N., Morita, H., Yasunaga, H., and Komuro I.
Surgical treatment for infective endocarditis in theageing society: a nationwide retrospective study inJapan. Open Heart 8: e001627, 2021.
Kobayashi, T., Kurano, M., Nanya, M., Shimizu, T.,
Ohkawa, R., Tozuka, M., and Yatomi, Y. Glycationof HDL Polymerizes Apolipoprotein M and
Attenuates Its Capacity to Bind to Sphingosine
1-Phosphate. J. Atheroscler. Thromb. 28: 730-741,
2021.
Kurano, M., Kobayashi, T., Sakai, E., Tsukamoto,K., and Yatomi, Y. Lysophosphatidylinositol,
especially albumin-bound form, induces inflam-

15.

16.

17.

18.

19.

20.

matory cytokines in macrophages. FASEB J. 35:
e21673, 2021.
Mitani, A., Hamada, K., Yoshikawa, N., Morita, Y.,
Horie, T., Inoue, Y., Saito, M., Ishii, T., Sunohara,
M., Takahashi, R., Emoto, N., Nishimoto, N.,
Murano, Y., Okazaki, S., Tateishi, S., Yao, A.,
Shimura, T., Kurano, M., Yatomi, Y., andYanagimoto, S. Epidemiological study using IgM
and IgG antibody titers against SARS-CoV-2 in
The University of Tokyo, Japan (UT-CATS). J.
Infect. Chemother. 27: 1342-1349, 2021.
Morita, Y., Kurano, M., Sakai, E., Sawabe, M.,
Aoki, J., Yatomi, Y. Simultaneous analyses ofurinary eicosanoids and related mediators identified
tetranor-prostaglandin E metabolite as a novel
biomarker of diabetic nephropathy. J. Lipid Res.
62: 100120, 2021.
Nakamura, N., Honjo, M., Yamagishi, R., Kurano,M., Yatomi, Y., Watanabe, S., and Aihara, M.
Neuroprotective role of sphingolipid rheostat in
excitotoxic retinal ganglion cell death. Exp. Eye.
Res.208: 108623, 2021.
Nakano, Y., Kurano, M., Morita, Y., Shimura, T.,
Yokoyama, R., Qian, C., Xia, F., He, F., Kishi, Y.,
Okada, J., Yoshikawa, N., Nagura, Y., Okazaki, H.,
Moriya, K., Seto, Y., Kodama, T., and Yatomi Y.
Time course of the sensitivity and specificity ofanti-SARS-CoV-2 IgM and IgG antibodies for
symptomatic COVID-19 in Japan. Sci. Rep. 11:2776, 2021.
Nakanishi, K., Daimon, M., Yoshida, Y., Ishiwata,J., Sawada, N., Hirose, K., Iwama, K., Yamamoto,Y., Hirokawa, M., Kaneko, H., Nakao, T., Mizuno,Y., Morita, H., Di, Tullio, M.R., Yatomi, Y.,
Homma, S., and Komuro I. Relation of Body Mass
Index to Adverse Right Ventricular Mechanics. Am.
J. Cardiol. 144: 137-142, 2021.
Nishikawa, M., Kanno, H., Zhou, Y., Xiao, TH.,
Suzuki, T., Ibayashi, Y., Harmon, J., Takizawa, S.,
Hiramatsu, K., Nitta, N., Kameyama, R., Peterson,
W., Takiguchi, J., Shifat-E-Rabbi, M., Zhuang, Y.,
Yin, X., Rubaiyat, AHM., Deng, Y., Zhang, H.,
Miyata, S., Rohde, GK., Iwasaki, W., Yatomi, Y.,
and Goda, K. Massive image-based single-cell
profiling reveals high levels of circulating platelet
aggregates in patients with COVID-19. Nat
Commun. 12: 7135, 2021.

471

21. Osawa, I., Okamoto, K., Ikeda, M., Otani, A.,
Wakimoto, Y., Yamashita, M., Shinohara, T.,
Kanno, Y., Jubishi, D., Kurano, M., Harada, S.,
Okugawa, S., Yatomi, Y., and Moriya, K. Dynamicchanges in fibrinogen and D-dimer levels in
COVID-19 patients on nafamostat mesylate. J.
Thromb. Thrombolysis. 51: 649-656, 2021.
22. Sato, M., Tateishi, R., Yatomi, Y., and Koike, K.
Artificial intelligence in the diagnosis andmanagement of hepatocellular carcinoma. J.
Gastroenterol. Hepatol. 36: 551-560, 2021.
23. Shimura, T., Kurano, M., Kanno, Y., Ikeda, M.,
Okamoto, K., Jubishi, D., Harada, S., Okugawa, S.,
Moriya, K., and Yatomi, Y. Clot waveform of
APTT has abnormal patterns in subjects with
COVID-19. Sci. Rep. 11: 5190, 2021.
24. Soulat-Dufour, L., Addetia, K., Miyoshi, T., Citro,R., Daimon, M., Gutierrez, Fajardo, P., Kasliwal,
R.R., Kirkpatrick, J.N., Monaghan, M.J., Muraru,D., Ogunyankin, K.O., Park, S.W., Ronderos, R.E.,
Sadeghpour, A., Scalia, G.M., Takeuchi, M., Tsang,W., Tucay, E.S., Tude, Rodrigues, A.C.,
Vivekanandan, A., Zhang, Y., Diehl, M.,
Schreckenberg, M., Mor-Avi, V., Asch, F.M., andLang, R.L. Normal values of right atrial size andfunction according to age, sex and ethnicities:
Results of the World Alliance of Societies of
Echocardiography study. J. Am. Soc. Echocardiogr.
34: 286-300, 2021.
25. Sugawara, M., Hoshina, K., Chigira, M., Suzuki, H.,
Daimon, M., Takayama, T., Ono, Y., and Yatomi,
Y. Usefulness of duplex ultrasonography to detectcollagen sponge misplacement into the arterial
lumen during the use of Angio-Seal: A case report.
SAGE Open Medical Case Reports 9: 1-3, 2021.
26. Sugawara, M., Nakao, T., Yatomi, Y., and Daimon,
M. Development of aortic regurgitation due tonon-bacterial thrombotic endocarditis. J. Med.
Ultrason (2001). 48: 363–364, 2021.
27. Takami, A., Watanabe, S., Yamamoto, Y., Kondo,
H., Bamba, Y., Ohata, M., Mishima, S., Kubota, H.,
Nishiura, A., Miura, R., Iwagami, M., Higashi, K.,
Yatomi, Y., Tohyama, K., Japanese Society forLaboratory Hematology Standardization, C., Joint
Working Group of the, J., and the Japanese
Association of Medical, T. Reference intervals of
red blood cell parameters and platelet count for

28.

29.

30.

31.

32.

33.

34.

healthy adults in Japan. Int. J. Hematol. 114: 373380, 2021.
Tanaka, R., Kaburaki, T., Taoka, K., Karakawa, A.,
Tsuji, H., Nishikawa, M., Yatomi, Y., ShinozakiUshiku, A., Ushiku, T., and Araki, F. More
Accurate Diagnosis of Vitreoretinal Lymphoma
Using a Combination of Diagnostic Test Results: A
Prospective Observational Study. Ocul. Immunol.
Inflamm. 4: 1-7, 2021.
Takano, H., Yasunaga, M., Yamazaki, I.,
Nishikawa, M., Masamoto, Y., Shinozaki-Ushiku,A., Kawakami, M., Yatomi, Y., and Kurokawa, M.
Degenerated mitochondria in leukemic blast
appeared as granules on May-Grunwald-Giemsa
staining. Ann Hematol. 10, 2021. Online ahead ofprint.
Tarao, K., Daimon, M., Son, K., Nakanishi, K.,
Nakao, T., Suwazono, Y., Isono, S. Risk factors
includingpreoperative
echocardiographic
parameters for post-induction hypotension in
general anesthesia. J. Cardiol. 78: 230-236, 2021.
Tokuoka, S.M., Kita, Y., Sato, M., Shimizu, T.,
Yatomi, Y., and Oda, Y. Development of Tandem
Mass Tag Labeling Method for Lipid Molecules
Containing Carboxy and Phosphate Groups, andTheir Stability in Human Serum. Metabolites. 11:
19, 2021.
Tsuchida, R., Tanabe, Y., Nishizawa, D., Ikeda, K.,
Abe, H., Inoue, R., Kurano, M., Yatomi, Y.,
Tamura, K., Takano, T., Shimizu, C., Uchida, K.,
and Sumitani, M. Genetic polymorphisms oflysophosphatidic acid receptor 1 are associated withthe onset of taxane-induced peripheral neuropathy.
Br. J. Anaesth. 7: e43-e46 ,2021.
Uranbileg, B., Ito, N., Kurano, M., Kano, K.,
Uchida, K., Sumitani, M., Aoki, J., and Yatomi Y.
Inhibition of autotaxin activity ameliorates
neuropathic pain derived from lumbar spinal canalstenosis. Sci. Rep. 11: 3984, 2021.
Xu, B., Daimon, M., Kawata, T., Nakao, T.,
Hirokawa, M., Sawada, N., Kimura, K., Yamanaka,Y., Morita, H., Komuro, I., and Yatomi Y.
Relationship Between Mitral Leaflet Size andCoaptation and Their Associated Factors in Patientswith Normal Left Ventricular Size and Systolic
Function. Int. Heart J. 62: 95-103, 2021.

472

35. Xu, B., Kawata, T., Nakao, T., Nakanishi, K.,
Hirokawa, M., Sawada, N., Kimura, K., Abe, Y.,
Komuro, I., Yatomi, Y., and Daimon, M. Mitral
Valvular Coaptation-Zone Area Is Associated with
the Severity of Atherosclerosis Assessed by CardioAnkle Vascular Index. Int. Heart J.62: 552-558,
2021.
36. Yasuda, N., Nishikawa, M., Shimosaka, H., Ono,Y., and Yatomi, Y. Effect of administration of
immunoglobulin preparations on the results of tests
for autoantibodies. Mod. Rheumatol. roab085,
2021.
37. Yokoyama, R., Kurano, M., Morita, Y., Shimura,T., Nakano, Y., Qian, C., Xia, F., He, F., Kishi, Y.,
Okada, J., Yoshikawa, N., Nagura, Y., Okazaki, H.,
Moriya, K., Seto, Y., Kodama, T., and Yatomi, Y.
Validation of a new automated chemiluminescentanti-SARS-CoV-2 IgM and IgG antibody assay
system detecting both N and S proteins in Japan.
PLoS One. 16: e0247711, 2021.
38. Yokoyama, R., Kurano, M., Nakano, Y., Morita, Y.,
Ohmiya, H., Kishi, Y., Okada, J., Qian, C., Xia, F.,
He, F., Zheng, L., Yu, Y., Jubishi, D., Okamoto, K.,
Moriya, K., Kodama, T., and Yatomi, Y.
Association of the serum levels of the nucleocapsid
antigen of SARS-CoV-2 with the diagnosis, disease
severity, and antibody titers in patients with
COVID-19: a retrospective cross-sectional study.
Front. Microbiol. 12: 791489, 2021.
39. Yoshida, Y., Nakanishi, K., Daimon, M., Ishiwata,J., Sawada, N., Hirokawa, M., Kaneko, H., Nakao,T., Mizuno, Y., Morita, H., Di, Tullio, M.R.,
Homma, S., and Komuro, I. Sex-specific Differencein the Association Between Arterial Stiffness and
Subclinical Left Ventricular Dysfunction. Eur.
Heart. J. Cardiovasc. Imaging 22: 817-823, 2021.

473

Surgical Center
Professor (Director)
Kazuhiko Fukatsu M.D., Ph.D.

Lecturer
Satoshi Murakoshi, M.D., Ph.D.
Yuhei Saito, Ph.D.
Yuki Taniguchi, M.D., Ph.D
Ryoji Fukushima, M.D., Ph.D.

Assistant Professor
Ryota Yamagami. M.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/syujutsu/index.html

Introduction and Organization
Uniform management of operating rooms (OR) firstbegan at the University of Tokyo Hospital in July 1955.
The office, so called the surgical center, was located at
the Old Central Building until December 1987. The
center moved to the new Central Clinical Service
Building 1 in January 1988, where there are 12 ORs
including one bio-clean room. The surgical center
became to provide managerial services of the OR to 18
surgical departments after moving into the new officebuilding. The total number of operations remained tobe below 6,300 a year between 1999 and 2000 becauseof the limitation of number of ORs and nurses.
In July 2001, the branch hospital in Mejiro area wasmerged with the University of Tokyo Hospital in
Hongo area, which opened a new Ward A Building in
October 2001. After the merger, the number of elective
operations markedly increased and became over 7,300.
Two additional ORs began to be used tentatively toaccommodate an enormous increase in the number ofelective operations. The one OR was set up on the
ICU/CCU/HCU floor in the new Ward A Building andthe other was in the Outpatient Clinic Building. The
outpatient OR for orthopedic outpatients was diverted
for the general OR, which was used for the short-stayand day surgery.

Until September 2001, the elective operations had
been performed in 9.5 ORs/day on average. After
October 2001, 12 ORs/day began to be used. In 2006,
the Central Clinical Service Building 2, which had 11
ORs, was completed to solve the shortage of thenumber of ORs. As a result, the total number of ORs
became 23, and then the number of operations has
tremendously increased. More recently, “On call PM
block time” has been introduced to improve OR
utilization. In April 2014, one of the ORs in the Central
Clinical Service Building 2 was renovated into a hybrid
OR which is equipped with advanced interventional
imaging system for the patients undergoinginterventional surgical treatment. In August 2020, Day
Surgery room was built at ICU-2 area for ophthalmic
operation.
A total of 8,485, 9,550, 9921, 9,944, 10,394, 10,170,
10,752, 11,235, 11,150, 10,960, 11,161, 11,014, 11,124,
11,323, 9,945 (under the circumstance of Covid-19
pandemic) and 11,047 operations were performed in
2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014,2015, 2016, 2017, 2018, 2019, 2020 and 2021 fiscal
year, respectively. The number of operations in 2021
fiscal year counts for approximately 1.8 times
comparing to that in 2001.
These days more and more patients undergo

474

endoscopic surgery such as laparoscopy/thoracoscopy
assisted operation. There is also an apparent increase in
the number of patients who are at high risk with criticalmorbidity or carrier of the particular types of pathogens
such as tuberculosis, MRSA, pseudomonas aeruginosa,
HBV, HCV and HIV.

Clinical Activities
All operations of in-patients are performed in 23
ORs and Day Surgery room at the surgical center.
Computer system has been utilized to handle theinformation on operation. In May 1999, the on-line
system was introduced to order the elective andurgent/emergent operations through the computer
terminal in the wards. The input of postoperative
patient information started from March 2000. Thissystem also enabled the medical staff to know theavailability of the ORs of the next day. From November
in 2000, the medical staff can see the operation
schedule through the hospital computer network.
The present status of the operation process began to
be seen through the computer monitor from May 1997.
The photographs of surgical sites, resected organs andlive video image began to be delivered to the clinicaldepartments from February 1997.
Hospital logistics system were totally replaced to
improve material flow of hospital in October 2001,
when supply processing and distribution (SPD)department was established and started its practice. In
the surgical center, this SPD system has been available
since September in 2002.
Recently, the number of complicated and long
surgical procedures using advanced technology has
dramatically increased. In addition, more and morepatients tend to undergo surgery using artificial implant,
joint prosthesis or intraocular lenses. Those operations
include organ transplantation, microvascular surgery,cardiovascular surgery, minimally invasive surgery andnavigation-guided orthopedic/neurosurgical surgery
and stent grafting for the abdominal or thoracic aortic
aneurysms. Organ transplantation and intraoperative
three-dimensional echo-guided surgery are alsofrequently performed. Minimally invasive surgery is
another recent trend of the operation. Those include
endovascular treatment for heart anomalies such as
ASD and VSD. More recently, the robotic surgery has

started at the surgical center.
Healthcare-Associated infections (HAIs) are criticalissues in the surgical center. It is essential to educate
staffs how to prevent HAIs and occupational infections.
As the number of operations associated with emerging
or re-emerging infectious diseases such as HIV andtuberculosis has increased, all healthcare staff are
required to adhere to the principles of standard and/ortransmission-based precautions also in the surgicalcenter.

Teaching Activities
The following lectures or seminar are given to theundergraduate and postgraduate medical students:
aseptic techniques, sterilization/disinfection methods,
prevention of perioperative infections, humoral andcellular responses to trauma and shock, training ofscrubbing and gown techniques. The curriculum is
updated each year. Introductory course for disinfection,sterilization and preservation of surgical instruments
and medical devices was added in the training courses
in 1998, which gained more interest and popularity
among many students.
In the surgical center, the innovative surgicalinstruments and medical devices are introduced toperform highly advanced operations such as in thenavigation
surgery,transplantation
surgery,
cardiovascular surgery and robotic surgery. As a result,the education related to the assist for those surgicalprocedure has become most important activities in thesurgical center. The lectures of advanced technologies
are in the curriculum for the surgeons, the nursing staff
and clinical engineers so that they can understand how
to use them in a proper way.
Lectures for the nursing staff consist of a freshmancourse and an advanced course. The freshman course isa basic training course for scrub nurses and circulating
nurses. It consists of lectures of aseptic techniques, decontamination/sterilization methods, prevention of
perioperative infections, and on-site training ofscrubbing and gown techniques as well as aseptic
preparation of surgical instruments in the OR. An
advanced course is prepared to the experienced nurses
as well. The purpose of this course is to upgrade theirperioperative nursing skills so that they candemonstrate full nursing skills even in the complicated475

and long operations such as transplant surgery, openheart surgery neurosurgery and robotic surgery.
There is also a training course to medical engineers
and students of biomedical engineers. This training
course consists of introduction on the medical devices
and electronic instruments, precautions of accidental
troubles in handling surgical instruments/medical
devices, development of new surgical instruments/
medical devices, cardiopulmonary bypass techniques
and illumination techniques in the operating fields. The
contents of this course are summarized in the manual
for the nursing staff and contribute to decrease thefrequency of incident associated with surgicalinstruments and medical devices.
The on-the-job training are given to the non-nursing
staff including technical officials and part-time
employees since they start their careers at the surgicalcenter. They are given lectures on aseptic techniques,
sterilization/disinfection methods, prevention of
perioperative infections, and maintenance of reusable
surgical instruments such as forceps, scissors andclamps. These subjects are stated and summarized in
the manual. Lectures are also given to the seniortechnical officers and part-time employees to promote
their technical knowledge and skills.

Research Activities
1) Safe surgery and risk management in the OR2) Improvement of cost-effectiveness in the surgicaltreatment
3) Development of central monitoring system using
IT technology
4) Introduction of robotic surgery5) Efficient use of human resources6) Introduction of advanced surgical procedureincluding microscopy surgery and laparoscopy
7) Management of equipment of endoscopy-assisted
surgery8) Centralization of the live video images of thesurgical field
9) Management of surgical instruments using uniquedevice identification (UDI)
10) Perioperative infection control and prevention
related to the sterilization
11) Maintenance of the surgical environment in the OR12) Maintenance and management of surgicalequipment13) Nutritional management of perioperative patients
14) Others

476Radiology Center
Professor (Director)
Osamu Abe, M.D., Ph.D.

Lecturer (Vice Director)
Wataru Gonoi, M.D., Ph.D.

Project Lecturer
Masaki Katsura, M.D., Ph.D.

Chief Technologist (Vice Director)
Hideyuki Iwanaga, R.T.

Homepagehttps://www.h.u-tokyo.ac.jp/patient/depts/houshasenbu/

Introduction and Organization
Radiology Center was established in August 1964
as a part of the Central Clinical Services. Currently,
the Department consists of three divisions: Diagnostic
Radiology (imaging and intervention), Nuclear
Medicine, and Radiotherapy, Radiation Safety Control
Center. The center engages in radiology services suchas various imaging examinations, radiotherapy, andradiation safety management.
The members are as follows: Professor Osamu Abe(Director, since Oct. 2016), Wataru Gonoi (ViceDirector/Lecturer), Masaki Katsura (Project Lecturer),
77 radiology technologists, including Chief
Technologist Hideyuki Iwanaga, and one technicalspecialist in charge of radiation control. In addition to
the above, Radiology Center is operated in corporation
with the staff radiologists, graduate students, andresidents of the Department of Radiology, as well as
physicians from other departments, nurses, andclinical engineering technicians of the Department ofClinical Laboratory. In recent years, the number ofradiological services has increased, and we are trying
to cope with this trend by improving work efficiency,
optimizing staffing, and introducing new equipment.
The development of technologies for advancing andimproving radiological practice is a cooperative effort
between physicians and radiologists. In addition to thefields of imaging and radiation therapy, theconstruction of image management systems, image
processing, and image transfer systems have become
essential themes in recent years. The radiology
information system (RIS) and diagnostic reporting
systems were digitalized in 1994. And a picturearchiving and communication system (PACS, thefilm-less imaging system) was introduced in thehospital in May 2003. To reduce and equalize theburden of radiologists, we started preparing for thetrial introduction of a new high-performance
diagnostic interpreting system in 2012 and started its
practical operation in 2015. In the field of radiation
safety control, stimulated by the need to evaluate theindividual accumulated exposure dose by medical
radiation, we have started a working group to solve
this problem. We provide the individualized
accumulated exposure dose data on RIS. We also workfor research on new radiology techniques such asimage-guided radiation therapy, CT, MRI, PET, flat
panel detector, postmortem imaging, artificial
intelligence, etc.

Clinical activities
1) Diagnostic Radiology Section:
The diagnostic radiology section is responsible forsimple radiography (bone, chest, abdomen, head,

477

pediatric, breast, pelvic measurement), various
radiography with contrast mediums (gastrointestinal
tract, urinary tract), radiography in the operatingrooms, radiography in the emergency rooms,
outpatient radiography, portable radiography in
hospital wards, dental and oral radiography, bonemineral content determination, CT, MRI, angiography
and interventional radiology (IVR), image processing
and analysis (3D image reconstruction and analysis).
Most examinations are performed in the diagnostic
radiology section on the 1st floor of the Central
Clinical Services Building 1. Some are performed in
the MRI rooms, Surgical Center, Critical Care andEmergency Medical Center/ER, and some otherdepartments in the Central Clinical Services Building
2. The number of examinations, especially CT and
MRI, is dramatically increasing. Six multi-slice CT
machines (2 x 320-row, 1 x 256-row, 1 x 64-row CT, 2
x 80-row), 7 MRI machines (5 x 3T MRI, 2 x 1.5T
MRI), 6 angiography systems (including one hybrid
angiography system in the Surgical Center) are in use.
2) Nuclear Medicine Section:
The nuclear medicine section is responsible forvarious nuclear medicine examinations (gamma
camera, single-photon emission computerized
tomography (SPECT), positron emission tomography(PET)), radiopharmaceutical management, productionof PET nuclides using accelerators, label synthesis,
qualityverification,
radioactive
contaminant
management, internal isotope irradiation therapy.
The nuclear medicine section in Central Clinical
Services Building 1 performs various medical services
using unsealed radionuclides. Nuclear medicine
examinations include conventional scintigraphy (bone,tumor, renal, thyroid), myocardial SPECT, and brain
SPECT. Functional and statistical images using tracer
methods are also available. In recent years, thedemand for PET examinations has been increasing,
especially for 18F-fluorodeoxyglucose-PET (FDGPET) in cases of malignant tumors. PET examinations
using tracers labeled with positron nuclides (18F)
produced by a small cyclotron are used to evaluate
blood flow and metabolism, receptor imaging, and thepresence of amyloid accumulation in the brain. With
the opening of the Central Clinical Service Building 2,
a PET-CT scanner and a cyclotron were installed. In

2009, we started internal radioisotope therapy for
castration-resistant prostate cancer with bonemetastasis and radioimmunotherapy for malignant
lymphoma.
3) Radiation Oncology Section:
The radiation oncology section is responsible forhigh-energy radiotherapy, gamma-knife therapy,
brachytherapy, and radioisotope (RI) internal therapy.
The radiation oncology section is on the thirdbasement floor of Central Clinical Services Building 2
and has dedicated rooms for RI internal therapy on the
9th floor of Inpatient Ward A.
The radiation oncology section has three linear
accelerators (LINAC), an iridium brachytherapy
machine, a gamma-knife for stereotactic irradiation of
the head, and a CT scanner for treatment planning. A
treatment planning system is used to perform radiation
therapy. All linear accelerators are equipped with a CT
imaging function for position matching, enablinghighly accurate image-guided radiation therapy. In
2014, one of the linear accelerators was upgraded, anda tomotherapy was introduced. Tomotherapy is ahelical intensity-modulated machine dedicated tohigh-precision radiotherapy for brain and head andneck tumors, whole-body irradiation, and whole-bodyskin irradiation. The Radiology Information System(RIS), introduced in 2012 from the viewpoint of
medical safety, is now in operation to construct acomprehensive management system for cancer
treatment. Recently, the gamma-knife system was
updated in February 2019, and image-guided
radiotherapy is now available in the gamma-knife
system.
4) Others:
The radiation control office handles the hospital's
management of X-ray generators, radioactive
contaminants, radiation education, and healthmanagement (glass badge management, etc.). In
addition, it conducts management and operation under
the Medical Service Law and the Law Concerning
Prevention of Radiation Hazards Act on thePrevention of Hazards to Persons with Disabilities.

478

Conclusion
In 2002, the diagnostic imaging equipment was fully
digitalized, and in the following year, a filmlesssystem was realized by distributing images anddiagnostic reports via the hospital information system.
The Critical Care and Emergency Medical Center/ER,
MRI rooms, and the radiation oncology section wererelocated to the Central Clinical Service Building 2(completed in 2006), and the latest equipment was
introduced. In January 2018, when Inpatient Ward B
started operation, a portable radiography system wasestablished.
As a result of the development of digital technology,
diagnostic equipment, image processing technology,
diagnostic imaging, and radiotherapy technology havebecome more sophisticated. Radiology Center willcontinue to contribute to improving the level of
medical care at the University of Tokyo Hospitalthrough improved services to other departments.

Publications
See the corresponding part of the Department ofRadiology.

Number of examinations in 2021.4
to 2022.3
Inpatient

Outpatient

Total

Radiography(plain)85,93870,930156,868

Radiography(enhanced)

3,849

1,390

5,239

Angiography

3,436

17

3,453

Computed
tomography

13,79836,93350,731

Magnetic
resonance
imaging

4,692

16,31421,006

Nuclearmedicine

1,471

3,003

4,474

Radiotherapy

4,659

8,427

13,086

Bone mineraldensitometry

287

2,556

2,843

479

Department of Pharmacy
Professor
Hiroshi Suzuki, Ph.D.

Lecturer
Tappei Takada, Ph.D.,

Masashi Honma, Ph.D.

Research Associate
Takahiro Amemiya, Ph.D.,

Yuki Ikebuchi, Ph.D.,

Yoshiaki Kariya, Ph.D.,

Hiroshi Miyata, Ph.D.

Yoshihide Yamanashi, Ph.D.

Homepage

http://plaza.umin.ac.jp/~todaiyak/

Introduction and Organization
We have 8 faculty members, 83 pharmacy staffs,
and 8 graduate students and 8 undergraduate students
from the faculty of pharmaceutical sciences (as ofMarch 1st, 2022).

Clinical activities
Department of Pharmacy consists of the following
six sections:1) Drug information and research section
This section offers drug information for questions
from medical persons, executes and supports the
medicine management to inpatients. In addition,
the section prepares materials for pharmaceuticalaffair committee, where each medicine isdiscussed whether it should be adopted or deleted.
Preparation of several periodicals regarding drug
information for clinicians is also included.
2) The dispensing section
After inspecting all prescriptions for contraindications or improper use, medications are
dispensed. Drug information is given to outpatientsfrom this section, using a private room ifnecessary. The computerized order system islinked with automatic packaging machines fororal medicines, automatic dispensing system andbarcode label printer for injection drugs.

3) Pharmaceutical section
This section sterilizes formulations of a pharmaceutical such as injection medicines, instillation
medicines and decontaminating chemicals. They
prepare capsule medicines, ointment medicines,
suppositories, central vein nutrition (IVH) for
inpatients and in-home care patients. After strict
inspection of prescriptions, they also dispenseanti-malignant tumor medicine (database isconstructed based on the submitted protocols andpatients’ information). In order to support
advanced medical care, they develop and check
formulations (characterization of the uniformity,
stability and so on) of the medicine which is quite
necessary for certain patients, but is not marketed.
4) Drug matters and drug management section
Drug matter section manages the adoption of
medical supplies (in-hospital and out-hospital),
periodically reconsiders the adopted medicines,
and also manages the accountings of all the
medicines and other materials used in our
department. This section also takes statistics ofevery information of drug affairs. Drug management section takes care of supplying and safekeeping of all the in-hospital medicines (2,681
items), out-patient medicines, anesthetics, muscle
relaxation drugs, psychotropic drugs, poison
medicines.

4805) Narcotic section
Under the supervision of authorized manager fornarcotics (the director of the department ofpharmacy), narcotics are properly managed,
recorded, reported, inspected and directed.
Narcotics are properly arranged and managed at
the dispensing section and each medical caresection.
6) Ward section
They contribute to the team medical care byproviding specialized drug information andsharing them with all the staffs involved in thetreatment as follows;① Supporting the proper use of medication bypharmacists stationed at ICU sections.
② Arrangement and mixing of injections forpatients at the staff station of Hematology andOncology.
③ Investigation of carrying medicines and theadverse effect histories, allergy histories etc. at
the time of hospitalization. Participation for
conferences. Procurement and appraisal ofpatients’ basic information about the disease,compilation of the medicine history. Monitoringof medication guidance and the adverse effectfor patients, and compilation of guidance record.
Offering the doctor with drug information,prescription design support and detailed
contents of medication guidance to each patient.
④ Investigation and management of ward stock
medicine.
⑤ Nutrient support of the patients as a member of
NST.
⑥ Management of proper use of narcotics as amember of palliative care team.
⑦ Management of proper use of antibiotics,
rounds of a hospital ward, and training of thestaffs as members of ICT and AST.
Statistical Data (fiscal year 2021)
Number of items on in-hospital formulary: 2,681
Number of prescriptions (ps.) filled or preparation(pp.) (annual)out-patients:
331,929 ps.
(outside :301,517 ps.)(inside :30,412 ps.)out-patient chemotherapy:
12,539 ps.

in-patients :236,172 ps.
injection drugs:
185,108 ps.
IVH:
2,949 pp.
chemotherapy:
11,565 pp.
TDM consultations (annual) :20,788 pp.
Numbers of hospital pharmaceutical cares (annual):
23,311 pp.

Education
The department of pharmacy takes various
responsibilities of education with regard to clinicalpharmacy, pharmacology, and pharmacokinetics forstudents and graduate students in the faculty of
medicine, in the faculty of pharmacy, and in theschool of integrated health sciences. We also have ourown half a year post-graduate training course
optimized for new pharmacists.
For students in the faculty of medicine, we are in
charge of "Pathogenetic and Pathology" as an optionalcourse lecture. We are providing a 3-days practicecourse as a part of compulsory clinical practice for theM3 or M4 students and teach clinical pharmaceutics
and practical knowledge of prescription and risk
management to them. For the students in the healthsciences and nursing, we are in charge of clinicalpharmacokinetics lectures as a part of a compulsory
subject, "Pharmacology and Toxicology".
For students in the faculty of pharmacy, we are in
charge of lectures for the undergraduate students:"Clinical Pharmacy" (compulsory subject). They are
educated for the clinical pharmacology andpharmacokinetics. For the graduate students, we are in
charge of “Special Lecture Basic Pharmaceutical
Science IV”, “Special Lecture Clinical Science”,“Advanced Course of Medical Pharmacy" as acooperator of the Clinical Pharmacokinetics. Recent
trends of the medical pharmacy as well as the practicaldevelopments and future visions of the department ofpharmacy are presented in this lecture. In addition tothem, we accept undergraduate and graduate students
from the faculty of pharmaceutical sciences andfaculty of medicine. They are doing various research
activities.
Six year course education system has been launchedin the field of pharmaceutical sciences since 2006. In
this system, the clinical training by pharmacists at the481

hospital is one of the most important curriculums. In
2021, we accepted clinical training students from The
University of Tokyo, Tokyo University of Pharmacy
and Life Sciences, Showa Pharmaceutical University,
Hoshi University, and Musashino University, Tokyo
University of Science, Keio University and educatedthem for 2.5 months. In addition, we have had an
original one-year post-graduate training course forpharmacists since long time before starting the 6-year
course education system. They learned various
practical knowledge and techniques necessary for
hospital pharmacists. Such education style is still
continuing by shortening the period to half a year. In
2021, 9 pharmacists finished this course.
In addition, we are promoting life-long education ofpharmacists in the local area by holding regular
technical workshops and seminars.

ment of new therapy for bone metabolic disease
based on those integrated understanding.
3. Establishment of the way to quantitative understanding and prediction of pharmacological-effectand adverse-effect of drugs directed against
particular molecular target. Finally, these outputs
would be feedbacked to early drug development
stages.
4. Elucidation of the molecular mechanism related tothe adverse effect of drugs using large-scale“-omics” analysis. Finally, the quantitative information would be applied to develop strategies toprevent / treat the adverse effect.
5. Absolute quantification of factors determining thepharmacokinetic profiles of drugs and its application to clinical pharmacokinetics and pharmacology field.

Research

Publications

It is evident that the molecular function ofparticular element cannot always be assigned to only
one function at whole body level, because one to one
simple correspondence is not common in our body. It
is also true that the understanding of the relationshipbetween drug and its ultimate target is not sufficient topredict the pharmacological/toxicological effects. We
need to understand not only the detailed molecularmachinery of drug target, but also its environment
surrounding the target (ex. other associated proteins,
signaling molecules, etc.), where and when it works,
and finally how it behaves as functional unit in our
body. This is a basic idea trying to understand “livingbody” as “system”. By further promoting this idea to“system pharmacology”, we will be able to identify amolecular target which is related to the pharmacological/toxicological output in clinical situation or evenat early drug development stage. Based on suchconcept, following projects are now ongoing:(1) Kawamura Y, Nakayama A, Shimizu S, Toyoda Y,
Nishida Y, Hishida A, Katsuura-Kamano S, Shibuya
K, Tamura T, Kawaguchi M, Suzuki S, Iwasawa S,
Nakashima H, Ibusuki R, Uemura H, Hara M,
Takeuchi K, Takada T, Tsunoda M, Arisawa K,
Takezaki T, Tanaka K, Ichida K, Wakai K,
Shinomiya N, Matsuo H. A proposal for practical
diagnosis of renal hypouricemia: Evidenced fromgenetic studies of nonfunctional variants of
URAT1/SLC22A12 among 30,685 Japaneseindividuals. Biomedicines. 2021;9:1012.
(2) Mitsuboshi S, Yamaguchi R, Uchida H, Kamoshida
S, Hashi H. Inappropriate use of ozone generatorsand their sales status: Questionnaire survey ofhealthcare providers and investigation of online
sales. J Hosp Infect. 2021;117:1-3.
(3) Nara K, Taguchi A, Tojima Y, Miyamoto Y,
Tanikawa M, Sone K, Mori M, Tsuruga T,
Yamamoto T, Takenaka R, Takada T, Osuga Y,
Suzuki H. History of whole pelvis plus para-aortic
radiation is a risk factor associated with febrileneutropenia during chemotherapy for recurrent
cervical cancer. Int J Clin Oncol. 2021;26:1759-66.
(4) Ogura M, Toyoda Y, Sakiyama M, Kawamura Y,
Nakayama A, Yamanashi Y, Takada T, Shimizu S,
Higashino T, Nakajima M, Naito M, Hishida A,
Kawai S, Okada R, Sasaki M, Ayaori M, Suzuki H,

1. Elucidation of the molecular mechanism which
controls in vivo disposition of lipids / bile acids /uric acid, and establishment of new therapy forlife-style related diseases based on those
integrated understanding.
2. Elucidation of the dynamic regulatory mechanismof bone resorption / bone formation, and establish-

482

(5)

(6)

(7)

(8)

Takata K, Ikewaki K, Harada-Shiba M, Shinomiya
N, Matsuo H. Increase of serum uric acid levels
associated with apoE 2 haplotype: A clinicogenetic investigation and in vivo approach. Hum
Cell. 2021;34:1727-33.
Takaoka R, Soejima Y, Guro S, Yoshioka H, Sato H,
Suzuki H, Hisaka A. Model-based meta-analysis ofchanges in circulatory system physiology in patients with chronic heart failure. CPT Pharmacometrics Syst Pharmacol. 2021;10:1081-91.
Taniguchi T, Omura K, Motoki K, Sakai M,
Chikamatsu N, Ashizawa N, Takada T, Iwanaga T.
Hypouricemic agents reduce indoxyl sulfate excretion by inhibiting the renal transporters OAT1/3 and
ABCG2. Sci Rep. 2021;11:7232.
Toyoda Y, Kawamura Y, Nakayama A, Nakaoka H,
Higashino T, Shimizu S, Ooyama H, Morimoto K,
Uchida N, Shigesawa R, Takeuchi K, Inoue I,
Ichida K, Suzuki H, Shinomiya N, Takada T, Matsuo H. Substantial anti-gout effect conferred bycommon and rare dysfunctional variants of URAT1/
SLC22A12. Rheumatology (Oxford). 2021;60:
5224-32.
Toyoda Y, Pavelcova K, Bohata J, Jesina P, Kubota
Y, Suzuki H, Takada T, Stiburkova B. Identificationof two dysfunctional variants in the ABCG2 uratetransporter associated with pediatric-onset of familial hyperuricemia and early-onset gout. Int J
Mol Sci. 2021;22:1935.

483

Rehabilitation Center
Professor
Toru Ogata, M.D.

Lecturer
Sayaka Fujiwara, M.D.

Research Associate
Haruhi Inokuchi, M.D., Kentaro Morita, M.D.,
Ryoko Sawada, M.D.

Homepage

http://todaireh.umin.ne.jp

Introduction and Organization
The physical therapy service started in 1963 at the
University of Tokyo Hospital, and then expanded toinclude occupational therapy and social work section.
In 1966 this service was converted to the central
rehabilitation service department as a part of theCentral Diagnostic and Therapeutic Service Department. The Central Rehabilitation Service became an
independent unit in 1970. After the reorganization of
the University of Tokyo Hospital according to majororganic classification in 1998, outpatient clinic asrehabilitation medicine was installed. The formal titleof our unit was changed from the Physical Therapy
Department to the Rehabilitation Department by thebudget measures in the fiscal year 2001, and we
integrated the related personnel categories, which
belonged to the orthopedic surgery department and thephysical medicine department.
At present our department consists of four sections.
Rehabilitation physicians’ section includes five fulltime doctors and two other part-time doctors. They
work chiefly for clinical practice in medical
rehabilitation service, but also have to engage inteaching activities for medical students. Nineteen
physical therapists are working in the physical therapy
section. In the occupational therapy section, six
occupational therapists work for the generalrehabilitation service and the other four therapists workfor the psychiatric rehabilitation. Four acupuncture
therapists perform acupuncture and moxbustion. In the
Day-care Unit, clinical psychologists and nurses also
work. In 2006, speech therapists who had belonged toother departments in the University of Tokyo Hospitalwere included in our department. From 2009, a speechtherapist added to our department, and now threetherapists perform therapy for patients with aphasia,
dysarthria, and dysphagia.

Clinical activities
The professor serves as a director of Rehabilitation
Center, the University of Tokyo Hospital. The Rehabilitation Center and the Department of Rehabilitation
Medicine are united and engage in clinical practice. We
have at present no charged ward, and treat about 4,700
new referrals annually from almost all the departmentsof the university hospital. We always take charge of
250-300 patients corresponding about 25-30% of thewhole number of inpatients. We also see 15 people per
day at the outpatient rehabilitation setting. The
numerical ratio of outpatient is being reduced in orderto give priority to the clinical service corresponding toneeds expansion of service to inpatients.

Teaching activities
We have provided several clinical curriculums on
rehabilitation medicine for 4th, 5th, and 6th year

484

medical students since 1973. The systematic lecture
series for 4th year medical students (M2) include thesubjects on rehabilitation for disorders such ascerebrovascular disturbances, respiratory disorders,
neuromuscular diseases, bone and joint diseases, andpediatric disorders as well as on outline of rehabilitation, and amputation/prostheses. We have provided aclinical practice in small group, so-called clinicalclerkship for 5th and 6th year students from Wednesday
to Friday every week. They experience a few patientsand learn how to take a patients’ history, physicalfindings, functional evaluation, and how to plan
rehabilitation programs. We have introduced a few ofelective students for elective clinical clerkship to ourcollaborating hospitals with specialized rehabilitationward.
In addition, we have provided the training ofstudents including physical therapy, occupational
therapy, and speech therapy. Twenty students or morecome and stay at the university hospital annually as along-term clerkship from several PT/OT/ST training
schools.

References
1.

2.

3.

4.

Research activities
Our research activities are growing up. In 2006, theRehabilitation Center moved to the new building and a
research laboratory was provided for the first time. As
the motion analysis system was partially renewed, weare planning our researches mainly in the field ofmusculoskeletal disabilities. In addition, we areplanning collaborating researches with other departments in our hospital, other faculties in our university,and institutions outside the University of Tokyo. The
ongoing and scheduled projects are as follows.
1) 3D Motion analysis of patients with musculoskeletal disorders
2) Study on the relationship between sensory deficit
and motor control
3) Rehabilitation and long-term outcome in patientswith skeletal dysplasias
4) Pathology and treatment for patients withcongenital limb deficiencies
5) Analysis of rehabilitation outcome using DPC data

5.

6.

7.

Kojima T, Ishikawa H, Tanaka S, Haga N, Nishida
K, Yukioka M, Hashimoto J, Miyahara H, Niki Y,
Kimura T, Oda H, Asai S, Funahashi K, Kojima M,
Ishiguro N: Validation and establishing targets forthe physician-based clinical scale for foot and ankle
surgery in patients with long-standing rheumatoid
arthritis based on patient-reported outcomes:
Results from a multicenter prospective
observational cohort study to evaluate the efficacy
of joint surgery in the treat-to-target era. Mod
Rheumatol, Online ahead of print
Mano H, Fujiwara S, Haga N: Body knowledge inchildren with congenital upper limb deficiency.
Brain Nerve 72(4): 445-451, 2020
Mano H, Fujiwara S, Haga N: Effect of prostheseson children with congenital lower limb deficiencies.
Pediatr Int 62: 1039-1043, 2020
Mano H, Fujiwara S, Takamura K, Kitoh H,
Takayama S, Ogata T, Haga N: Treatment
approaches for congenital transverse limb
deficiency: Data analysis from an epidemiologicalnation survey in Japan. J Orthop Sci, Online aheadof print
Matsuoka M, Tsukamoto S, Orihara Y, Kawamura
R, Kuratani M, Haga N, Ikebuchi K, Katagiri T:
Design of primers for direct sequencing of nine
coding exons in the human ACVR1 gene. Bone138: 115469, 2020
Matsushita M, Mishima K, Yamashita S, Haga N,
Fujiwara S, Ozono K, Kubota T, Kitaoka T,
Ishiguro N, Kitoh H: Impact of fracture
characteristics and disease-specific complications
on health-related quality of life in osteogenesis
imperfecta. J Bone Miner Metabol 38(1): 109-116,
2020
Pignolo RJ, Cheung K, Kile S, Fitzpatrick MA, De
Cunto C, Al Mukaddam M, Hsiao EC, Baujat G,
Delai P, Eekhoff EMW, Di Rocco M, Grunwald Z,
Haga N, Keen R, Levi B, Morhart R, Scott C,
Sherman A, Zhang K, Kaplan FS: Self-reported
baseline phenotypes from the International
Fibrodysplasia Ossificans Progressiva (FOP)
Association Global Registry. Bone 134: 115274,
2020

485

8.

9.

10.

11.

12.

13.

Sawada R, Yamana H, Shinoda Y*, Tsuda Y, Matsui
H, Fushimi K, Kobayashi H, Matsubayashi Y,
Yasunaga H, Tanaka S, Haga N: Predictive factorsof 30-day mortality after surgery for spinal
metastasis: Analysis of a nationwide database. J
Orthop Sci S0949-2658(20)30208-6, 2020, Online
ahead of print
Shinoda Y, Sawada R, Ishibashi Y, Akiyama T,
Zhang L, Hirai T, Oka H, Ohki T, Ikegami M,
Okajima K, Okuma T, Kobayashi H, Goto T, Haga
N, Tanaka S: Prediction of pathological fracture inpatients with lower limb bone metastasis using
computed tomography imaging. Clin Exp
Metastasis 37(5): 607-616, 2020
Takeda J, Nanatsue K, Yamagishi R, Ito M, Haga N,
Hirata H, Ogi T, Ohno K: InMeRF: Prediction ofpathogenicity of missense variants by individualmodeling for each amino acid substitution. NAR
Genom Bioinform 2(2):lqaa038,2020
Taya M, Hatano M, Saito A, Nitta D, Maki H,
Hosoya Y, Minatsuki S, Tsuji M, Sato T, Murakami
H, Narita K, Konishi Y, Watanabe S, Yokota K,
Haga N, Komuro I: Clinical importance of
respiratory muscle fatigue in patients withcardiovasculardisease.
Medicine(Baltimore)
99(34): e21794, 2020
Umezaki S, Shinoda Y, Mukasa A, Tanaka S,
Takayanagi S, Oka H, Tagawa H, Haga N, Yoshino
M: Factors associated with health-related quality oflife in patients with malignant glioma: Impact ofsymptoms and implications for rehabilitation. Jap J
Clin Oncol 50(9): 990-998, 2020
Haga N, Nakashima Y, Kitoh H, Kamizono J,
Katagiri T, Saijo H, Tsukamoto S, Shinoda Y,
Sawada R, Nakahara Y: Fibrodysplasia ossificans
progressiva: review and research activities in Japan.
Pediatr Int 62: 3-13, 2020

486

Central Supply Service
Professor
Kazuhiko Fukatsu, M.D., Ph.D.
Lecturer
Satoshi Murakoshi, M.D., Ph.D.

Assistant Professor
Hiroshi Ookawa

Homepage

http://www.cc.h.u-tokyo.ac.jp/mulins/zairyobu/

Introduction
Central supply service is an integrated place in thehospital for cleaning and sterilization of previously
used devices. All re-usable devices are transported toour division via automated guided vehicle system fromsurgical center, ward and outpatient clinics. The used
instruments are cleaned using standard precautionary
procedures, disinfected, reassembled, packaged, andsterilized. The sterilized instruments are then placed at
designated sites for use.
One professor and one assistant professor, one
nurse, one 8 staff members, and 26 members fromexternal staff sources are the main members of thisdivision.

Facilities
The following facilities are located in an area of
1,077 square meters:
Cleaning equipment: 7 washer disinfectors (WDs), 1
vacuum-ultrasonic cleaning unit, 1 decompression
boiling washer
Drying equipment: 5 system drying units.
Sterilizing equipment: 6 autoclaves, 1 hydrogen
peroxide plasma sterilizer, 1 hydrogen peroxide
sterilizer, 1 low temperature steam formaldehyde
sterilizer.

Activities
Used devices are cleaned with automated washer

disinfectors and/or manual washing, then packaged
carefully into container sets or paper bags. The
packaged materials are sterilized with autoclaves,
ethylene oxide gas sterilizer or hydrogen peroxide
plasma sterilizer according to their characteristics. The
cleaning procedure is checked with test device. All
sterilization process is recorded and ensured bychemical indicators and biological indicators.
Performance validation is also carried out for autoclavesterilization.
The number of devices handled in the central
supply service is dramatically increasing withincreased number of operations in the surgical centers.
Staffs of central supply service have also worked
for re-counting of used surgical devices on surgicalcenter floor since 2011. The work has contributed
towards risk management in the hospital.
Staffs also join infection control team round andperiodically count device number in each ward forappropriate management of medical devices.

Research activities
To establish more efficient procedures forcleaning, intensive trials have been performed and thedata have been presented at academic conferences.
Moreover, basic research on host response to surgicalinsult is another theme of our division. The research isimportant for improving outcome of surgical patientsand our data have been published as original articles

487

Department of Pathology
Director
Tetsuo Ushiku, M.D., Ph.D. (Professor, Department of Pathology and Diagnostic Pathology)

Deputy Director
Masako Ikemura, M.D., Ph.D. (Lecturer, Office for “Promotion of CPC Education andGeneral Integrative Medicine”)
Aya Shinozaki-Ushiku, M.D., Ph.D. (Associate Professor, Division of Integrative Genomics)

Project Professor
Takeshi Sasaki, M.D., Ph.D. (Next-Generation Pathology Information Networking)Lecturer
Mariko Tanaka, M.D., Ph.D.
Yoko Tateishi, M.D., Ph.D (~May 31), Hiroyuki Abe, M.D., Ph.D. (Department of Pathology
and Diagnostic Pathology)

Research Associate
Naoko Yamauchi, M.D., Ph.D. (~May 31, Hospital Lecturer),
Hirofumi Rokutan, M.D., Ph.D., Ryohei Kuroda, M.D., Ph.D. (Oct 1~), Masaki Suzuki,
Munetoshi Hinata, M.D., Ph.D., Sho Yamazawa, M.D., Ph.D.
Naohiro Makise, M.D., Ph.D., Akiko Iwasaki, M.D., Ph.D., Mayu Hakozaki, M.D., Ph.D.
(Department of Pathology and Diagnostic Pathology)
Yoichi Yasunaga, M.D., Ph.D. (~Nov 30, Project Research Associate, "Tsunagu"Fukushima-Kanto Pathology- Forensic Pathology Cooperation Program, Dec 1~,
Department of Pathology and Diagnostic Pathology)

Homepage http://pathol.umin.ac.jp/
Introduction and Organization
Department of Pathology and Diagnostic Pathology
and Department of Pathology of the University ofTokyo Hospital have been organized to function as aunit to perform pathology practice (autopsy, surgicalpathology, cytology, molecular testing, etc.) at the
University of Tokyo Hospital as well as education andresearch on human pathology.
We set up Telepathology & Remote Diagnosis

Promotion Center (TRDP Center) in 2013. We also
started Outpatient Clinic of Pathology to provide
detailed information and explanation about pathologic
diagnosis to the patients with breast cancer.
In February 2018, the University of Tokyo
Hospital was selected as one of the core hospitals to
promote cancer genomic medicine in Japan. From
August 2018 to December 2019, the advanced medicalcare (category B) named ‘Trial of a multiplex genomic
testing by "Todai OncoPanel" for Geneprofiling of

488

malignant solid tumors’ was conducted which enrolled
200 patients. In addition, cancer panel testing coveredby public health insurance (NCC Oncopanel andFoundationOne CDx) started in November 2019. We
serve as members of expert panel to contribute to thepromotion of genomic medicine.

Clinical activities(diagnostic pathology and autopsy)
The annual statistics of the pathology practice in 2021
fiscal year consisted of 17,434 surgical cases, 15,098
cytology, 824 intraoperative histologic diagnosis, 372
intraoperative cytology, 33 autopsy cases (autopsy rate,
10.4%). The numbers of surgical and cytology cases
returned to those before COVID-19 pandemic, while
the numbers of intraoperative diagnosis and autopsy
cases remained small due to the pandemic. Fortunately,
there was no need to limit activity in our department
The following surgical pathology conferences are
regularly held; thoracic organs (Drs. ShinozakiUshiku, Suzuki and Hinata in charge), liver andpancreato-biliary tract (Drs. Yamauchi,Tanaka andRokutan), liver metastasis (Dr. Abe), and female
genital tracts (Drs. Ikemura and Iwasaki), breast (Dr.
Ikemura), hematology (Dr. Shinozaki-Ushiku), boneand soft tissues (Drs. Ushiku and Yasunaga), kidney(Drs. Abe and Hinata), and skin (Dr. Tanaka).
We provide FFPE specimens suitable formultiplex genomic testing. We also join clinicopathologic and genomic conference which is held
every week to present histology of the cases and join
the discussion. Conventional companion diagnoses
using immunohistochemistry and FISH are also
provided.
Our mission is to provide the correct diagnosis assoon as possible. We also perform double check byreviewing the reports and slides of all cases to assure
the quality of pathologic diagnosis. Whole slide
imaging system have been installed, which enabled us
to deposit and review all the biopsy specimens as
digital information in daily practice.
We hold autopsy case conferences every Monday.
Hospital clinico-pathologic conferences (CPC) arealso held every month, in which two cases are
discussed. The contents are provided as CPC Digest
through the hospital internet.

Teaching activities
The lectures and exercise course of systemic
pathology are for the 2nd grade medical students.
Clinical Clerkship (CC) courses of autopsy andsurgical pathology are for the 3rd and 4th grade medical
students. We accepted several medical students inElective Clerkship course as well as Free Quarter
program.
We instructed all clinical residents (junior course)
to submit a report of CPC case as an obligatory
requirement of their medical training. We have madeout the digest version of CPC slides open in thehospital and started e-learning program for interns tosolve the problems in CPC by themselves, thereby
facilitating their understanding.
The Department of Pathology accepted sevenjunior residents (total 16 months) in 2021 for theirfirst and second-year program.

Research activities
We are working on the pathologic research projects ofneoplastic diseases based on observation obtained
from pathologic diagnosis as well as discussion withclinicians at surgical pathology conferences.
To develop AI-based pathology diagnosis system,some projects are currently in progress. Dr. Abe
focuses on gastrointestinal tract biopsy diagnosis
using machine learning. Dr. Hinata has developed an
automatic system to detect immunotherapy-sensitive
subtype in gastric cancer using histologic image-based
deep learning.
The development of automatic grossing andsectioning system using AI-equipped robot is also inprogress as collaborative research with engineering
faculty-of the University of Tokyo (Prof. Mamoru
Mitsuishi).
We continue the study to investigate the usefulness of post-mortem CT images for hospital autopsy
in collaboration with the department of radiology. We
obtain post-mortem images with a CT apparatus in the
autopsy-assisting CT room and compare the resultswith those of autopsy to better understand thepatients’ pathophysiology.
In addition, a lot of collaborative research
projects are also being conducted with various
departments and laboratories.

489

References

8.

(Only case reports are provided here. Original articles
are included in the section of “Department Pathology
and Diagnostic Pathology”)
1.

2.

3.

4.

5.

6.

7.

Ando T, Kage H, Shinozaki-Ushiku A, Tatsuno
K, Tsutsumi S, Nagayama K, Nakajima J,
Kohsaka S, Miyagawa K, Aburatani H, Mano H,
Nagase T. Composite Clonal Analysis Reveals
Transition of NSCLC Subtypes ThroughAccumulation of Gene Mutations: A Case Report.
JTO Clin Res Rep. 2022;3(2):100277.
Ideyama M, Abe H, Mori K, Yamagata Y, Seto Y,
Ushiku T. Acquired mini-stomach developmentin the esophagus after caustic injury. Pathol Int.
2021;71(11):792-794.
Ishigami D, Miyawaki S, Nakatomi H,
Takayanagi S, Teranishi Y, Ohara K, Hongo H,
Dofuku S, Kin T, Abe H, Mitsui J, Komura D,
Katoh H, Ishikawa S, Saito N. Brainstem
intraparenchymal schwannoma with genetic
analysis: a case report and literature review.
BMC Med Genomics. 2021;14(1):205.
Kaneko M, Nozawa H, Rokutan H, Murono K,
Ushiku T, Ishihara S. Ectopic decidua of theappendix: a case report. Surg Case Rep. 2021;
7(1):117.
Kato S, Kubota Y, Sekiguchi M, Watanabe K,
Shinozaki-Ushiku A, Takita J, Hiwatari M.
KMT2A-rearranged
diffuselarge
B-celllymphoma in a child: a case report and molecularcharacterization. Pediatr Hematol Oncol. 2021;
38(3):281-289.
Kobayashi H, Makise N, Shinozaki-Ushiku A,
Ishibashi Y, Ikegami M, Kohsaka S, Ushiku T,
Oda K, Miyagawa K, Aburatani H, Mano H,
Tanaka S. Scapular Angiomatoid Fibrous
Histiocytoma with EWSR1-CREB1 Fusion in an
Adult Patient. Case Rep Orthop. 2021;2021:
9434222.
Makise N, Yoshida KI, Iijima T, Yoshida A,
Ushiku T, Ishida T. Skeletal EWSR1-NFATC2
sarcoma previously diagnosed as Ewing-likeadamantinoma: A case report and literature
review emphasizing its unique radiologicalfeatures. Pathol Int. 2021;71(9):614-620.

9.

10.

11.

12.

13.

14.

Murakami D, Maki H, Matsuda K, Masamoto Y,
Suzuki F, Amemiya S, Osawa K, Hinata M,
Ikemura M, Ushiku T, Kurokawa M. Cerebral
toxoplasmosis complicating lymphoplasmacytic
lymphoma in partial remission. J InfectChemother. 2022;28(2):279-282.
Nakazaki K, Yoshida M, Masamoto Y,
Shinozaki-Ushiku A, Ikemura M, Hisamoto T,
Yasunaga M, Sato S, Kurokawa M. Discordant
lymphomas of classic Hodgkin lymphoma andperipheral T-cell lymphoma following dupilumab
treatment for atopic dermatitis. Int J Hematol.
2022;Epub ahead of print.
Ohki D, Tsuji Y, Yamazawa S, Ushiku T,
TateishiK.
Gastrointestinal:
Esophageal
adenocarcinoma arising from circumferential
ectopic gastric mucosa: A case report. J
Gastroenterol Hepatol. 2022;37(1):47.
Sakamoto A, Nozawa H, Sonoda H, Hinata M,
Ishii H, Emoto S, Anzai H, Yokoyama Y,
Murono K, Sasaki K, Kawai K, Ushiku T,
Ishihara S. Rectal neuroendocrine tumor withextracapsular lymph node metastasis: a casereport. Clin J Gastroenterol. 2021;14(5):14261430.
Sasaki K, Honda A, Shinozaki-Ushiku A, Fujioka
Y, Maki H, Toyama K, Ushiku T, Kurokawa M.
A case of transplantation-associated thrombotic
microangiopathy with autopsy-proven fatal
myocardialischemia
after
allogeneic
hematopoietic stem cell transplantation. Ann
Hematol. 2021;100(6):1621-1622.
Sone K, Inoue F, Taguchi A, Hinata M, Ikemura
M, Miyamoto Y, Michihiro T, Ohno T, Iriyama T,
Mori-Uchino M, Tsuruga T, Mishima M, Osuga
Y. A case of difficult-to-diagnose non-invasive
papillary squamous cell carcinoma of the uterine
cervix infected with human papilloma virus 6: A
diagnostic pitfall. Clin Case Rep. 2021;9(10):e04905.
Sone K, Kukita A, Masui Y, Yamada D,
Shinozaki-Ushiku A, Kawata A, Taguchi A,
Miyamoto Y, Tanikawa M, Iriyama T,
Mori-Uchino M, Tsuruga T, Osuga Y. Recurrent
malignant melanoma of the uterine cervix treatedwith anti-PD-1 antibodies and anti-CTLA-4

490

15.

16.

17.

18.

19.

20.

21.

antibodies: A case report. Mol Clin Oncol. 2022;
16(3):63.
Suzuki S, Kurokawa R, Tsuruga T, Mori-Uchino
M, Nishida H, Kato T, Abe H, Ushiku T,
Amemiya S, Katayama A, Abe O. CT, MRI, and
FDG-PET imaging findings of low-grade
extrauterine endometrial stromal sarcoma arisingfrom the mesentery:A case report. Radiol Case
Rep. 2021;16(9):2774-2779.
Tachikawa Y, Nozawa H, Hata K, Abe H, Ushiku
T, Ishihara S. Metachronous ileal cancer after
surgery for ascending colon cancer in a patientwith Lynch syndrome: A case report. Int J Surg
Case Rep. 2021;81:105714.
Taguchi A, Rokutan H, Oda K, Tanikawa M,
Tanimoto S, Sone K, Mori M, Tsuruga T,
Kohsaka S, Tatsuno K, Shinozaki-Ushiku A,
Miyagawa K, Mano H, Aburatani H, Ushiku T,
Osuga Y. Genetic diagnosis of pseudomyxoma
peritonei originating from mucinous borderline
tumor inside an ovarian teratoma. BMC Med
Genomics. 2022;15(1):51.
Takamiya A, Ishibashi Y, Makise N, Hirata M,
Ushiku T, Tanaka S, Kobayashi H. Imaging
characteristics of NTRK-rearranged spindle cell
neoplasm of the soft tissue: A case report. J
Orthop Sci. 2022;S0949-2658(21)00367-5.
Tsuda Y, Kobayashi H, Makise N, Zhang L,
Shinoda Y, Ushiku T, Tanaka S. Hemangioma of
the Rib Mimicking Chondrosarcoma: A Report of
Two Cases and Literature Review. Case Rep
Orthop. 2021;2021:9996380.
Tsuzuki S, Komai T, Terada K, Tsuchida Y,
Tanaka M, Tateishi Y, Shinozaki-Ushiku A,
Shoda H, Fujio K. Nailfold capillaroscopic
abnormalities in angioedema with eosinophilia.
Allergol Int. 2021;70(4):501-503.
Yamamoto A, Tateishi Y, Aikou S, Seto Y,
Ushiku T. The first case of gastricleiomyosarcoma developed through malignant
transformation of leiomyoma. Pathol Int. 2021;
71(12):837-843.

491

Department of Corneal
Transplantation
Professor
Makoto Aihara, M.D., Ph.D.

Lecturer
Takashi Miyai, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/kakumaku.html

Introduction and Organization
The department of corneal transplantation wasestablished in 1976 as one of clinical sections in the
University of Tokyo Hospital. The purpose of theestablishment of this section is to carry out and promotecorneal transplantation and to perform clinical andbasic research in the corneal diseases and corneal
transplantation. The section is composed of two
members (Professor Makoto Aihara, Lecturer Takashi
Miyai).

Clinical activities
The clinical activities of this section include corneal
transplantation and outpatient clinics for various
corneal diseases as a consulting corneal service. The
members are responsible not only for corneal transplantation but also for general ophthalmologicalpractice as a senior staff member of Department ofOphthalmology, University of Tokyo. The corneal
service for special cases is held every Monday (PM),Wednesday (AM), Thursday (AM), and Friday (AM).
Keratoconus clinic for providing corneal crosslinking
surgery, which is a brand-new treatment to halt
keratoconus progression, were held in the afternoon ofThursday. Special contact lens clinic for keratoconus
and post-keratoplasty eyes were in the afternoon of thesecond and fourth Thursday. At the corneal service, we
determine indication for corneal transplantation andfollow up patients after the surgery. Total 71 corneal

surgeries including keratoplasty were performed in
2021. In addition to the full-thickness corneal
transplantation (penetrating keratoplasty), we havesuccessfully performed corneal endothelial transplantation for patients with bullous keratopathy, themost common disease of corneal transplantation.
Generally, corneal transplantation is performed as
emergency operation, because we need to transplant
corneas as soon as possible.
The other important activities of the section include
mediation of donor eyes to other university hospitals
and medical institutes that need donor eyes for corneal
transplantation with cooperation of Eyebank. We arealso performing corneal transplantation using corneas
from American Eyebank as needed.
Followings are our main clinical themes to be
pursued to improve the safety and prognosis of corneal
transplantation.
1) Positive proof that donors were free of such
infectious diseases as viral hepatitis, syphilis,
AIDS and acute T-cell leukemia to prevent
transmission to recipient patients through grafting.
2) Postoperative clinical outcomes are evaluated inregenerative medicine for ocular surface
reconstruction, such as cultured corneal limbal,
oral mucosal and conjunctival epithelial sheettransplantation on the amniotic membrane, fullthickness corneal transplantation, lamellar keratopasty, and endothelial keratoplasty.
3) Critical factors to affect clinical outcomes are492

statistically investigated in various kinds of corneal
operation technique.

Teaching activities
We give lectures on corneal diseases and corneal
transplantation to medical students and practitioners. In
addition, we are engaged in practical training for young
ophthalmologists on ophthalmological examinations at
the outpatient clinic.

Research activities
We are conducting clinical research of postoperative
results of DSAEK, clinical results of corneal
crosslinking, and clinical research of corneal biometryby using anterior segment OCT.
In addition, we are investigating genetic analysis andgenome editing research for corneal dystrophy. And weare also conducting research to elucidate the pathology
using corneal transplant specimens.

References
1:

2:

3:

Yamamoto R, Ono T, Toyono T, Shirakawa R,
Noda M, Yoshida J, Miyai T. Assessment ofLong-Term Anterior and Posterior Topographic
Changes in the Cornea After Ptosis Surgery Using
Fourier Harmonic Analysis. Cornea. 2021 Apr;
40(4):440-444. doi:10.1097/ICO.000000000000
2429. PMID: 33881809.
Nakagawa S, Ishii H, Takamoto M, Kaburaki T,
Ishii K, Miyai T. Diagnosis of cytomegalovirus
corneal endotheliitis using surgically removed
Descemet's membrane and endothelium despite
negative results with aqueous humor PCR: a casereport. BMC Ophthalmol. 2021 May 1;21(1):194.
doi: 10.1186/s12886-021-01962-y. PMID: 33933
006; PMCID: PMC8088667.
Ueda K, Ono T, Toyono T, Yoshida J, Kaburaki T,
Miyai T. Descemet stripping endothelial keratoplasty after cytomegalovirus corneal endotheliitis
and immunosuppression for Mooren's ulcer. Am J
Ophthalmol Case Rep. 2021 Apr 14;22:101088.
doi:10.1016/j.ajoc.2021.101088. PMID:33937582;
PMCID: PMC8079431.

4:

Omoto T, Agata C, Akiyama R, Kitamoto K,
Toyono T, Yoshida J, Yamagami S, Usui T, Miyai
T. Iridotrabecular and Iridocorneal Contact
Changes after Cataract Surgery and Endothelial
Keratoplasty in Bilateral Iridoschisis. Case Rep
Ophthalmol. 2021 Apr 12;12(1):198-203. doi:
10.1159/000513793. PMID: 33976682; PMCID:
PMC8077475.
5: Takahashi S, Ono T, Abe K, Mori Y, Nejima R,
Iwasaki T, Miyai T, Miyata K. Prognosis andetiology of traumatic and non-traumatic corneal
perforations in a tertiary referral hospital: a 30year retrospective study. Graefes Arch Clin Exp
Ophthalmol. 2022 Feb;260(2):629-635. doi:
10.1007/s00417-021-05389-5. Epub 2021 Sep 1.
PMID: 34468830.
6: Ono T, Mori Y, Nejima R, Iwasaki T, Miyai T,
Aihara M, Miyata K. Comparison of Corneal
Irregularity After Recurrent and Primary
Pterygium Surgery Using Fourier Harmonic
Analysis. Transl Vis Sci Technol. 2021 Sep 1;10(11):13. doi: 10.1167/tvst.10.11.13. PMID:
34515760; PMCID: PMC8444459.
7: Ono T, Mori Y, Nejima R, Iwasaki T, Miyai T,
Miyata K. Corneal endothelial cell density andmorphology in ophthalmologically healthy young
individuals in Japan: An observational study of16842 eyes. Sci Rep. 2021 Sep 14;11(1):18224.
doi:
10.1038/s41598-021-97776-5.
PMID:
34521951; PMCID: PMC8440503.
8: Kamiya K, Ayatsuka Y, Kato Y, Shoji N, Miyai T,
Ishii H, Mori Y, Miyata K. Prediction of
keratoconus progression using deep learning ofanterior segment optical coherence tomography
maps. Ann Transl Med. 2021 Aug;9(16):1287.
doi: 10.21037/atm-21-1772. PMID: 34532424;
PMCID: PMC8422102.
9: Ono T, Mori Y, Nejima R, Iwasaki T, Miyai T,
Ohtani S, Miyata K. Corneal Edema with Anterior
Uveitis after Exposure to the Sap of Euphorbia
trigona: A Case Report. Case Rep Ophthalmol.
2021 Aug 6;12(2):699-705. doi: 10.1159/
000517742. PMID: 34594207; PMCID: PMC
8436689.
10: Miyoshi Y, Ono T, Seki S, Toyono T, Kitamoto K,
Hayashi T, Usui T, Aihara M, Miyai T. Corneal

493

11:

12:

13:

14:

Graft Rejection after Descemet's Membrane
Endothelial Keratoplasty with Peripheral Anterior
Synechiae. Case Rep Ophthalmol. 2022 Jan
31;13(1):17-22. doi: 10.1159/000520877. PMID:
35221975; PMCID: PMC8832220.
Ishii H, Yoshida J, Toyono T, Yamagami S, Usui
T, Miyai T. Three-year results of accelerated
transepithelial cross-linking (30 mW/cm2 × 3min) for keratoconus: a prospective study. BMJ
Open Ophthalmol. 2022 Feb 8;7(1):e000827. doi:
10.1136/bmjophth-2021-000827. PMID: 35224204;
PMCID: PMC8830257.
Inamochi A, Miyai T, Usui T, Aihara M,
Yamagami S. Effects of corneal epithelial
superficial keratectomy in patients with focal
limbal stem cell disease. Am J Ophthalmol Case
Rep. 2021 Dec 7;25:101239. doi: 10.1016/j.ajoc.
2021.101239. PMID: 34917856; PMCID: PMC
8666511.
Ono T, Takahashi S, Mori Y, Nejima R, Iwasaki
T, Kataoka Y, Miyai T, Miyata K. Severe
fishhook-related ocular injury: A case series.
Trauma Case Rep. 2021 Dec 8;37:100574. doi:
10.1016/j.tcr.2021.100574. PMID: 34917740;
PMCID: PMC8666537.
Abe K, Miyai T, Toyono T, Aixinjueluo W, Inoue
T, Asano S, Ishii H, Yoshida J, Shirakawa R, Usui
T. Comparison of efficacy and safety ofaccelerated trans- epithelial crosslinking for
keratoconus patients with corneas thicker andthinner than 380μm. Curr Eye Res. 2022 Apr;
47(4):511-516. doi: 10.1080/02713683.2021.
2018466. Epub 2021 Dec 27. PMID: 34898348.

494

Department of Cell Therapy andTransplantation Medicine
Professor
Mineo Kurokawa, M.D., Ph.D. (Hematology-Oncology)

Lecturer
Mitsuteru Hiwatari, M.D., Ph.D. (Pediatrics/Hematology-Oncology)

Assistant Professor
Junji Tokushige, M.D., Ph.D. (Hematology-Oncology)

Homepage

http://www.h.u-tokyo.ac.jp/mukin/

Introduction and Organization
The Department of Cell Therapy and Transplantation Medicine was institutionally established in
1995, and was formally organized in 1996. At present,
the staff consists of the above-mentioned medical
doctors. Clinical facilities include 8 single-patient
rooms with high- efficiency particulate air filtrationand other high standards. Patients who are eligible forthe treatment with high-grade infectious prophylaxis
are admitted to the facilities.

Clinical activities
Approximately 1100 patients have undergone
hematopoietic stem cell transplantation (HSCT) in our
department since 1995. Allogeneic bone marrowtransplantation from donors Japan Marrow Donor
Program (JMDP) as well as international bone marrowdonor programs, HSCT from HLA-mismatcheddonors, and donor lymphocyte infusion are available.
In 2021, 17 patients (including 1 children) received
autologous HSCT and 29 patients (including 5children) allogeneic HSCT. We cooperate with themembers of Department of Hematology and Oncology,
Hematology/Oncology group in the Department ofPediatrics, and Department of Transfusion Medicine.
Allogeneic hematopoietic stem cell transplantation:

Bone marrow cells are operatively harvested andinfused without preservation. For peripheral blood
stem cell transplantation, leukapheresis is performed
with the use of an automated continuous flow blood
cell separator, and harvested cells are preserved at-196°C in cooperation with Department of Transfusion Medicine. Recently, transplantation after preconditioning of reduced intensity (RIST for reducedintensity HSCT or NST for non-myeloablative HSCT)
is commonly performed for the elderly and patientswith organ dysfunction. The development of thisstrategy is expanding the eligibility of transplant
recipients.
Some patients cannot get transplantation treatment
because they don’t have eligible donors with at least a
90% match of HLA. Recently, with the developmentof new methods of transplantation management, suchas immunosuppression, it has become possible tosafely carry out transplants from donors with a 50%
HLA match(HLA haploidentical transplantation; haplotransplants), and the procedure is expected to spread
more widely in the future. The department proactively
performs haplo transplants for patients in need toovercome diseases.
Allogeneic HSCT for the elderly and HLA
haploidentical transplantation are performed under theadmission of Patient Relations and Clinical Ethics
Center.

495

High-dose chemotherapy with or without autologous stem cell support: High-dose chemotherapy isadministered according to the malignant disease. For
the autologous stem cell support, peripheral blood
stem cell is usually selected as a source of stem cells.
Similar procedures used in the allogeneic stem cell
harvest are performed for leukapheresis and preservation of autologous stem cell. Malignant lymphomasarising from the central nervous system (brain andspinal cord) are known to be refractory to treatment
and have a poor prognosis. Recently, chemotherapy
including autologous HSCT has been used to treat thisdisease with good efficacy. In our department, we are
striving to improve the prognosis of patients with CNS
malignant lymphoma by providing treatment
including autologous transplantation.
Clinical conference for hematopoietic stem celltransplantation: The conference is held monthly. The
members of Department of Hematology and Oncology,
Hematology/Oncology group in Department ofPediatrics, and Department of Transfusion Medicine
join the conference and discuss on HSCT recipients.

poietic cells. In the area of pediatric oncology, we
continue the studies on molecular mechanisms ofpediatric malignancies such as neuroblastoma,
rhabdomyosarcoma, and infant leukemia.

References
1.

2.

3.

Teaching activities
Together with the members of Department of
Hematology and Oncology and Hematology/Oncology
group in the Department of Pediatrics, lecture courses
on etiology, pathogenesis, clinical and laboratory
features, differential diagnosis, therapy and prognosis
for all hematological diseases are provided to thesecond grade medical students. Clinical clerkshipcourses are given to the third grade medical students,
who join the patient care teams consisting of juniorand senior medical doctors and learn medical practices
and patient management, through playing a role as a
junior member of the team, as well as throughdiscussions and presentations.

4.

5.

Research activities
The major research projects are focused on clinicalstudies such as development of improved/new
methods for hematopoietic stem cell transplantation,
immunotherapy for hematopoietic malignancies, andbasic studies on hematopoietic stem cells, leukemogenesis and regenerative medicine using hemato-

6.

Sasaki K, Honda A, Shinozaki-Ushiku A, Fujioka
Y, Maki H, Toyama K, UshikuT, and Kurokawa
M. A case of transplantation-associatedthrombotic microangiopathy with autopsy-provenfatal myocardial ischemia after allogeneic
hematopoietic stem cell transplantation. Annals
of Hematology, 100(6): 1621-1622,2021.
Yasunaga M, Yasuda Y, Honda A, Maki H,
Toyama K, Masamoto Y, Bujo C, Amiya E,
Hatano M, Ono M, Komuro I, and Kurokawa M.
Successful treatment of EBV-related lymphoproliferative disease after heart transplantation
with autologous hematopoietic stem celltransplantation despite transient heart failure
associated with engraftment syndrome. Annals
of Hematology 100(4):1097-1100, 2021.
Oyama Y, Yasunaga M, Honda A, Maki H,
Masamoto Y, Kobayashi T, Wakabayashi Y,
Okugawa S, Moriya K, and Kurokawa M.
Severe cellulitis caused by Achromobacter
xylosoxidans after allogeneic hematopoietic stem
cell transplantation. Journal of Infection andChemotherapy 27(5): 770-772, 2021.
Sato M, Honda A, Maki H, Toyama K,
Yamaguchi R, Ikeda M, Moriya K, andKurokawa M.
Successful treatment ofpneumonia caused by multidrug-resistantPseudomonas aeruginosa after allogeneic
hematopoietic stem cell transplantation withcolistin and amikacin inhalation therapy.
Journal of Infection and Chemotherapy, 28(1):91-94, 2022.
Ebisawa K, Honda A, Chiba A, Masamoto Y,
Okazaki H, and Kurokawa M. High D-index
during mobilization predicts poor mobilization of
CD34+ cells after anti-lymphoma salvage
chemotherapy. Journal of Clinical Apheresis,37(1):4-12, 2022.
Kawahara Y, Morimoto A, Inagaki J, Koh K,
Noguchi M, Goto H, Yoshida N, Cho Y, Hori T,496

Hiwatari M, Kato K, Ogawa A, Hashii Y, Inoue
M, Kato K, Atsuta Y, Kimura F, Kato M.
Unrelated cord blood transplantation withmyeloablative conditioning for pediatric acutelymphoblastic leukemia in remission: prognostic
factors. Bone Marrow Transplant. 56(2): 357-367,
2021

497

Department of Endoscopy andEndoscopic Surgery
Associate Professor
Yousuke Nakai, M.D., Ph.D.

Assistant Professor
Ryunosuke Hakuta, M.D., Ph.D.

Homepagehttps://www.h.u-tokyo.ac.jp/patient/depts/kougaku/

Introduction and Organization
Department of Endoscopy and Endoscopic Surgery
were established in April 1997. Although the present
regular staffs of our department include only two
doctors, about 80 doctors from other departments
including the department of gastroenterology,
gastrointestinal surgery, surgical oncology, respiratory
medicine, thoracic surgery, gynecologic oncology andotorhinolaryngology, perform endoscopic procedures.

Clinical activities
Endoscopic procedures, including upper gastrointestinal endoscopy, colonoscopy, bronchoscopy,
otorhinolaryngological endoscopy and gynecologicalendoscopy, are performed from Monday to Friday.
Emergency endoscopy is performed in the nighttime
or holidays. The numbers of endoscopic procedures ineach field are increasing gradually year by year andthe total number during 2016 reached to 20,000. In thegastrointestinal tract, image enhanced endoscopy fordetailed inspection and therapeutic endoscopy,
including endoscopic submucosal dissection foresophageal, gastric and colorectal tumors, are majoradvanced fields. In addition, endoscopic diagnosis andmanagement of pancreatobiliary diseases is also
performed. Our recent clinical activities are

summarized in Table 1.
Another important activity of our department is thedisinfection and maintenance of endoscopic
apparatuses used in other units including theoutpatient clinic, radiotherapy department, surgery
department or intensive care units. Endoscopes in our
hospital are collected in our department after use anddisinfected.
In 2020-2021, due to COVID-19 pandemic,
prevention of COVID-19 infection both among
patients and staffs has been an important topic. We
will provide safe endoscopic procedures byappropriate PPE (personal protective equipment) andthe social distance in the endoscopy suite.

Teaching activities
We participate in under-graduate education as a part ofsystemic lectures and bed-side learning by thedepartment of gastroenterology, surgery and otherdepartments. As for post-graduate education, training
opportunities for endoscopy and endoscopic surgery
are given to residents or young doctors in a programof each department. We accept foreign doctors to learn
advanced endoscopic procedures.

498

2012

2013

2014

2015

2016

2017

EGD*

11376

11840

11740

11874

11944

11490

Colonoscopy

5688

6000

6043

6394

6814

5921

Bronchoscopy

196

169

218

228

362

ERCP

956

912

1035

946

698

763

766

Enteroscopy

282

375

Laryngoscopy

83

Colposcopy
Total

EUS

**

†

2018

2019

11699

11226

（2177） （2501）

2020

2021

8.906

10232

4,548

5619

5530

5675

（109）

（329）

350

316

395

300

312

1206

1137

1057

1314

1302

1166

882

1084

1023

923

1059

711

847

396

310

86

304

138

151

74

23

128

102

105

125

114

92

102

42

39

365

404

327

295

417

430

414

392

333

364

19644

20591

20627

21034

22038

20769

20169

20314

16226

18602

*Esophagogastroduodenoscopy, **Endoscopic ultrasonography, †Endoscopic retrograde cholangiopancreatography,‡performed at Center for Epidemiology and Preventive Medicine

Research activities
Our research activities cover a variety of endoscopic
fields in cooperation with other departments. In thefield of gastrointestinal endoscopy, our department
participates in the JED (Japan Endoscopy Project)
project endorsed by Japan GastroenterologicalEndoscopy Society and contributes to thedevelopment of the nationwide endoscopy database.

4.

References
1.

2.

3.

Gotoda T, Akamatsu T, Abe S, Shimatani M,
Nakai Y, Hatta W, Hosoe N, Miura Y, Miyahara
R, Yamaguchi D, Yoshida N, Kawaguchi Y,
Fukuda S, Isomoto H, Irisawa A, Iwao Y, Uraoka
T, Yokota M, Nakayama T, Fujimoto K, Inoue H.
Guidelines for sedation in gastroenterologicalendoscopy (second edition). Dig Endosc. 2021;
33(1):21-53.
Hakuta R, Kogure H, Nakai Y, Kawakami H,
Maguchi H, Mukai T, Iwashita T, Saito T,
Togawa O, Matsubara S, Hayashi T, Maetani I,
Ito Y, Hasebe O, Itoi T, Hanada K, Isayama H.
Unilateral versus bilateral endoscopic nasobiliary
drainage and subsequent metal stent placement
for unsectable malignant hilar obstruction: A
Multicenter Randomized Controlled Trial. J Clin
Med. 2021;10(2):206.
Saito K, Nakai Y, Isayama H, Yamamoto R,
Kawakubo K, Kodama Y, Katanuma A, Kanno
A, Itonaga M, Koike K. A prospective

5.

6.

7.

8.

multicenter study of partially covered metal
stents in patients receiving neoadjuvant
chemotherapy for resectable and borderline
resectable pancreatic cancer: BTS-NAC study.
Gut Liver. 2021;15(1):135-141.
Niikura R, Fujishiro M, Nakai Y, Matsuda K,
Kawahara T, Yamada A, Tsuji Y, Hayakawa Y,
Koike K. International observational survey ofthe effectiveness of personal protective equipment during endoscopic procedures performed inpatients with COVID-19. Digestion. 2021:1-9.
Hamada T, Nakai Y, Isayama H, Koike K.
Antireflux metal stent for biliary obstruction:
Any benefits? Dig Endosc. 2021;33(3):310-320.
Kogure H, Sato T, Nakai Y, Ishigaki K, Hakuta
R, Saito K, Saito T, Takahara N, Hamada T,
Mizuno S, Yamada A, Tada M, Isayama H,
Koike K. Endoscopic management of pancreaticdiseases in patients with surgically alteredanatomy: clinical outcomes of combination of
double-balloon endoscopy- and endoscopic
ultrasound-guided interventions. Dig Endosc.
2021;33(3):441-450.
Sato T, Kogure H, Nakai Y, Kanai S, Ishigaki K,
Hakuta R, Saito K, Saito T, Takahara N, Hamada
T, Mizuno S, Yamada A, Isayama H, Koike K.
Endoscopic treatment of hepaticojejunostomy
anastomotic strictures using fully-covered metal
stents. Dig Endosc. 2021;33(3):451-457.
Watanabe T, Nakai Y, Mizuno S, Hamada T,
Kogure H, Hirano K, Akamatsu N, Hasegawa K,

499

9.

10.

11.

12.

13.

14.

Isayama H, Koike K. Prognosis of primarysclerosing cholangitis according to age of onset. J
Hepatobiliary Pancreat Sci. 2021;28(12):11151120.
Hamada T, Oyama H, Nakai Y, Tada M , Koh H,
Tateishi K, Arita J, Hakuta R, Ijichi H, Ishigaki
K, Kawaguchi Y,
Kogure H, Mizuno S,
Morikawa T, Saito K, Saito T, Sato T, Takagi K,
Takahara N, Takahashi R, Tanaka A, Tanaka M,
Ushiku T, Hasegawa K, Koike K. ABO BloodGroup and Risk of Pancreatic Carcinogenesis in
Intraductal Papillary Mucinous Neoplasms.
Cancer Epidemiol Biomarkers Prev. 2021;30(59):1020-1028.
Ishigaki K, Nakai Y, Sasahira N, Sugimori K,
Kitamura K, Iwai T, Matsubara S, Shimura K,
Itoi T, Ryozawa S, Ushio J, Doi S, Imazu H,
Maetani I, Isayama H, Acquire Study Group. A
prospective multicenter study of endoscopic
ultrasound-guided fine needle biopsy using a
22-gauge Franseen needle for pancreatic solid
lesions. J Gastroenterol Hepatol. 2021;36(10)2754-2761.
Nakai Y, Hamada T, Hakuta R, Sato T, Ishigaki
K, Saito K, Saito T, Takahara N, Mizuno S,
Kogure H, Koike K. A Meta-Analysis of Slow
Pull versus Suction for Endoscopic UltrasoundGuided Tissue Acquisition. Gut Liver 2021;
15(4):625-633.
Kogure H, Kato H, Kawakubo K, Ishiwatari H,
Katanuma A, Okabe Y, Ueki T, Ban T, Hanada
K, Sugimori K, Nakai Y, Isayama H. A
Prospective Multicenter Study of "Inside Stents"for Biliary Stricture: Multicenter Evolving Inside
Stent Registry (MEISteR). J Clin Med. 2021;
10(13):2936.
Hasegawa Y, Ijichi H, Saito K, Ishigaki K,
Takami M, Sekine R, Usami S, Nakai Y, Koike
K, Kubota N. Protein intake after the initiation ofchemotherapy is an independent prognostic factor
for overall survival in patients with unresectablepancreatic cancer: A prospective cohort study.
Clin Nutr. 2021;40(7):4792-4798.
So H, Oh D, Takenaka M, Minaga K, Uemura S,
Iwashita T, Saito T, Nakai Y, Kim S, Park D.
Initial experience of endoscopic ultrasoundguided antegrade covered stent placement with

15.

16.

17.

18.

long duodenal extension for malignant distalbiliary obstruction (with video). J Hepatobiliary
Pancreat Sci. 2021;28(12):1130-1137.
Sano M, Takahashi R Ijichi H, Ishigaki K,
Yamada T, Miyabayashi K, Kimura G, Mizuno S,
Kato H, Fujiwara H, Nakatsuka T, Tanaka Y,
Kim J, Masugi Y, Morishita Y, Tanaka M,
Ushiku T, Nakai Y, Tateishi K, Ishii Y, Isayama
H, Moses H, Koike K. Blocking VCAM-1
inhibits pancreatic tumour progression andcancer-associated thrombosis/thromboembolism.
Gut 2021;70(9):1713-1723.
Kurokawa R, Inui S, Tanishima T, Nakaya M,
Kurokawa M, Ishida M, Gonoi W, Amemiya S,
Nakai Y, Ishigaki K, Tateishi R, Koike K, Abe
O. Incidence and computed tomography findingsof lenvatinib-induced pancreatobiliary inflammation A single-center, retrospective study.
Medicine. 2021;100(35):e27182.
Nakai Y, Smith Z, Chang K, Dua K. Advanced
Endoscopic Techniques for the Diagnosis of
Pancreatic Cancer and Management of Biliary
and GastricOutlet Obstruction. Surg Oncol Clin
N Am. 2021;30(4):639-656.
Nakai Y, Oyama H, Kanai S, Noguchi K, Sato T,
Hakuta R, Ishigaki K, Saito K, Saito T, Hamada
T, Takahara N, Mizuno S, Kogure H, Isayama H,
Koike K. Double Guidewire Technique Using an
Uneven Double Lumen Catheter for Endoscopic
Ultrasound-Guided Interventions. Dig Dis Sci
2021;;66(5):1540-1547.

500

Department of Hemodialysis andApheresis
Professor
Masaomi Nangaku, M.D.,Ph.D.

Lecturer
Daisuke Yamada, M.D., Ph.D.
Yoshifumi Hamasaki, M.D., Ph.D.

Introduction and Organization
Hemodialysis and related blood purification therapy
had been individually performed in their respective
departments. However, all the departments’ apparatus
and human resources were centralized to form the
Department of Hemodialysis and Center for
Hemodialysis in 2000 at the University Hospital. The
Center for Hemodialysis was further renovated andstarted operations in Fall of 2006. This new Center for
Hemodialysis is equipped with one pressure control
unit in addition to 12 hemodialysis machines under astate-of-the-art hemodialysis control system. Ourconcept of a hemodialysis controlling system is a hub
to transfer all digital and analog data from patients andto monitor machines, including blood purification
machines, to the host computer in our hospital,
centralizing all data and administering medical coding
and billing robustly. Blood purification machines in
the ICU are also connectable to this system, which
was developed collaboratively with Nihon Kohden
Corp. Blood purification machines are selected
uniformly to secure patients’ safety while avoiding
human error and increasing the overall educational
quality of staff members.

Clinical activities
1.
2.

Start of maintenance hemodialysis therapy forend-stage renal disease (ESRD).
Regular hemodialysis therapy for hospitalized

3.
4.

5.
6.
7.
8.

ESRD patients. Please note that our center does
not accept holiday dialysis.
Emergency hemodialysis and hemodiafiltration
for ICU patients.
Plasmapheresis for neurodegenerative diseases,
myasthenia gravis, dermatological disorders,waldenstrom
macroglobulinemia,
collagendiseases, TMA(TTP), and pre/post solid organtransplant patients.
LDL apheresis for familial hypercholesterolemia,
nephrotic syndrome, and PAD patients.
White blood cell elimination therapy for inflamematory bowel diseases such as ulcerative colitis.
Cell-free and concentrated ascites reinfusion
therapy (CART) for refractory ascites.
Induction and maintenance of peritoneal dialysis
for ESRD.

Teaching activities
1.

2.
3.
4.
5.

A systematic review course for M2 students,
which covers clinical features, diagnosis, andevidence-based therapeutic strategies for acutekidney injury and acute renal failure.
Technical development course for medical
engineers and nurses.
Tutorial course for clinical fellows applying to
the speciality of blood purification therapy.
Exposure in hemodialysis & apheresis course to
second year residents on request.
Our state-of-the-art blood purification protocols

501

6.

are summarized in Japanese handbook in 2010
[Apheresis Pocket Manual] and 2011 [CRRTPocket Manual]. English and Chinese version of“Apheresis Pocket Manual” is available for
global experts of Apheresis therapy.
Our department takes main part in Critical Care
Nephrology Course for educating young clinicalresearchers and fellows in collaboration with
Department of Critical Care Medicine.

Research activities
1.
2.

3.

4.

5.
6.
7.
8.

Prognostic analysis for post-liver transplantpatients received plasma exchange therapy.
Identification of prognostic factors in AKI/CRRT
patients. AKI biomarkers and those clinicalsignificance in ICU/CCU.
Associations between factors at the initiation ofrenal replacement therapy and prognosis in
ESRD patients.
Identification of prognostic factors at initiation of
peritoneal dialysis (PD), and at the onset of
infectious complications in PD patients.
Elucidation of basic mechanisms in cardio-renal
syndrome and intervention.
Pathophysiology of acute kidney injury and its
applicability for renal regenerative study.
Renal biomarker to determine clinicalactionability in CKD and type-2 DN.
The potentiality of urine biomarker tests fordeveloping country [JICA-JST: Science andTechnology Research Partnership for Sustainable
Development].

References
1.

2.

Oki R, Hamasaki Y, Komaru Y, Miyamoto Y,
Matsuura R, Akari S, Nakamura T, Murase T, Doi
K, Nangaku M. Plasma xanthine oxidoreductase isassociated with carotid atherosclerosis in stable
kidneytransplant
recipients.
Nephrology(Carlton). 2022 Apr;27(4):363-370. Epub 2021
Oct 14.
Komai T, Iwasaki Y, Tsuchida Y, Hanata N,
Tsuchiya H, Harada H, Hamasaki Y, Nangaku M,
Shoda H, Fujio K. Efficacy and safety of plasma
exchange in interstitial lung diseases with
anti-melanoma differentiation-associated 5 gene

antibody positive clinically amyopathic dermatomyositis. Scand J Rheumatol. 2021 Dec 13:1-7.
3. Matsuura R, Yamashita T, Hayase N, Hamasaki Y,
Noiri E, Numata G, Takimoto E, Nangaku M, Doi
K. Preexisting heart failure with reduced ejection
fraction attenuates renal fibrosis after ischemia
reperfusion via sympathetic activation. Sci Rep.
2021 Jul 23;11(1):15091.
4. Tomura M, Hamasaki Y, Komaru Y, Miyamoto Y,
Matsuura R, Matsumoto A, Doi K, Kume H,
Nangaku M. Prognostic significance of concentricleft ventricular hypertrophy at peritoneal dialysis
initiation. BMC Nephrol. 2021 Apr 16;22(1):135.
5. Kotani A, Oda Y, Hirakawa Y, Nakamura M,
Hamasaki Y, Nangaku M. Peritoneal Dialysisrelated Peritonitis Caused by Streptococcus oralis.
Intern Med. 2021 May 22.
6. Oki R, Tsuji S, Hamasaki Y, Komaru Y, Miyamoto
Y, Matsuura R, Yamada D, Doi K, Kume H,
Nangaku M. Time until treatment initiation isassociated with catheter survival in peritoneal
dialysis-related peritonitis. Sci Rep. 2021 Mar 22;
11(1):6547.
7. Oki R, Hamasaki Y, Komaru Y, Miyamoto Y,
Matsuura R, Yamada D, Iwagami M, Doi K, Kume
H, Nangaku M. Catheter Diversion Procedure
With Exit-Site Renewal Promotes Peritoneal
Dialysis Catheter Survival. Kidney Int Rep. 2020
Dec 7;6(2):325-332.
8. Matsuura R, Doi K, Hamasaki Y, Nangaku M.
RRT Selection for AKI Patients With Critical
Illness. Semin Nephrol. 2020 Sep;40(5):498-505.
9. Matsuura R, Hiraishi A, Holzman LB, Hanayama
H, Harano K, Nakamura E, Hamasaki Y, Doi K,
Nangaku M, Noiri E. SHROOM3, the geneassociated with chronic kidney disease, affects the
podocyte structure. Sci Rep. 2020 Dec 3;10(1):21103.
10. Miyamoto Y, Aso S, Iwagami M, Morita K,
Fushimi K, Hamasaki Y, Nangaku M, Doi K,
Yasunaga
H.
Expanded
Indication
for
Recombinant Tissue Plasminogen Activator from
3 to 4.5 h after Onset of Stroke in Japan. J Stroke
Cerebrovasc Dis. 2020 Dec;29(12):105341.
11. Komaru Y, Doi K, Nangaku M. Urinary
Neutrophil Gelatinase-Associated Lipocalin in

502

12.

13.

14.

15.

16.

17.

18.

19.

Critically Ill Patients With Coronavirus Disease2019. Crit Care Explor. 2020 Aug 20;2(8):e0181.
Komaru Y, Yoshida T, Hamasaki Y, Nangaku M,
Doi K. Hierarchical Clustering Analysis for
Predicting 1-Year Mortality After Starting
Hemodialysis. Kidney Int Rep. 2020 May 23;5(8):1188-1195.
Miyamoto Y, Aso S, Iwagami M, Yasunaga H,
Matsui H, Fushimi K, Hamasaki Y, Nangaku M,
Doi K. Association Between IV Thiamine andMortality in Patients With Septic Shock: A
Nationwide Observational Study. Crit Care Med.
2020 Aug;48(8):1135-1139.
Matsuura R, Komaru Y, Miyamoto Y, Yoshida T,
Yoshimoto K, Hamasaki Y, Nangaku M, Doi K.
Different Biomarker Kinetics in Critically Ill
Patients with High Lactate Levels. Diagnostics(Basel). 2020 Jul 4;10(7):454.
Matsuura R, Iwagami M, Moriya H, Ohtake T,
Hamasaki Y, Nangaku M, Doi K, Kobayashi S,
Noiri E. The Clinical Course of Acute Kidney
Disease after Cardiac Surgery: A Retrospective
Observational Study. Sci Rep. 2020 Apr 16;10(1):6490.
Komaru Y, Inokuchi R, Iwagami M, Hamasaki Y,
Nangaku M, Doi K. Inverse Correlation Between
Incidence and Mortality of Acute Kidney Injury in
Critically Ill Patients: A Systematic Review. Shock.
2020 Sep;54(3):280-284.
Kimura C, Oki R, Hamasaki Y, Nangaku M. An
Abscess Developing in an Old Subcutaneous
Tunnel after Catheter Diversion. Intern Med. 2021
Mar 1;60(5):813-814.
Tanaka M, Ishibashi Y, Hamasaki Y, Kamijo Y,
Idei M, Nishi T, Takeda M, Nonaka H, Nangaku
M, Mise N. Ultrafiltration volume by once-weekly
hemodialysis is a predictor of technique survivalof combination therapy with peritoneal dialysis
and hemodialysis. Ther Apher Dial. 2021 Feb;
25(1):82-87.
Tanaka M, Ishibashi Y, Hamasaki Y, Kamijo Y,
Idei M, Nishi T, Takeda M, Nonaka H, Nangaku
M, Mise N. Bioimpedance Spectroscopy-Based
Fluid Status in Combined Dialysis Compared With
Hemodialysis and Peritoneal Dialysis: A CrossSectional Study. Ther Apher Dial. 2020 Aug;24(4): 373-379.

20. Komaru Y, Doi K, Matsuura R, Yoshida T,
Miyamoto Y, Yoshimoto K, Nangaku M. Urinarychloride concentration as a prognostic marker incritically ill patients. Nephrology (Carlton). 2020
May;25(5):384-389.
21. Matsuura R, Iwagami M, Moriya H, Ohtake T,
Hamasaki Y, Nangaku M, Doi K, Kobayashi S,
Noiri E. A Simple Scoring Method for Predicting
the Low Risk of Persistent Acute Kidney Injury in
Critically Ill Adult Patients. Sci Rep. 2020 Mar 31;
10(1):5726.
22. Miyamoto Y, Iwagami M, Aso S, Matsui H, Doi K,
Yasunaga H. Pregabalin and injury: A nested
case-control
andcase-crossoverstudy.
Pharmacoepidemiol Drug Saf. 2020 Feb 21.
23. Tanaka M, Ishibashi Y, Hamasaki Y, Kamijo Y,
Idei M, Kawahara T, Nishi T, Takeda M, Nonaka
H, Nangaku M, Mise N. Hospitalization for
Patients on Combination Therapy With Peritoneal
Dialysis and Hemodialysis Compared With
Hemodialysis. Kidney Int Rep. 2020 Jan 23;5(4):468-474.
24. Tanaka M, Ishibashi Y, Hamasaki Y, Kamijo Y,
Idei M, Kawahara T, Nishi T, Takeda M, Nonaka
H, Nangaku M, Mise N. Health-related quality oflife on combination therapy with peritoneal
dialysis and hemodialysis in comparison withhemodialysis and peritoneal dialysis: A crosssectional study. Perit Dial Int. 2020 Jan 17:
896860819894066.
25. Hayase N, Doi K, Hiruma T, Matsuura R,
Hamasaki Y, Noiri E, Nangaku M, Morimura N.
Recombinant thrombomodulin prevents acute lunginjury induced by renal ischemia-reperfusion
injury. Sci Rep. 2020 Jan 14;10(1):289.
26. Komaru Y, Inokuchi R, Iwagami M, Matsuura R,
Hamasaki Y, Nangaku M, Doi K. Correlation
between the Incidence and Attributable Mortality
Fraction of Acute Kidney Injury: A Systematic
Review. Blood Purif. 2020 Jan 22:1-8.
27. Miyamoto Y, Iwagami M, Aso S, Yasunaga H,
Matsui H, Fushimi K, Hamasaki Y, Nangaku M,
Doi K. Association between intravenous contrast
media exposure and non-recovery from dialysisrequiring septic acute kidney injury: a nationwide
observational study. Intensive Care Med. 45,
1570-1579 (2019).

503

28. Hayase N, Doi K, Hiruma T, Matsuura R,
Hamasaki Y, Noiri E, Nangaku M, Morimura N.
Recombinant Thrombomodulin on Neutrophil
Extracellular Traps in Murine Intestinal IschemiaReperfusion. Anesthesiology. 131, 866-882(2019).
29. Miyamoto Y, Iwagami M, Aso S, Yasunaga H,
Matsui H, Fushimi K, Hamasaki Y, Nangaku M,
Doi K. Temporal change in characteristics andoutcomes of acute kidney injury on renal
replacement therapy in intensive care units:
analysis of a nationwide administrative database inJapan, 2007-2016. Crit Care. 23, 172 (2019).
30. Matsuura R, Doi K, Komaru Y, Miyamoto Y,
Yoshida T, Isegawa T, Yoshimoto K, Yamashita T,
Noiri E, Nangaku M. Endogenous Erythropoietin
and Hepatic Dysfunction in Acute Kidney Injury
Requiring Renal Replacement Therapy. Nephron.
142, 10-16(2019).
31. Yoshida T, Matsuura R, Komaru Y, Miyamoto Y,
Yoshimoto K, Hamasaki Y, Noiri E, Morimura N,
Nangaku M, Doi K. Kinetic estimated glomerular
filtration rate as a predictor of successful
continuous renal replacement therapy discontinuation. Nephrology (Carlton). 24, 287-293 (2019).
32. Miyamoto Y, Hamasaki Y, Matsumoto A, Doi K,
Noiri E, Nangaku M. Prediction of immuneglobulin M reduction via therapeutic dose of
simple plasma exchange and double filtration
plasmapheresis using membrane separation inpatients with hyperviscosity syndrome caused by
Waldenstrom macroglobulinemia. J Clin Apher.
33, 611-615 (2018).
33. Nakamura Y, Kurata Y, Hamasaki Y, Nangaku M.
Extraperitoneal Placement of a Peritoneal Dialysis
Catheter. Intern Med. 58, 147-148 (2019).
34. Isshiki R, Asada T, Sumida M, Hamasaki Y,
Nangaku M, Noiri E, Doi K. Modest Impact ofSerial Measurements of Acute Kidney Injury
Biomarkers in an Adult Intensive Care Unit.
Nephron. 139, 243-253 (2018).
35. Matsuura R, Srisawat N, Claure-Del Granado R,
Doi K, Yoshida T, Nangaku M, Noiri E. Use of the
Renal Angina Index in Determining Acute Kidney
Injury. Kidney Int Rep. 3, 677-683 (2018)36. Matsuura R, Komaru Y, Miyamoto Y, Yoshida T,
Yoshimoto K, Isshiki R, Mayumi K, Yamashita T,

Hamasaki Y, Nangaku M, Noiri E, Morimura N,
Doi K. Response to different furosemide doses
predicts AKI progression in ICU patients withelevated plasma NGAL levels. Ann Intensive
Care. 8, 8 (2018)
37. Komaru Y, Inokuchi R, Ueda Y, Nangaku M, Doi
K. Use of the anion gap and intermittent hemodialysis following continuous hemodiafiltration in
extremely high dose acute-on-chronic lithium
poisoning: A case report. Hemodial Int. 22, E15E18 (2018)38. Iwagami M, Yasunaga H, Matsui H, Horiguchi H,
Fushimi K, Noiri E, Nangaku M, Doi K. Impact ofend-stage renal disease on hospital outcomesamong patients admitted to intensive care units: A
retrospective
matched-paircohortstudy.
Nephrology (Carlton). 22, 617-623 (2017)

504

University Hospital Medical
Information Network (UMIN)
CenterProfessor
Takahiro Kiuchi, M.D., Ph.D.

Associate Professor
Tsuyoshi Okuhara, Ph.D., M.P.H.

Instructor
Hiroko Okada, R.N., Ph.D., M.P.H.
Eiko Goto, R.D., Ph.D., M.P.H.

Homepage

http://www.umin.ac.jp/

Introduction and Organization
The University hospital Medical Information Network(UMIN) (the original name was the University Medical
Information Network), was established in 1989.
While
general-use
computersystems
wereimplemented at all national university hospitals aroundthe end of the Showa era (late 1980s), Dr. Shigekoto
Kaihara, chair and professor at the Hospital Computer
Center, University of Tokyo Hospital, led a project toconnect these computer systems in a network in orderto share information for better communication.
Finally, the Ministry of Education, Culture, Sports,
Science and Technology approved a budget to initiate
the UMIN Center. The UMIN Center was foundedwithin the Hospital Computer Center, University ofTokyo Hospital, and was officially opened in March
1989. Dr. Tsunetaro Sakurai became an associate
professor as the first full-time UMIN staff. The
following are the objectives of the UMIN Center, as
initially outlined in 1989 (No.6 was added later):
1. Provide up-to-date information for healthcare
professionals
2. Promote digitalized communication among

3.
4.
5.
6.

healthcare professionals
Support collaborative projects among university
hospitals
Support collaborative medical researchStandardize data format and support data collection
Support medical education and clinical training

The original UMIN system utilized an N1 protocol,
which was developed in Japan and was the only
solution at the time to connect general-use computersof the five major computer vendors in Japan, although
it was poor in function, supporting only line-mode,character-based terminals.
In 1994, we launched a service through the Internet,
and it began to spread in those days. The number of
UMIN users gradually increased, mainly in the E-mailservice.
In 1996, Dr. Takahiro Kiuchi took up a new post while
Dr. Sakurai was promoted to professor at Hokkaido
University. Dr, Kiuchi updated the system to be webbased. With the rapid spread of the Internet in Japan,
UMIN users dramatically increased.
The UMIN Center subsequently started to provide threemajor information services: (1) the ELBIS (Electronic

505

Library for Biomedical Sciences) as of 1997, (2) the
INDICE (Internet Data and Information Center ofClinical Research) as of 2000, and (3) the EPOC
(Evaluation System of Postgraduate Clinical Training)
as of 2004.
In April 2002, the UMIN Center became an
independent entity, with the adjusted name of
University Hospital Medical Information Network
Center, as per an internal arrangement at the Universityof Tokyo Hospital. In 2003, a budget for a new
professor position was officially approved by the
Ministry of Education, Culture, Sports, Science andTechnology. Then, Dr. Kiuchi was promoted to become
the first professor of the UMIN Center on April 1, 2004.
The UMIN Center became part of the Faculty of
Medicine, as the Department of Health Communication,
School of Public Health, which was established in April
2007.

Clinical Activities
Although the UMIN Center is one of the central
medical examination and treatment institutions of the
University of Tokyo Hospital, the center does notprovide direct patient care services, but provides
services for medical researchers and practitioners
throughout Japan. We currently have about 470,000
registrants, and approximately 120,000,000 monthly
website accesses, which is currently in the scale of theworld’s highest access rates. The service extends tostudy / education / medical examination and treatment/ hospital duties and encompasses many divergences as
indicated below:
 Research: http://www.umin.ac.jp/research
AC:
Information for Academic Conferences
ELBIS:
Electronic Library for Biomedical
Sciences
FIND:
Fund Information Database
INDICE: Internet Data and Information Center ofClinical Research
ROCOLS: Recruiting System for Our Colleagues’
and Students’
CTR:
Clinical Trial Registry
ICDR:
Individual Case Data Repository Education: http://www.umin.ac.jp/education
CC-EPOC: Clinical Clerkship E-Portfolio of ClinicalTraining
EPOC2:
E-Portfolio of Clinical Training 2
Debut:
Dental Training Evaluation andTabulation System
Web-QME: Medical Education Evaluation System
ARIA:
Online Recruiting System for General
Use Medical Examination and Treatment
http://www.umin.ac.jp/uhosp/
 Intoxication database Medical supplies and materials database Classification for Nursing
 Ministry of Education, Culture, Sports,
Science and Technology document public
information system National university hospital-related medical
dispute report Lists for people and committees
 Various government official appointments,
administrative websites and ML
 General Services(1) General information and search Medical / biology related websites
 Medical terminology A medical research organization / medical
institution database(2) Services for information providersWeb service for publicWeb service for members
Website preservation service(3) Communication support
 E-mail Listserv
 Discussion board
 File exchange

Teaching Activities
Please refer to Department of Health Communication
for information about graduate and undergraduate
education.

506

Research Activities
Please refer to Department of Health Communication
for information about research activities.

References
Please refer to Department of Health Communication.

507

Department of Clinical Research
GovernanceDirector & Project Professor
Junji Moriya, M.D., Ph.D.

Research Associate
Kazuyoshi Ichihashi, Ph.D.

Websitehttp://www.h.u-tokyo.ac.jp/english/centers-services/organization/l4/
researchgovernance.html

History and Overview of theOrganization
The Department of Clinical Research Governance
was established independently from the ClinicalResearch Support Center on January 1st, 2015, for the
management of clinical research. The aim of thedepartment is an appropriate and rapid response tovarious issues surrounding clinical research in recent
years, to prevent problems related to research ethics
and research misconduct, and to promote highly
reliable clinical research. The intention of the
Department of Clinical Research Governance is toestablish a system that would enable the University ofTokyo Hospital to take the initiative in managing andpromoting clinical research so as to ensure thereliability of clinical research and compliance with the
ethics of clinical research promoted by university
hospitals providing advanced medical care.
The Department of Clinical Research Governance is
now composed of three offices: 1) Office of Strategic
Planning and Promotion, 2) Office of ResearchIntegrity and Promotion, and 3) Office of ClinicalCompliance. These offices mutually cooperate topromote and strengthen governance functions within
the hospital.
The following activities are carried out by the
Office of Strategic Planning and Promotion ; (1)formulating comprehensive strategies for research anddevelopment at the University of Tokyo Hospital, (2)adopting the role of administrative headquarters whenpublicly applying for large-scale research projects, (3)serving as a liaison for consultations regarding theacquisition of research funds and intellectual
properties, (4) examination financial self-reliancestrategies of the clinical research base, (5) discoveringneeds and seeds in clinical practice, (6) investigating
research activities at the University of Tokyo Hospitaland creating a database, (7) collecting clinicalresearch information from external organizations, (8)activities related to conflicts of interest at the
University of Tokyo Hospital, (9) clerical work related
to the Advanced Medicine Development Support
Management Committee, and (10) clerical work
related to the Special Clinical Research Steering
Committee.
The activities of the Office of Research Integrity
and Promotion are as follows; (1) responding to
problems related to research ethics and research
misconduct, (2) educational activities for clinicalresearchers; and (3) the dissemination of workshop
summaries.
The activities of the Office of Clinical Complianceare as follows; (1) auditing of clinical researches andclinical trials, (2) integrated management ofoutsourced auditing, (3) integrated management ofaudit results of the University of Tokyo Hospital, and(4) educational workshops and guidance related toauditing.

508

The Department of Clinical Research Governanceconsists of one director (a full-time post), one
Research Associate/URA in the Office of Strategic
Planning and Promotion, three staffs (2 auditors andone temporary staffs (an auditor staff) in the Office ofClinical Compliance, and two staffs in the Office of
Research Integrity and Promotion as of March 2022.

Activities
The Office of Strategic Planning and Promotion has
undertaken the following activities in the fiscal year2021.
1) Coordination of organization for clinical
trials/researches; assisting the holding of Specified
Clinical Research Steering Committee and theSpecified Clinical Research Auditing Committee, andassisting the preparation of reports on clinical research
activities as the Clinical Research Core Hospitals
under the Medical Care Act (Act No. 205 of July 30,1948) for surveys conducted by the Ministry of Health,
Labor and Welfare (MHLW).
2) Others; investigations of research paper publication
activities, co-operating the “Forum for Developmentof Seeds for Advanced Medicine”, etc.
The Office of Clinical Compliance has undertaken
the following activities in the fiscal year 2021.
1) Audit activities; as regard to trials/researches
conducted by the University of Tokyo Hospital, theoffice conducted a total of eight trials (six audits forinvestigator-initiated clinical trials, and two audits forSpecified Clinical Researches).
2) Consolidating information; the office collected all
the information on audit results including directly
outsourced by principal investigators, and has been
centrally managing the GCP inspections findings
conducted at the University of Tokyo Hospital.
3) Preparing documents; the office prepareddocuments of SOP in general auditing, templates forauditing of each trial, start-up meetings, and protocols,
along with maintenance of existing checklists.
4) MHLW program for educational workshops andguidance related to auditing; the office has a central
role in performing workshops in the fiscal year 2021,
and held a beginners workshop in September 2nd and3rd, and a mid-career workshop in November 18th and
19th.
The Office of Research Integrity and Promotion has
undertaken the following activities in the fiscal year2021.
1) Collecting and disseminating information forclinical quality assurance; the office has sent a total ofsix e-mails for all personnel in the University ofTokyo Hospital, along with disclosing a total of 16
information in the website of the Department ofClinical Research Governance.
2) Educational activities for clinical researchers; theoffice has held an e-learning seminar regarding to the
management of conflict of interest and quality
assurance in clinical researches (there were 1935
participants in a Step1 seminar, and 1888 participantsin a Step2 seminar).
3) Promotion of activities for research integrity; theoffice has engaged in creating a team for supporting
activities regarding to QMS in investigator-initiatedclinical trials conducted in the University of Tokyo
Hospital. The team consists of members of the Officeof Research Integrity and Promotion, and the ClinicalResearch Promotion Center. The team extracted
problems and points to consider as to working flows
of collecting and reporting information for deviations
or misconducts of clinical trials performed in the
University of Tokyo Hospital.

509

Department of Child Psychiatry
Associate Professor
Yukiko Kano, M.D., Ph.D.

Assistant professor
Yosuke Eriguchi, M.D., Ph.D.

Homepage

http://kokoro.umin.jp/

Introduction and Organization
The Department of Child Psychiatry wasestablished in April 2005 as the clinical counterpart to
the Clinical Education Center of Mental Development,
both of which are funded by the special grant forfaculty development. The major aim of the Clinical
Education Center is to train mental health specialists
in various fields with a fundamental grounding inchild psychiatry and neurosciences. Much of theservices provided are based on the 38 years ofexperience in intervention and treatment for developmentally disabled children established in the former
child psychiatry division of Department of Neuropsychiatry. Our department uses a multidisciplinary
approach by working in collaboration not only with
the Department of Neuropsychiatry, Department ofPediatrics and Graduate School of Education in the
University of Tokyo but also several other educational
and/or clinical facilities on mental development ordevelopmental disorders. The Department of Child
Psychiatry complemented the Clinical Education
Center by providing fieldwork for clinical training andoffered clinical services to patients with various
development problems also.
The Clinical Education Center of Mental Development was closed in March 2010 because of time limitof the fund, and Department of Child Neuropsychiatry,
Graduate School of Medicine was established in April
2010. The Department of Child Psychiatry, as theclinical counterpart to the department in graduate
school, focuses on clinical activity related to research
as well as quality practice of child psychiatry andeducation of leading child psychiatrists and allied

professionals. In addition to professors of the graduate
school, 2 psychiatrists and 3 psychologists (2 full-timeones for a definite term and 1 part-time one) areofficially assigned to the Department of Child
Psychiatry. One psychiatric social worker works
mainly for the Department of Child Psychiatry since2013 also.

Clinical activities
In the year 2021, 9 psychiatrists and 4 psychologists(full-time and part-time) and 1 psychiatric social
worker are in charge of treatment at the Department ofChild Psychiatry. Although patients with various
disorders are seen, the focus of the department ismainly on patients with developmental disorders. We
offer services to patients with a broad range ofdevelopmental disorders including Autism Spectrum
Disorder (ASD), Attention-Deficit/Hyperactivity Disorder (ADHD), Learning Disabilities (LD), Intellectual
Disability (ID), tic disorders, and child & adolescentObsessive-Compulsive Disorders (OCD).
Number of new patients in 2021 was 247, anincrease of about 70 from the number of new patientslast year, which had decreased due to the spread of
COVID-19 infection. More than 35% of the newpatients consisted of patients with ASD, ADHD or tic
disorders. Out of 247 patients, children of elementary
school age were 107, and children of junior highschool age were 31. In other words, children ofelementary or junior high school age were more thanhalf of the patients. Number of preschool children was
94, suggesting our response to ongoing needs for early
diagnosis and intervention.

510

The follow-up clinic consisted of general clinic andspecial clinic (Tic/OCD clinic). At the general clinic, arigorous diagnosis based on detailed assessment anddecision about treatment course are provided forchildren and adolescents with any kinds of mental
problems. After fine adjustment of treatment course
within a given period, the patients are referred tocommunity hospitals/clinics or intervention/education
facilities with a detailed report. The special clinic
meets a need for high level services and works withresearch for special diseases.
Services for the general child psychiatry outpatientsare provided by psychiatrists in the areas of pharmacotherapy, psychotherapy, psychoeducation and also
work closely with the schools and community.
Psychologists have charge of psychological consultation as well as psychological examination. Patients
involved in those are mainly individuals with
developmental disabilities, and individualized treatment focusing on developmental viewpoint is plannedfor each. Psychological consultation includes services
in the following areas: (1) evaluation of cognitive andbehavioral development, (2) individualized treatmentof the disabled individual (3) counseling of parents
and providing information to the disabled individual’s
support network (relatives, schools) and environmental coordination. In addition to psychologists,
psychiatric social worker participates in actual
environmental coordination. Cognitive behavior
therapy for obsessive-compulsive symptoms oranxiety is sometimes provided also.
As for intervention for preschool children with ASD,
intensive individualized therapy consisting of weekly
10 sessions was provided for children aged 3 years or
younger.
Parent-training for parents with ADHD children,which started in 2011, was provided. This program
aimed that the parents learn deeper understanding ofdifficult children and appropriate strategy of copingwith them.
In addition to these outpatient services, “inpatient
assessment on developmental disorders” program
started in 2010. This program is provided in theinpatient ward of neuropsychiatry for adolescents oradults who have mental problems such as depression
and wish a detailed examination about possibility ofhidden developmental disorders including ASD and

ADHD. Based on this assessment, psychoeducation on
strategies coping with problems related todevelopmental disorders is provided to patients andtheir families.
We also focus on psychiatric liaison activity withother departments in the University hospital,
especially pediatrics.

Education
Undergraduates of the University of Tokyo haveopportunities to participate in an assessment anddiagnosis session at the general first visit outpatient
clinic and intervention for preschool children.
Graduate students in clinical psychology course fromthe University of Tokyo participate in intervention forpreschoolers also.
One month training course is offered to juniorresidents especially in pediatric specialty course. This
course includes intake interview of first visit patients,
attendance for assessment and treatment for follow-up
patients, intervention for preschoolers, and theparent-training. Eighteen residents participated inthis course. For general psychiatrists including seniorresidents of the Department of Neuropsychiatry, an
inpatient program of assessment about developmental
disorders is provided as opportunity to get knowledge
and experience of developmental disorders.

Research
We participate in investigation of etiology anddevelopment of effective treatment on ASD and
ADHD, which are organized in collaboration with the
Department of Neuropsychiatry and other research,educational and clinical facilities. In addition, research
related specifically to the clinical activities in the
Department of Child Psychiatry is currently being
investigated.
Clinical evaluation and treatment
Effectiveness study of early intervention for autisticpreschoolers is being undertaken. We focused oninvestigating early intervention including treatment
for children and parent support.
We are also considering support for transition fromkindergarten/nursery school to elementary school forchildren with ASD.

511

Effectiveness of a program of group cognitive
behavior therapy for adults with high-functioning
ASD is investigated in a randomized control trial.
We are also analyzing the data obtained from
“inpatient assessment on developmental disorders”
program.
In order to develop predictor of parent training for
ADHD, we are collecting and analyzing data.
The possible relations among clinical characteristics
such as tics and obsessive-compulsive symptoms in
Tourette syndrome (chronic tic disorder with multiple
motor tics and one or more vocal tics) and child &adolescent OCD are being evaluated.
Multi-institutional collaborative study about
treatment-refractory Tourette syndrome in which
severe tics persist even after adulthood are conductedwith multidisciplinary professionals including
neurosurgeons who perform deep brain stimulation.
Comprehensive Behavioral Intervention for Tics
(CBIT) is provided for children and adolescents with
Tourette syndrome, and investigation of its
effectiveness is undertaken. We have also begun todevelop psychoeducation materials via the iuternetthat will lead to CBIT.
We continued survey of tics and related symptoms
in community preschoolers and development ofobjective assessment for tics also.
Neuropsychological research
Neuropsychological data on ASD, ADHD andTourette syndrome are being collected. Analysis of therelations among neuropsychological findings and theclinical evaluation are being conducted.
Neuroimaging
Studies include structural MRI, Near-Infrared Spectroscopy (NIRS) and functional MRI with exploring
the pathogenesis of developmental disorders such as
ASD and ADHD.

References
1.

Yagi T, Ando S, Usami S, Yamasaki S, Morita M,
Kiyono T, Hayashi N, Endo K, Iijima Y,
Morimoto Y, Kanata S, Fujikawa S, Koike S,
Kano Y, Hiraiwa-Hasegawa M, Nishida A,
Kasai K. Longitudinal Bidirectional Relation-

2.

3.

4.

5.

6.

7.

ships Between Maternal Depressive/Anxious
Symptoms and Children's Tic Frequency in Early
Adolescence. Front Psychiatry, 12: 767571, 2021.
Kaji N, Ando S, Nishida A, Yamasaki S,
Kuwabara H, Kanehara A, Satomura Y, Jinde S,
Kano Y, Hiraiwa-Hasegawa M, Igarashi T, Kasai
K. Children with special health care needs andmothers' anxiety/depression: Findings from theTokyo Teen Cohort study. Psychiatry Clin
Neurosci.,75(12): 394-400, 2021.
Eriguchi Y, Gu X, Aoki N, Nonaka M, Goto R,
Kuwabara H, Kano Y, Kasai K. A 2-year
longitudinal follow-up of quantitative assessment
neck tics in Tourette's syndrome. PLoS One,
16(12): e0261560, 2021.
Okada N, Yamamoto Y, Yahata N, Morita S,
Koshiyama D, Morita K, Sawada K, Kanata S,
Fujikawa S, Sugimoto N, Toriyama R, Masaoka
M, Koike S, Araki T, KanoY, Endo K, Yamasaki
S, Ando S, Nishida A, Hiraiwa-Hasegawa M,
Yokoyama C, Kasai K, Birth order andprosociality in the early adolescent brain. Sci Rep,
11(1): 21806, 2021.
Kimura Y, Iijima K, Takayama Y, Yokosako S,
Kaneko Y, Omori M, Kaido T, Kano Y, Iwasaki
M. Deep Brain Stimulation for Refractory
Tourette Syndrome: Electrode Position andClinical Outcome. Neurol Med Chir (Tokyo),
61(1): 33-39, 2021.
Kato Y, Kuwabara H, Okada T, Munesue T,
Benner S, Kuroda M, Kojima M, Yassin W,
Eriguchi Y, Kameno Y, Murayama C, Nishimura
T, Tsuchiya K, Kasai K, Ozaki N, Kosaka H,
Yamasue H. Oxytocin-induced increase in
N,N-dimethylglycine and time course of changesin oxytocin efficacy for autism social core
symptoms. Mol Autism, 12(1):15, 2021.
Kuru Y, Nishiyama T, Sumi S, Suzuki F, Shiino T,
Kimura T, Hirai K, Kuroda M, Kamio Y, Kikuchi
S. Practical applications of brief screening
questionnaires for autism spectrum disorder in a
psychiatry outpatient setting. Int J Methods
Psychiatr Res, 30(2): e1857, 2021.

512

Tissue Bank
Director and Associate Professor
Sumihito Tamura, M.D., Ph.D. FACS

Homepage https://www.h.u-tokyo.ac.jp/english/centers-services/centralclinical-facilities/tissue-bank/index.html
Introduction and Organization

Target Diseases

The tissue bank handles cardiac arrest and brain death
donor information on a 24-7-365 basis, and is
responsible for the retrieval and cryo-preservation
management of homograft cardiac valve and bloodvessels. We provide these cryo-preserved vascular
tissues to medical organizations nationwide forpatients that require vascular tissue transplantation.
Additionally, we initiated allograft bone banking
program limited to in-house retrieval and suppy since
2018. Dissemination and educational activities for theadvancement of tissue transplantation and transplantation medicine is our important mission. In thisline of effort, starting 2020, our staff now function as
in-house organ donor coordinator.

Cardiac valve transplantation:
Infectious endocarditis, prosthetic valve infection,aortic valve periannular abscess, some cases ofcongenital cardiovascular diseases (hypoplastic left
heart syndrome, pulmonary artery/aorta reconstruction,etc.), etc.
Vascular transplantationvascular prosthesis infection, infected aortic aneurysm,
hepatobiliary tract and pancreas diseases, some casesof congenital cardiac diseases.

Activities
Tissue retrieval is carried out by a team of surgeons
after a transplantation coordinator certified by theJapan Society of Tissue Transplantation (JSTT)
explains tissue donation to the donor’s family, andobtains their consent. The donated tissue undergoes
preservation work in the cleanroom located within theCentral Clinical Facilities and is stored under strict
round-the-clock online management, so that it may betransplanted to a patient (recipient) who is deemed tonecessitate a tissue transplantation. As a rare tissuebank that handles homograft cardiac valves andvascular tissues in Japan, the department is certified
by the JSTT and has the largest number of stored
tissues in Japan.

Characteristics
Excellent resistance to infections: Homograft tissues
are cryopreserved in a state in which the cells are alive,
and provide higher resistance to infections by bacteria
than artificial cardiac valves and vessels.
No need for anticoagulation: It is not always
necessary to use coagulants throughout one’s life, as
in the case of post-replacement of artificial cardiac
valves and blood vessels, and it is particularly usefulfor people who are engaged with strenuous exercise,young children, or women who have a desire to givebirth.
Durability: As long as 15 to 20 years. However, re-do
operations may be necessary in some cases.
Banking system: In collaboration with other tissuebanking facilities in Japan, responds to recovery cases
mainly in the Kanto region. Certified cardiac and liver
surgeons consists the donor response team. Shipment
area covers entire nation.
Honoring the donor: Importance is non-comparable toartificial grafts. Human tissues are recovered fromdeceased donors. Since donation is rare in Japan, graft

513

supply remains scarce. We honor donor and family
members, who decided to give to others in their final
moments. It is our mission to maintain and spread this
precious and important therapeutic option in Japan.

514Center for Epidemiology andPreventive Medicine
Director & Associate Professor
Nobutake Yamamichi, M.D., Ph.D.

Associate & Deputy Director
Lumine Matsumoto, M.D., Ph.D.

Associates
Atsuko Ozeki, M.D., Ph.D., Keiko Niimi, M.D., Ph.D., Yukari Masuda, M.D., Ph.D.
Hirotaka Matsuzaki, M.D., Ph.D., Eriko Hasumi, M.D., Ph.D.,
Takako Nishikawa, M.D., Ph.D., Kazushi Fukagawa, M.D., Ph.D.,

Homepage:

http://www.h.u-tokyo.ac.jp/patient/depts/kenshin/index.html
https://www.todai-yobouigaku-dock.jp/

Introduction and Organization
Following the inauguration of a new Central Clinical
Service Building in November 2006 in the Universityof Tokyo Hospital, the Center for Epidemiology andPreventive Medicine was established on January 1st,
2007, within the Central Clinical Facilities and therelevant regulations were revised. On January 9th, theWorking Group for the Establishment of the Center for
Epidemiology and Preventive Medicine was organized;
on April 1st, Steering Committee for the Establishmentof the Center for Epidemiology and Preventive
Medicine was organized; on June 4th, the department
started offering its services on a trial basis (in-hospital
services) and was officially inaugurated in July, starting
to provide public services.
The principal objectives of the establishment of theCenter for Epidemiology and Preventive Medicine are1) to scientifically demonstrate the utility andeffectiveness of examinations and preventive interventions, 2) to integrate a vast amount of clinical data andhealth-related information to develop more efficientmodels for disease management, 3) through 1) and 2),
to promote preventive medicine and medicine forhealth promotion in an effort to contribute to theimprovement of public health, and 4) to train medical
personnel who can put above-mentioned 1), 2) and 3)
into practice.
In these twelve years since the official opening, ourcenter has increased the number of examinees from ten
subjects per day to twelve per day (March 2018).
Following the reorganization in April 2018, the Center
was transferred to the 15th floor of the inpatientbuilding B in September 2018. As the area for
examination was expanded, we have been able toincrease the number of examinees to 16 in October
2018, and to 20 in April 2019, and to 22 in January
2021. Most of the examinations except for MRI and CT
scan can be performed within our floor, which
increased the convenience and comfort for theexaminees.
In the administrative organization of the Center for
Epidemiology and Preventive Medicine, the Director
directly under the head of the hospital is responsible forthe entire organization. Examinations in the
Department are administered in collaboration withthree Central Clinical Facilities (Clinical Laboratory
Center, Radiological Center, and Department of515

Endoscopy and Endoscopic Surgery) and four Clinical
Divisions (Gastroenterology, Breast and Endocrine
Surgery, Gynecologic Surgery and Ophthalmology and
Vision Collection).
The staff of the Center for Epidemiology andPreventive Medicine is composed of nine physicians.
Three of the regular physicians also perform uppergastrointestinal endoscopy and colonoscopy. Our
department also has nine nurses, six assistant clerks,
and one medical clerk.

Clinical activities
In addition to basic examinations, we provide ten
optional examinations: 1) comprehensive cardiovascular examinations, 2) comprehensive cerebrovascularexaminations, 3) check up for dementia, 4) colorectal
cancer screening, 5) uterine cancer screening, 6) breast
cancer screening, 7) lung cancer screening, 8) tumor
marker diagnosis, 9) estimation of gastric cancer risk,and 10) pancreatic cancer screening. While meeting theneeds of examinees, we have increased the number ofthe optional examinations.
The physicians of our department are responsible foranalyzing the results of examinations and performing
overall evaluations. We take plenty of time to perform
comprehensive medical examinations and instantly
write a referral letter to each department in the
University of Tokyo Hospital when we find any
abnormality through the examinations. Formally, theexaminee is notified in writing within approximately
three weeks after the examination. We also offer eachexaminee a free consultation so that we can help
him/her understand the results or decide whether tohave further detailed examination.

Teaching activities
We started clinical teaching for medical students in
April 2017. Following the lecture of preventive
medicine, students observe explanations by physiciansto the examinees. They learn not only how to apply
preventive medicine to practice, but also the manner ofphysicians to examinees.

Research activities
The University of Tokyo Hospital is expected not
only to provide its service of comprehensive medical
examinations but also to promote evidence-based
practice and scientific examinations, which is themission of our department. Academically, we aim toestablish a database from clinical data and to promoteepidemiological research. This will enable us toprevent disease based on scientific data. We haveconducted cross-sectional/longitudinal analysis. We
also work in collaboration with other departments in
our hospital and other facilities.

Past activities
The total number of examinees (who had basic
examinations and optional examinations) in the FY
2021 was 8636 including 3022 in basic examinations,543 in complete cardiovascular examinations, 682 incomplete cerebrovascular examinations, 114 in checkup for dementia, 391 in colorectal cancer screening,
660 in uterine cancer screening, 788 in breast cancer
screening, 704 in lung cancer screening, 1236 in tumor
marker diagnosis, 279 in estimation of gastric cancer
risk, 217 in pancreatic cancer screening, and 14 inupper gastrointestinal endoscopy (later). Respiratory
function test has been cancelled from March 31,2020
due to coronavirus.
One of the most important role of our center is toprovide the appropriate medicine to the examinees
when any abnormal finding was detected. We provide
referral letters to the department within/outside of our
hospital for detailed examination or treatment,
according to the request by the examinees. Prompt
reference to the medical department in the Universityof Tokyo Hospital is one of the most contributablefactor for the satisfaction of the examinees. In the FY
2021, we issued 1506 letters of referral to otherdepartments in our hospital and 50 to other hospitals.
We have expanded our public relations efforts. We
renewed brochures and 15,000 brochures weredelivered during the FY 2021.
We also renewed posters which were placed within
our hospital and on and off campus of the University ofTokyo as well. We have established preferential
treatment system for graduates, faculty and staff toacquire new examinees. We have updated our original516

website (https://www.todai-yobouigaku-dock.jp/) andoffering up-to-date information to the examinees.
The University of Tokyo Hospital is aiming toestablish the Center for International Preventive
Medicine, and we provide full cooperation to prepare
for establishment.

References
Academic Papers in English
1. Fukuda K, Matsuzaki H, Mikami Y, Makita K,
Miyakawa K, Miyashita N, Hosoki K, Ishii T,
Noguchi S, Urushiyama H, Horie M, Mitani A,
Yamauchi Y, Shimura E, Nakae S, Saito A, Nagase
T, Hiraishi Y. A mouse model of asthma-chronic
obstructive pulmonary disease overlap induced byintratracheal papain. Allergy. 2021 Jan;76(1):390394.
2. Sugita J, Fujiu K, Nakayama Y, Matsubara T,
Matsuda J, Oshima T, Liu Y, Maru Y, Hasumi E,
Kojima T, Seno H, Asano K, Ishijima A, Tomii N,
Yamazaki M, Kudo F, Sakuma I, Nagai R, Manabe
I, Komuro I. Cardiac macrophages prevent sudden
death during heart stress. Nat Commun. 2021 Mar
26;12(1):1910.
3. Sakaguchi Y, Tsuji Y, Ushiku T, Kubota D, Sato J,
Obata M, Cho R, Nagao S, Sakuma N, Tamura N,
Miura Y, Fukagawa K, Ohki D, Mizutani H,
Takeuchi C, Takahashi Y, Minatsuki C, Niimi K,
Yamamichi N, Koike K. The natural history of
sporadic non-ampullary duodenal epithelial
tumors: Can we wait and see? DEN open. 2021
Apr 21;1(1):e9.
4. Kirita K, Kodaka Y, Shibata Y, Ueki N, Agawa S,
Yamawaki H, Niikura R, Yamamichi N, Izumi K,
Hojo M, Maruyama K, Yamamoto T, Gudis K,
Watanabe M, Kaise M, Iwakiri K, Futagami S.
Impact of clinical characteristics of colonic
diverticular bleeding in extremely elderly patientstreated with direct oral anti-coagulant drugs: a
retrospective multi-center study. J Clin Biochem
Nutr. 2021 Sep;69(2):222-228.
5. Yamamichi N, Shimamoto T, Hirano C, Takahashi
Y, Minatsuki C, Takeuchi C, Takahashi M,
Sakaguchi Y, Tsuji Y, Niimi K, Wada R,
Mitsushima T, Koike K. Clinicopathologicalfeatures and prognosis of developed gastric cancer

based on the diagnosis of mucosal atrophy andenlarged folds of stomach by double-contrast
upper gastrointestinal barium X-ray radiography.
Clin J Gastroenterol. 2021 Aug;14(4):947-954.
6. Yokota J, Fujiu K, Oshima T, Matsubara TJ,
Matsuda J, Shimizu Y, Hasumi E, Kojima T, Doi
K, Komuro I. Pseudo-elevation of conduction
system pacing threshold through parallel
connection of an intracardiac electrogram
recording system. J Cardiovasc Electrophysiol.
2021 Aug;32(8):2329-2332.
7. Oshima T, Fujiu K, Matsunaga H, Matsuda J,
Matsubara T, Saga A, Yoshida Y, Shimizu Y,
Hasumi E, Oguri G, Kojima T, Komuro I.
Uninterrupted Direct Oral Anticoagulants Withouta Change in Regimen for Catheter Ablation for
Atrial Fibrillation Is an Acceptable Protocol Circ
Rep. 2021 Jul 30;3(9):481-487.
8. Miura Y, Tsuji Y, Cho R, Fujisawa A, Fujisawa M,
Kamata H, Yoshikawa Y, Yamamichi N, Sakai T,
Koike K. The feasibility of a novel injectablehydrogel for protecting artificial gastrointestinal
ulcers after endoscopic resection: an animal pilot
study. Sci Rep. 2021 Sep 16;11(1):18508.
9. Mehrazad Saber Z, Takeuchi Y, Sawada Y, Aita Y,
Ho MH, Karkoutly S, Tao D, Katabami K, Ye C,
Murayama Y, Shikama A, Masuda Y, Izumida Y,
Miyamoto T, Matsuzaka T, Sugasawa T,
Takekoshi K, Kawakami Y, Shimano H, Yahagi N.
High protein diet-induced metabolic changes aretranscriptionally regulated via KLF15-dependentand independent pathways. Biochem Biophys Res
Commun. 2021 Dec 10;582:35-42.
10. Kamon T, Kaneko H, Itoh H, Kiriyama H, Mizuno
Y, Morita H, Takeda N, Yamamichi N, Komuro I.
Possible Gender Difference in the Association
Between Abdominal Obesity, Chronic Inflammation, and Preclinical Atherosclerosis in the
General Population. Int Heart J. 2021;62(4):837842.
11. Hasumi E, Fujiu K. Tripartite Left Bundle Branch
Area Pacing. Int Heart J. 2021;62(1):1-3.
12. Takeuchi Y, Yahagi N, Aita Y, Mehrazad-Saber Z,
Ho MH, Huyan Y, Murayama Y, Shikama A,
Masuda Y, Izumida Y, Miyamoto T, Matsuzaka T,
Kawakami Y, Shimano H. FoxO-KLF15 pathway
switches the flow of macronutrients under the517

control of insulin. iScience. 2021 Nov 15;24(12):103446.
International conferences
1. Yamamichi N. Gastric Cancer Screening in Japan.
KCA-DDF Joint Symposium. (2021/6/18, WEB
congress)
2. Nishikawa T, Kurano M, Ikeda H, Yamamichi N,
Yatomi Y, Koike K. Lysophosphatidylserine may
be involved in liver fibrosis. AASLD2021.
(2021/11/12-15)

518

Department of Pain and Palliative
Medicine
Associate Professor
Masahiko Sumitani, M.D., Ph.D.

Lecturer
Hiroaki Abe, M.D, Ph.D.

Homepagehttps://www.h.u-tokyo.ac.jp/english/centers-services/centralclinical-facilities/department-of-palliative-medicine/index.html

History and outline of organization
About a half of the cancer patients die by cancer
though of the recent innovations of anti-cancer
treatments. It mainly depends on the efficacy of thefirst-line strategies whether cancer is curable or not.
Almost all the cancer patients whose initial treatment
was unsuccessful die after the distressing struggle
against their disease within several years. It is clear
for such patients that both sufficient anti-cancer
treatments and appropriate approaches to improvetheir quality of life (QOL) are simultaneously indispensable.
However in our nation, most attention has been
entirely paid to the improvement of cure rate andsurvival time of cancer patients. On the other hand, we
have to consider that their QOL is scarcely
concentrated until quite recently.
Palliative care means the combination of active
therapeutic approach and total human care for thepatients no matter which their cancer does or does not
respond to anti-cancer treatments. Pain relief, othersymptom management, psychological, social andspiritual cares are as a top priority for these patients. It
is also emphasized that palliative care is necessary to
be applied in the cancer treatment even for patients inearly stage of their diseases as well as the progressiveor terminal phase of their clinical courses.
In Department of Pain and Palliative Medicine of The
University of Tokyo Hospital, we pain and palliative

care team takes a leading role not only to control
physical symptoms of cancer patients but also to carefor the mental and social support at the same time, andto improve the overall QOL of patients. Moreover, we
also promote the education, research and innovation ofpain and palliative medicine of our hospital anduniversity.
Palliative care is described clearly in the law "Cancer
Control Act" approved by the National Diet on June
2006 that "The medical treatment to aim at relieving
many kinds of pain and problems of cancer patients is
applicable from the early course of the illness".

Consultation
In The University of Tokyo Hospital, we pain andpalliative care team are composed of many kinds ofspecialists containing three full-time staff doctors, twofull-time doctors, and two certificated cancer andhospice care nurses who take an initiative in thismultidisciplinary team. We visit to bedsides, consultation rooms and everywhere in the hospital, and offer
palliative care to cancer patients who have received
cancer care in cooperation with patients’ attending
doctors, ward staff, therapists of rehabilitation, social
workers and every kind of professionals.
The annual number of consultation by our pain andpalliative care team is getting increased. In 2019, thenumbers achieved to more than total 1000 cases per
year and further increased. To date we have become to519

collaborate with almost all departments treating
cancer in our hospital. These results indicate that thehospital understands the significance of palliative carewell and relies on our team.

Education
In the Department of Pain and Palliative Medicine,junior residents of the first and second year can learn
the basic knowledge and practice of palliative care by
selecting an optional subject for one, two, four oreight months. And then they can participate in the pain
and palliative care team and attend the daily teamconference on weekdays.
1) Palliative care training program
The training course (selection) for two months (or *for one month )･ Program to acquire basic knowledge and practice ofpalliative care for targeting all junior residents. *Only in "Comprehensive Internal Medicine”
selection.
The training course (selection) for four or eightmonths･ Program to acquire basic knowledge, practice, andskills of communication for doctors who need to beclinical oncologists or pain and palliative carespecialists.
2) CurriculumContents of training･ All junior residents are assigned to the pain andpalliative care team. They chiefly participate inpalliative care practice as a member of the team.
･ In the course for four and eight months, they learn
to make palliative care plans for inpatients, discuss
palliative care of the cases with patients’ attending
doctors, ward staff, and execute these palliative careplans.
Goal to attain･ Palliative care for inpatients (around 40 cases aday): They acquire the outline of control of physicaland psychiatric symptoms of the patients with
common diseases in our country such as digestivecancers. They also learn the outline of spiritual andfamily care.
･ Cancer registry: In The University of Tokyo

Hospital, it is not unusual that the patient whom thepain and palliative care team treats is often in an
end stage, and his or her condition changes
physically and mentally day by day. Residents
should input the clinical data about palliative careof such patients concisely to the database. Theyacquire the outline of data management of thepalliative care connected directly to a clinicalresearch.
･ Communicative competence: The clinician often
has to break "Bad news" to his patients time after
time along the course of their illness. It is very
difficult for the clinician to provide the appropriate
information about diagnoses, recurrence, progression and prognosis of illness to his patients.
The oncologist has to deal with patients’ strong grief
and feeling of loss when their illness is obviously progressive as well as has to manage both their accepting
realities and expecting hopes. We practice according
to the guidelines of communication that is recommended by the Japanese Psycho-Oncology Society.
Educational･ In the intensive course for the first-year residents,
we prepare lectures about:# pain management# diagnoses and management of delirium# Introduction of guidelines in the field of palliative
medicine and their use# Basic medication for palliative care
# Spirituality and whole person care for Japanesepatients facing death
Daily and weekly schedule･ Conference: Monday-Friday (every weekday);9:00-10:30am･ Consultation: Monday-Friday (every weekday);from the end of morning conference, up to the completion of all the requested consulting of the day.
･ The cancer registry: They input data in the ward
round with the HIS (Hospital information system)
terminal on each floor.
The instruction system･ Inpatient care: Residents participate in the
consultation team (pain and palliative care team)that contains medical instructors. We pain andpalliative care team take charge of about 40-50
inpatients usually.

520･ Multidisciplinary conference: Psychiatrists, pain
clinicians/Anesthesiologists, orthopaedicians, pharmacists, medical social workers and others
participate in the daily or weekly conference
besides the regular member of the pain andpalliative care team. Residents can discuss actively
the multidisciplinary palliative care plans which ourteam should carry out. Participants from each
occupation also guide the care plans from their
viewpoints of experts.

Research
The clinical information accumulated from thepalliative care consultation is input to the concise
database simultaneously and utilized for various kindsof clinical researches to submit to the international
medical journal such as "International Journal of
Radiation Oncology Biology Physics", "Journal ofPain and Symptom Management" and so on.
To date, we the Department of Palliative Medicine
have contributed to the progress of following fields ofinvestigations. Please refer to our homepage forresults in details and acquisition of the research fund.
1) Evaluation and quality assurance of special pain
and palliative care team2) Cancer Survivorship
3) Investigating cognitive dysfunction induced bypain4) Cancer treatments-induced neurological side
effect5) Synergistic influence between sleep disorder andpain6) Assessment of neuropathic pain
7) Relationships among our university hospital andlocal hospitals and clinics
8) Palliative care supporting metastatic breast cancer
patient9) In palliative medicine field, clinical researchesand questionnaires

Publications
1.

Mietani K, et al. Elevateed neuron-specificenolase level is associated with postoperativedelirium and detection of phosphorylated
neurofilament heavy subunit: A prospective

observational study. PLoS ONE 2021; 16:e0259217
2. The OSCIS investigators. Effect of early vsdelayed surgery on motor recovery in incomplete
cervical spinal cord injury with pre-existingcervical stenosis: a randomized clinical trial.
JAMA Network Open 2021; 4: e2133604
3. Inoue R, et al. Capecitabine-induced hand-footsyndrome does not emerge in the complex
regional pain syndrome-affected limb: Case
Report. Mol Clin Oncol 2021; 15: 254
4. Kato K, et al. Development of a severity
discrimination scale based on physical quality oflife for patients with chronic pain. J Orthop Sci
2021; 26: 1124-9
5. Osumi M, et al. Fear of movement-related pain
disturbs cortical preparatory activity after
becoming aware of motor intention. Behav Brain
Res 2021; 411: 113379
6. Osumi M, et al. Pain quality of thermal grill
illusion is similar to that of central neuropathic
pain rather than peripheral neuropathic pain.
Scand J Pain 2021; 22: 40-7
7. Tsuchida R, et al. Genetic polymorphisms oflysophosphatidic acid receptor 1 are associatedwith the onset of taxane-induced peripheral
neuropathy. Br J Anaesth 2021; 127: e43-6
8. Sumitani M. Time to act for reappraising the
educational system for universal access to opioid
analgesics, for quality palliative care andcancer-related pain relief in East Asian countries.
Lancet Regional Health – Western Pacific 2021;
16: 100270
9. Saita K, et al. Exponential correlations amongneuropathic components, pain intensity andcatastrophic
thoughts
inpatients
withmusculoskeletal pain disorder. Curr Med Res
Opin 2021; 37: 1341-8
10. Ikeda K, et al. Required research activities toovercome addiction problems in Japan. Taiwan J
Psychiatr 2021; 35: 6-11
11. Uranbileg B, et al. Inhibition of autotaxin activity
ameliorates neuropathic pain derived fromlumbar spinal stenosis. Scientific Reports 2021;
11: 3984
12. Ando M, et al. Tele virtual reality-based peer
support programme for cancer patients: a521

preliminary feasibility and acceptability study. Br
J Cancer Res 2021; 3: 443-8
13. Nagata K, et al. Diabetes is associated withgreater leg pain and worse patient-reported
outcomes at one year after lumbar spine surgery.
Scientific Reports 2021; 11: 8142
14. Owada H, et al. Peripheral nerve field stimulation
successfully manages axial pain after posteriorcervical spine surgery: case report. Ann Palliat
Med 2021; 10: 579-96
15. Nishi Y, et al. Kinematic change in goal-directedmovements in a fear-conditioning paradigm.
Scientific Reports 2021; 11: 11162
16. Kaizu M, Komatsu H, Yamauchi H, et al.
Characteristics of taste alterations in people
receiving taxane-based chemotherapy and theirassociation with appetite, weight and quality oflife. Supp Care Cancer 2021; 29: 5103-14(And, 18 Japanese articles)522

Department of Disaster Medical
Management
Professor
Kent Doi, M.D.,Ph.D.

Lecturer
Chiaki Toida M.D.,Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/dmm/index.html

Introduction and Organization
Responding to the Great East Japan Earthquake in2011, the University of Tokyo Hospital has decided to
set out to establish “disaster medical management
studies” in terms of need not only to provide medical
treatment at the time of disaster but also to develop a
new academic field that provides bird’s-eye view on
overall disaster medicine. In March 2012, we made anannouncement to establish “Department of Disaster
Medical Management” in the Public Comment.
In July 2012, Associate Professor Dr. Hiroyuki
Nakao was assigned the post as the first General
Manager of the Department of Disaster Medical
Management. Afterwards, in January 2015, Professor Dr. Tadashi Iwanaka, the Hospital Vice Director,
was assigned the post as the second General Manager.
In April 2015, Professor Dr. Masaomi Nangaku, theHospital Vice Director in charge of crisis managementand disaster prevention, was assigned the post as thethird General Manager. In April 2017, Professor Dr.
Naoto Morimura was assigned the post as the fourth
General Manager of the Department of Disaster
Medical Management and was appointed as the chairman of the in-hospital Disaster Prevention Committee.
This department belongs to the Central ClinicalFacilities Division and is involved in activities within
this hospital and inside/outside of the University.
In order to establish disaster medical management
studies, we are aiming at 1) fostering leaders who candevelop plans for disaster medicine and educate

personnel engaged in disaster medicine, 2) relationship building with relevant institutions for establishinga system for the University of Tokyo Hospital to leaddisaster medicine and 3) developing a system as abase of formation of organizations at the time ofdisaster.

Clinical activities
Since 2012, the Disaster Prevention Committee
carries out planning and conduct the University ofTokyo Hospital Comprehensive Disaster Drill
regularly. Drills of launching a new earthquake early
warning system, building hospital headquarter fordisaster control, reporting in-hospital damage situation,
establishing triage and casualty clearing station, triage
and rescue of mass casualties, were performed yearlywith cooperation of the University of Tokyo, theMetropolitan Tokyo Fire Department, and the Ministryof Health Labor and Welfare.

Teaching activities
As educational activities inside and outside of the
University, we are holding and teaching MIMMS,
Major Incident Medical Management and Support,
courses accredited by English ALSG, Advanced Life
Support Group, regularly for the purpose of developing leadership of health care professionals who canprovide ideal medical care in times of disaster.

523

Research activities
We are seeking ways of cooperation between
institutions through workshops with relevant
institutions from the perspective that day-to-day
cooperation with relevant institutions can be alsoutilized at the time of disaster. We consider that it canbe also utilized for cross-business formation oforganizations at the time of disaster.
Other than that, we are holding outside researchgroups and cooperating for building up a functional
emergency medical system at the time of disaster.

References
1. Toida C, Muguruma T, Gakumazawa M,
Shinohara M, Abe T, Takeuchi I, Morimura N.
Age- and Severity-Related In-Hospital Mortality
Trends and Risks of Severe Traumatic Brain
Injury in Japan: A Nationwide 10-Year Retrospective Study. J Clin Med. 2021 Mar 4;10(5):1072.
2. Toida C, Muguruma T, Gakumazawa M,
Shinohara M, Abe T, Takeuchi I, Morimura N.
Correlation between Hospital Volume of Severely
Injured Patients and In-Hospital Mortality of
Severely Injured Pediatric Patients in Japan: A
Nationwide 5-Year Retrospective Study. J Clin
Med. 2021 Apr 1;10(7):1422.
3. Hirayama I, Doi K, Yamamoto M, Toida C,
Morimura N. Evaluation of Autonomous Actions
on Bystander-Initiated Cardiopulmonary Resuscitation and Public Access Defibrillation in Tokyo.
Int Heart J. 2021 Jul 30;62(4):879-884.

524International Medical Center
Director and Associate Professor
Sumihito Tamura, M.D., Ph.D. FACS

Homepage

http://www.h.u-tokyo.ac.jp/english/international-patients/index.html

Introduction and Organization
The International Medical Center is a Division within
the Central Clinical Facilities established to enhance
The University of Tokyo Hospital’s development as aninternational medical hub in coordination with the
University of Tokyo’s significant movement inglobalization. Designated management position has
been assigned.

Activities and challenges
The University of Tokyo Hospital offers sophisticatedsurgery and state-of-the-art treatment in variety offields. One of the roles of the International Medical
Center is to establish a system through which we
provide medical expertise to patients from overseas.
The International Medical Center will cater to thevarious requirements that must be met when accepting
overseas patients, including multilingual support,
translation of medical documents, and offeringsolutions to financial challenges, so that each department can focus solely on providing medical treatment
to those patients.
As well as receiving patients, another important
aspect is the globalization of clinical education. We
hope to establish a system in which non-Japanese
doctors accepted for residencies, or those who come toreceive cutting-edge medical training can carry out
operations, interventions or demonstrations without
being hindered by their nationality. Similarly, we hopeto establish a system through which overseas doctors
can learn new techniques alongside Japanese doctors,
and to provide an environment where doctors fromvarious countries can mingle with young doctors
working at our hospital, as well as student physiciansin participatory clinical training. We have been

actively accepting observership trainees per hospitalruling and advanced clinical trainees granted
permission for hands-on clinical experience by the
Ministry of Health, Labor and Welfare under the
Exceptional Cases of the Medical Practitioners ‘Act,
Article 17, regarding Advanced Clinical Training of
Foreign Medical Practitioners, etc.
Lastly, heightening the capability of physicians andmedical staff to cater to international needs is an
important factor in globalizing The University ofTokyo Hospital. Starting last year, International
Continuous Professional Development Program has
been introduced, attracting multiple groups fromaround the globe for learning experience at the
University of Tokyo Hospital. To this end, theInternational Medical Center will attempt to cultivate
personnel by hosting various international exchanges
so as to further develop the hospital’s capabilities tobecome an international hub in the field.

525

Clinical Nutrition Center
Head of the Center
Kazuhiko Fukatsu (Professor)

Assistant Head of the Center
Naoto Kubota (Associate Professor) Department of Clinical Nutrition Therapy
Hideaki Ijichi (Lecturer) Division of Dietary Treatment and Nutritional Care

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/eiyou/

Introduction and Organization
In 1922, a stall in the outpatient department of thehospital and hospital ward shop sold milk, baked goods,
cider and ice cream. In 1925, a service contract between
the hospital and the Kojinkai Foundation resulted in thestart of a patient food service. In 1936, a “special
therapeutic diet” approach for newborn infants,
diabetes, nephropathy in which a physician prescribed
the food composition individually for each patient was
instituted for the first time in Japan. In 1950, a nationalhospital complete food service system was announced,
and the nutrient content provided was standardized.
The nutrient content provision for patient meals at thetime was 2400 kcal/day. In 1952, the inpatient meal
service was officially outsourced to a foundation.
In 1957, the first nationwide meeting of nationaluniversity-hospital head dietitians was held at the
University of Tokyo with the aim of improving patients’
diets.
In 1958, the complete food service was abolished.
Implementation of a standard food service and staffing
with a dietitian became required conditions, and thefood service section was staffed by a part-time section
chief and a dietitian. In 1962, a request from thenationwide meeting of national-university-hospitalhead dietitians, which primarily conducted its activities
at the University of Tokyo, was realized, and the
managerial dietitian system was established by a partial
revision of the Nutritionists Act. In 1972, nutritional
guidance was actively provided to inpatients andoutpatients with the aim of obtaining approval tocharge fees, and in 1978 a medical diet charge andnutrition guidance charge were established. In 1988, atimely tray service achieved by using hot and cold
food-tray carts was instituted in order to dispel the “tooearly, cold, unappetizing” reputation of hospital meals.
In 1991, the name of the food service section waschanged to the “Department of Nutrition Management”,
a change that had a long been sought by nationwide
national-university-hospital managerial dietitian staff
members. At the same time, the nutrition sections of themain hospital and branch hospital were consolidated,
and the head of the Department of Nutrition
Management, who was a managerial dietitian, assumed
the section manager post to form a system composed of
5 managerial dietitians at the main hospital and 3
managerial dietitians at the branch hospital.
In 1994, as a result of a partial revision of the
National Health Insurance Act, a diet therapy
notification system on admission was set up. An onadmission nutrition guidance fee was also established.
In 1998, the first Diet Therapy Exhibit organized by
the Department of Nutrition Management was
conducted as part of the diabetes week events by the
Tokyo Diabetes Association. Since then, Diet Therapy
Exibit has been conducted every year for over 20 years.
In 2001, integration of the branch hospital with themain hospital resulted in an 8-managerial- dietitiansystem. In 2004, the Department of Nutrition
Management was separated from the medical service
division. In 2005, the introduction of the self-pay
system for inpatient meals meant that inpatients began
to be charged for their meals. During the same year one

526

managerial dietitian (limited-term employment) was
added to the staff.
In 2006, charges for the performance of nutrition
management were newly established, and that meant
providing nutrition management for all patients. The
increase in work was accompanied by the addition of
one managerial dietitian (limited-term employment) to
the staff. Team care was introduced the same year, andin-hospital activity in the form of an all-department
nutrition support team (NST) was inaugurated. Eachhospital ward was staffed with a physician, managerial
dietitian, and nurse in charge of an NST, and whenevernecessary members from other fields (pharmacists,
medical technologists, physical therapists) joined, andthey held a hospital ward meeting once a week. In 2010,
an NST committee was created as a result of theestablishment of charges for NSTs. The NST director
up until that time became a member of the committee
and played an active role as the center of in-hospital
NST activities. The addition of one managerial dietitian(full time) was approved as a full-time employee toengage in the activities of charges for the NST. In 2011,
the inauguration of a nutritional guidance service forrecipients of health checkups in the Department of
Epidemiology and Preventive Medicine wasaccompanied by the addition of one managerial
dietitian (limited-term employment) to the staff. In
2012, charges for conducting nutrition management
were abolished. They were incorporated into the basic
hospital-admission fee, and the nutrition management
system by physicians, managerial dietitians, and nurses
was improved.
In 2013, the Department of Nutrition Management
was reorganized as the Department of ClinicalNutrition Therapy. A physician (Professor, the head of
the Central Clinical Services Administration) assumed
the concurrent post of head of the Department, and thehead of the Department of Nutrition Management
assumed the post of Assistant Head of the Department;
they undertook responsibility for managing the foodservice, maintaining activities of the NST, andstrengthening its functions. In 2014, two physicians,
full-time department head (associate professor) and
lecturer, were assigned and improvements were madeto NST activities and to the nutrition therapy, education,and research system. As a result of a managerial
strategic personnel distribution, 5 new managerial

dietitians (full-time) have also been assigned this fiscal
year. Along with the increase in work of managerial
dietitians for strengthening the nutrition management
system and expanding the number of clinical trials in
P1 unit, another managerial dietitian (limited-term
employment) was added to the staff in May 2015.
Long-coveted introduction of the New Cook Chill
System was eventually admitted by the University ofTokyo and the process was started in October 2016.
Renovation of the main kitchen was started in June
2017. During the renovation, the makeshift kitchen wasplaced on the 1st floor (the main kitchen) and the 3rdbasement floor (the washing room and the formularoom) of the Inpatients Ward A and the menu wasrestricted for the makeshift kitchen use. In February
2018, the New Cook Chill System in the University ofTokyo Hospital began. The menu was considerably
modified for the new cooking system.
In April 2018, a new formula room was launched on
the first floor of the Inpatients Ward A for the expansionof Pediatric Medical Center. Monthly issue of diet news
for the patients started in June 2018 and Grand Menu
for the special admission room was newly set up in
January 2019.
In 2019, the University of Tokyo Hospital wasrecognized as Tokyo Food Hygiene Meister by Tokyo
Metropolitan Certification System for SelfManagement of Food Hygiene, and also as an Elite
Institution of Food Hygiene by Bunkyo-ku.
In April 2020, the department was reorganized to be
the Clinical Nutrition Center, composed of the
Department of Clinical Nutrition Therapy in charge ofnutritional guidance and the Division of Dietary
Treatment and Nutritional Care in charge of meal
service and nutritional care for inpatients. A professorof the Surgical Center assumed the Head of the ClinicalNutrition Center, and the both sections named a
director (physician) and a deputy director (managerial
dietitian), respectively. All the other managerial
dietitians belong to the Center and engage in the worksof both sections.
During the pandemic of COVID-19, the hospital
closed the special admission room and the Grand Menu
was stopped in 2021.

527

Clinical Activities
The Center is proactively conducting nutritional
guidance in regard to metabolic diseases, including
diabetes, chronic kidney disease, dyslipidemia, andobesity, perioperative guidance, including in regard to
postgastrectomy diets, hepatobiliary and pancreaticdisease diets, and cardiac disease diets, etc.
In 2021, nutritional guidance of inpatients andoutpatients increased upto3648 instances for inpatientsand 6916 instances for outpatients. Nutritional
guidance for malignant tumor patients was performedfor 822 instances.
The Center is also proactively cooperating withseveral departments in the hospital. In 2021,
perioperative guidance was 91 instances, diabetes anddialysis prevention guidance for outpatients was 141
instances, dietary management with palliative care was
339 instances, nutritional guidance for outpatientchemotherapy was 161 instances, nutritional guidanceat the preventive medicine center was 60 instances. In
addition, the provision of inpatient nutrition
information was 61 instances.
In April 2014, the department started calculating
charges for NST and counted 1261 instances in the firstfiscal year. In April 2016, dentists joined the NST
round and started to calculate the additional charge.
After 2020, due to the COVID-19 pandemic, theinstances decreased. 260 rounds were performed and204 instances were calculated in 2021.
In November 2014, a procedure manual ofnutritional management was revised and an original
two-step nutritional screening by physicians,
managerial dietitians, nurses and pharmacists wasintroduced. In this system, the high-risk patients ofmalnutrition were weekly screened through thecommon criteria in our hospital and referred to the NSTof each floor (ward NST). In April 2015, alternative
initial screening criteria specific for pediatric andpregnant patients were added to the procedure manualof nutritional management, respectively. By 2019,
almost all the floor started the ward NST, whichindicated raised awareness of nutritional care as a team
medicine in our hospital. Then, in 2020, instead of thecommon screening criteria, each floor started more
specific screening for the ward NST, based on thecharacteristics of the patients and treatment department.

In 2018, related with the start of surgery for severe
obesity patients (sleeve gastrectomy), sleeve diet was
newly introduced. In January 2019, ketogenic diet wasalso introduced in cooperation with Epilepsy Center.
In 2019, in addition to the Tokyo Food Hygiene
Meister and Elite Institution of Food Hygiene by
Bunkyo-ku, the safe and assured food service in our
hospital was evaluated “S” rank (the highest) by thehospital function evaluation.

Educational Activities
The department has accepted managerial dietitian
clinical trainees. In 2019, the department accepted 45
trainees from 7 training schools: Ochanomizu
University, Tokyo Kasei University, Otsuma Women’s
University, Kagawa Education Institute of Nutrition,
Jissen Women’s Educational Institute, Japan Women’s
University, and Wayo Women’s University.
In 2011, the department began accepting NST
trainees. From 1 to 4 or 5 terms are conducted a year (5days/ week/ term). Participants are mainly managerial
dietitians, pharmacists, nurses, medical technologists,and physical therapists, and candidates are trainees
whose aim is acquiring the qualifications certified byacademic societies or to become a full-time employee
to calculate the billing charges for the NST. There were18 participants in 2019. Due to the COVID-19
pandemic, these programs accepting external trainee
were cancelled in 2020-2021.
In 2017, the department was involved in the
curriculum of Clinical Clerkship 2, the medical education program of the Faculty of Medicine, the Universityof Tokyo. 106 medical students at M4 grade
participated in the two-day practice course in 2021.
To disseminate NST activities fully in the hospital,
the department has organized two NST-related
seminars throughout the year: Basic Series for
Nutrition Therapy and Clinical Nutrition Seminar. The
department has also organized NST Conference andJoint Conference of Team Medicine (JCTM) for casediscussions to facilitate cooperation with each floor
NST and other medical teams. In 2020, due to the
COVID-19 pandemic, all the seminars and JCTM wereconducted online and the NST Conference wasadjourned. In 2021, the Center combined the twoseminars and restarted with a hybrid style, on-site and528

online, with total 546 attendee.
In 2015, the department started “Nutritional
Management e-learning” for all employee to learn basic
knowledge of nutritional management procedure.
In 2016, “The Manual of The Department of ClinicalNutrition Therapy 2015-2016” was published. After
that, “The Pocket Manual of The Department ofClinical Nutrition Therapy 2016-2017”, “The Manualof The Department of Clinical Nutrition Therapy 20172019”, “Records of the Kitchen Renovation 20162018”, “The Pocket Manual of The Department ofClinical Nutrition Therapy 2018-2021”, “Illustrated
Tools of Nutritional Guidance 2018-2022” and “New
Cook Chill Manual 2018-2022” were published byMarch 2020.

Research・Research topic: “Retrospective study using databaseof patients records who have undergone nutritional
guidance”
・Research topic: “Surveillance of nutritional status
and its change in pancreatic cancer patients receiving
chemotherapy”
・ Research topic: “Surveillance of change in bodycomposition by using visceral fat measuring device”
・Research topic: “Roles of microbiome in lifestylerelated diseases” (Joint research)
・ Research topic: “Exploratory research in theassociation of plasma amino acids and the nutrition
status of patients with diabetes mellitus and thecomorbidities”
・Research topic: “Exploratory research of biomarkers
in the blood and body fluid for diabetes mellitus”
・Research topic: “Impact of periodical measurementof serum glycoalbumin on the patients with diabetes
mellitus”
・Research topic: “Impact of periodical measurementof diabetes mellitus-related biomarkers in tear fluid”
・Research topic: “Association of food diversity andobesity in patients with diabetes mellitus”
・Research topic: “Evaluation of nutritional guidanceon the treatment-naïve patients with high LDLcholesterolemia”
・ Research topic: “Association of initial nutritional
condition and prognosis in elderly patients at NST
round”

・ Research topic: “Assessment of dietary intake of
inpatients with diabetes mellitus”
・Research topics: “Correlation research of biomarkers
in the blood and body fluid and diabetes mellitus”
・Research topic: “Association of diet and nutritional
factors and control of blood sugar and lipid inpatients with diabetes mellitus”
・Research topic: “Association of diet and nutritional
factors and sarcopenia and frail in elderly patientswith diabetes mellitus”
・Research topic: “Association of dietary intake andbackground dietary habit in inpatients with diabetes
mellitus”
・Research topic: “Assessment of dietary intake andbodily characteristics in patients with eating disorder”
・Research topic: “Association of change of dietaryintake and weight loss effect in highly obese patients
after bariatric surgery”
・Research topic: “Surveillance of nutritional status
and its change in patients with severe heart failure”
・ Research topic: “Surveillance of nutritional
assessment and guidance at the perioperative clinic”

References<Publications (English)>
1. Nakatsuka T, Tateishi K, Kato H, Fujiwara H,
Yamamoto K, Kudo Y, Nakagawa H, Tanaka Y,
Ijichi H, Ikenoue T, Ishizawa T, Hasegawa K,
Tachibana M, Shinkai Y, Koike K. Inhibition ofhistone methyltransferase G9a attenuates livercancer initiation by sensitizing DNA-damaged
hepatocytes to p53-induced apoptosis. Cell Death
Dis. 12:99, 2021.
2. Yamazaki T, Inada S, Sawada M, Sekine R,
Kubota N, Fukatsu K, Yoshiuchi K. Diets withhigh carbohydrate contents were associated withrefeeding hypophosphatemia: A retrospective
study in Japanese inpatients with anorexia nervosa.
Int J Eat Disord. 54:88-94, 2021.
3. Tanaka Y, Shimanaka Y, Caddeo A, Kubo T, Mao
Y, Kubota T, Kubota N, Yamauchi T, Mancina RM,
Baselli G, Luukkonen P, Pihlajamäki J, YkiJärvinen H, Valenti L, Arai H, Romeo S, Kono N.
LPIAT1/MBOAT7
depletion
increases
triglyceride synthesis fueled by high phosphatidylinositol turnover. Gut. 70:180-193, 2021.

529

4.

Aihara M, Kubota N, Minami T, Shirakawa R,
Sakurai Y, Hayashi T, Iwamoto M, Takamoto I,
Kubota T, Suzuki R, Usami S, Jinnouchi H, Aihara
M, Yamauchi T, Sakata T, Kadowaki T.
Association between tear and blood glucose
concentrations: Random intercept model adjustedwith confounders in tear samples negative foroccult blood. J Diabetes Investig. 12:266-276,
2021.
5. Saito K, Nakai Y, Takahara N, Ishigaki K, Suzuki
Y, Inokuma A, Noguchi K, Kanai S, Sato T,
Hakuta R, Saito T, Hamada T, Mizuno S, Kogure
H, Ijichi H, Tateishi K, Koike K. A retrospective
comparative study of S-IROX and modified
FOLFIRINOX for patients with advanced
pancreatic cancer refractory to gemcitabine plus
nab-paclitaxel. Invest New Drugs. 39:605-613,
2021.
6. Sakurai Y, Kubota N, Yamauchi T, Kadowaki T.
Role of Insulin Resistance in MAFLD. Int J Mol
Sci. 22:4156, 2021.
7. Hamada T, Oyama H, Nakai Y, Tada M, Koh H,
Tateishi K, Arita J, Hakuta R, Ijichi H, Ishigaki K,
Kawaguchi Y, Kogure H, Mizuno S, Morikawa T,
Saito K, Saito T, Sato T, Takagi K, Takahara N,
Takahashi R, Tanaka A, Tanaka M, Ushiku T,
Hasegawa K, Koike K. ABO Blood Group and
Risk of Pancreatic Carcinogenesis in Intraductal
Papillary
Mucinous
Neoplasms.
CancerEpidemiol Biomarkers Prev. 30:1020-1028, 2021.
8. Kubota N, Kubota T, Kadowaki T. Midlobularzone 2 hepatocytes: A gatekeeper of liver
homeostasis. Cell Metab. 33:855-856, 2021.
9. Watanabe D, Murakami H, Ohno H, Tanisawa K,
Konishi K, Todoroki-Mori K, Tsunematsu Y, Sato
M, Ogata Y, Miyoshi N, Kubota N, Kunisawa J,
Wakabayashi K, Kubota T, Watanabe K, Miyachi
M. Stool pattern is associated with not only theprevalence of tumorigenic bacteria isolated fromfecal matter but also plasma and fecal fatty acids
in healthy Japanese adults. BMC Microbiol. 21:
196, 2021.
10. Hasegawa Y, Ijichi H, Saito K, Ishigaki K, Takami
M, Sekine R, Usami S, Nakai Y, Koike K, Kubota
N. Protein intake after the initiation ofchemotherapy is an independent prognostic factor
for overall survival in patients with unresectable

11.

12.

13.

14.

15.

16.

pancreatic cancer: A prospective cohort study.
Clin Nutr. 40:4792-4798, 2021.
Watkins A, Fukatsu K, Higashizono K, Watanabe
T, Noguchi M, Tominaga E, Murakoshi S,
Yasuhara H. Influence of a Low-Carbohydrate
High-Fat Diet on Peritoneal Inflammation,
Cancer-Associated Lymphocytes, and Survival ina Murine Carcinomatous Peritonitis Model. JPENJ Parenter Enteral Nutr. 45:1293-1301, 2021.
Hayashi T, Kubota T, Mariko I, Takamoto I,
Aihara M, Sakurai Y, Wada N, Miki T, Yamauchi
T, Kubota N, Kadowaki T. Lack of Brain Insulin
Receptor Substrate-1 Causes Growth Retardation,
With Decreased Expression of Growth HormoneReleasing Hormone in the Hypothalamus.
Diabetes. 70:1640-1653, 2021.
Furuzono S, Kubota T, Taura J, Konishi M, Naito
A, Tsutsui M, Karasawa H, Kubota N, Kadowaki
T. A xanthene derivative, DS20060511, attenuates
glucose intolerance by inducing skeletal musclespecific GLUT4 translocation in mice. Commun
Biol. 4:994, 2021.
Sano M, Takahashi R, Ijichi H, Ishigaki K,
Yamada T, Miyabayashi K, Kimura G, Mizuno S,
Kato H, Fujiwara H, Nakatsuka T, Tanaka Y, Kim
J, Masugi Y, Morishita Y, Tanaka M, Ushiku T,
Nakai Y, Tateishi K, Ishii Y, Isayama H, Moses HL,
Koike K. Blocking VCAM-1 inhibits pancreatictumour progression and cancer-associatedthrombosis/thromboembolism. Gut. 70:17131723, 2021.
Ochiai T, Sano T, Nagayama T, Kubota N,
Kadowaki T, Wakabayashi T, Iwatsubo T.
Differential involvement of insulin receptor
substrate (IRS)-1 and IRS-2 in brain insulin
signaling is associated with the effects on amyloid
pathology in a mouse model of Alzheimer's
disease. Neurobiol Dis. 159:105510, 2021.
Ishihama S, Yoshida S, Yoshida T, Mori Y, Ouchi
N, Eguchi S, Sakaguchi T, Tsuda T, Kato K,
Shimizu Y, Ohashi K, Okumura T, Bando YK,
Yagyu H, Wettschureck N, Kubota N, Offermanns
S, Kadowaki T, Murohara T, Takefuji M.
LPL/AQP7/GPD2 promotes glycerol metabolism
under hypoxia and prevents cardiac dysfunction
during ischemia. FASEB J. 35:e22048, 2021.

530

17. Jinnouchi T, Sakurai Y, Miyoshi K, Koizumi C,
Waki H, Kubota N, Yamauchi T. Chronic
Intestinal Pseudo-obstruction with Mitochondrial
Diseases. Intern Med. 61:469-474, 2021.
18. Kato H, Tateishi K, Fujiwara H, Nakatsuka T,
Yamamoto K, Kudo Y, Hayakawa Y, Nakagawa H,
Tanaka Y, Ijichi H, Otsuka M, Iwadate D, Oyama
H, Kanai S, Noguchi K, Suzuki T, Sato T, Hakuta
R, Ishigaki K, Saito K, Saito T, Takahara N,
Kishikawa T, Hamada T, Takahashi R,
Miyabayashi K, Mizuno S, Kogure H, Nakai Y,
Hirata Y, Toyoda A, Ichikawa K, Qu W, Morishita
S, Arita J, Tanaka M, Ushiku T, Hasegawa K,
Fujishiro M, Koike K. MNX1-HNF1B Axis Is
Indispensable for Intraductal Papillary Mucinous
Neoplasm Lineages. Gastroenterology. Epub 2021
Dec 22.

531

Department of Clinical Genomics
Director & Professor
Katsutoshi Oda, M.D., Ph.D.

Project Associate Professor
Hidenori Kage, M.D., Ph.D.

Associate Professor
Aya Ushiku, M.D., Ph.D.

Organization
The Department of Clinical Genomics started as a
special unit providing clinical genomics services in
2003. The department functions as the core unit toprovide genetic counseling services to support anappropriate and efficient application of genetic testing,as well as genomic medicine in cancer. The department also provides a training program for physicians
preparing for board-certified clinical geneticists.
Many medical staffs with diverse specialties including
pediatricians, obstetricians, neurologists, cardiologists diabetologists and surgeons participate in theactivities of the Department.

Activities
Genetic Counseling
The room (Room 200) is specifically allocated in
the outpatient clinic. Genetic counseling is performed
by a team of board-certified clinical geneticist andcertified genetic counselors in cooperation with otherclinical departments. All cases are reviewed anddiscussed at the conference which is held once every
month. We also provide support to clinicaldepartments for establishing genetic diagnosis invarious types of diseases, including neurologicaldisorder, pediatric and perinatal disorders, Marfan’sSyndrome and Hereditary Breast and Ovarian Cancer.
Genomic Medicine in Cancer
We provide cancer genomic profiling (clinicalsequencing) for incurable malignant solid tumors with12 collaborative hospitals, as a “Cancer Genome Core
Hospital”. Two types of cancer genomic profiling(OncoGuideTM
NCC
Oncopanel
System,FoundationOne® CDx Cancer Genomic Profililng)
were approved by PMDA in June, 2019.
FoundationOne® Liquid CDx Cancer Genomic
Profililng will be also approved in 2021. As well, we
provide an original multiplex genome sequencing,named "Todai OncoPanel”, which is composed of
DNA panel and RNA panel. The room (Room 202) is
specifically allocated in the outpatient clinic forgenomic medicine in cancer (twice weekly).

Publications
1.

2.

3.

Iwasaki A, Shinozaki-Ushiku A, Kunita A,
Yamazawa S, Sato Y, Yamashita H, Fukayama
M, Seto Y, Ushiku T: Human Leukocyte Antigen
Class I Deficiency in Gastric Carcinoma: An
Adaptive Immune Evasion Strategy Most
Common in Microsatellite Instable Tumors. Am
J Surg Pathol 45:1213-1220,2021.
Nagano M, Kohsaka S, Hayashi T, Ueno T,
Kojima S, Shinozaki-Ushiku A, Morita S, Tsuda
M, Tanaka S, Shinohara T, Omori Y, Sugaya F,
Kato H, Narita Y, Nakajima J, Suzuki K,
Takamochi K, Mano H: Comprehensive
molecular profiling of pulmonary pleomorphic
carcinoma. NPJ Precis Oncol 5:57,2021.
Sato A, Tanabe M, Tsuboi Y, Niwa T, ShinozakiUshiku A, Seto Y, Murakami Y: Circulating

532

4.

5.

6.

7.

8.

9.

Tumor DNA Harboring the BRAF(V600E)
Mutation May Predict Poor Outcomes of Primary
Papillary Thyroid Cancer Patients. Thyroid 31:
1822-1828,2021.
Kato S, Kubota Y, Sekiguchi M, Watanabe K,
Shinozaki-Ushiku A, Takita J, Hiwatari M:
KMT2A-rearranged
diffuselarge
B-celllymphoma in a child: a case report and molecularcharacterization. Pediatr Hematol Oncol 38:
281-289,2021.
Sunami K, Naito Y, Aimono E, Amano T,
Ennishi D, Kage H, Kanai M, Komine K,
Koyama T, Maeda T, Morita S, Sakai D, Kohsaka
S, Tsuchihara K, Yoshino T: Correction to: The
initial assessment of expert panel performance incore hospitals for cancer genomic medicine inJapan. Int J Clin Oncol 26:1007,2021.
Sunami K, Naito Y, Aimono E, Amano T,
Ennishi D, Kage H, Kanai M, Komine K,
Koyama T, Maeda T, Morita S, Sakai D, Kohsaka
S, Tsuchihara K, Yoshino T: The initialassessment of expert panel performance in core
hospitals for cancer genomic medicine in Japan.
Int J Clin Oncol 26:443-449,2021.
Ikushima H, Hiraishi Y, Toriumi K, Ando T,
Tamiya H, Ishida J, Amano Y, Kage H, Tanaka
G, Nagase T: Multiple cerebral infarctions in
ROS1-rearrangedlungadenocarcinoma.
Respirol Case Rep 9:e0831,2021.
Naito Y, Aburatani H, Amano T, Baba E,
Furukawa T, Hayashida T, Hiyama E, Ikeda S,
Kanai M, Kato M, Kinoshita I, Kiyota N, Kohno
T, Kohsaka S, Komine K, Matsumura I, Miura Y,
Nakamura Y, Natsume A, Nishio K, Oda K, Oda
N, Okita N, Oseto K, Sunami K, Takahashi H,
Takeda M, Tashiro S, Toyooka S, Ueno H,
Yachida S, Yoshino T, Tsuchihara K: Clinicalpractice guidance for next-generation sequencing
in cancer diagnosis and treatment (edition 2.1).
Int J Clin Oncol 26:233-283,2021.
Ebihara T, Nagatomo T, Sugiyama Y, Tsuruoka
T, Osone Y, Shimura M, Tajika M, Matsuhashi T,
Ichimoto K, Matsunaga A, Akiyama N, OgawaTominaga M, Yatsuka Y, Nitta KR, Kishita Y,
Fushimi T, Imai-Okazaki A, Ohtake A, Okazaki
Y, Murayama K: Neonatal-onset mitochondrial
disease: clinical features, molecular diagnosis

and prognosis. Arch Dis Child Fetal Neonatal
Ed 107:329-334,2022.
10. Akiyama N, Shimura M, Yamazaki T, Harashima
H, Fushimi T, Tsuruoka T, Ebihara T, Ichimoto
K, Matsunaga A, Saito-Tsuruoka M, Yatsuka Y,
Kishita Y, Kohda M, Namba A, Kamei Y,
Okazaki Y, Kosugi S, Ohtake A, Murayama K:
Prenatal diagnosis of severe mitochondrial
diseases caused by nuclear gene defects: a study
in Japan. Sci Rep 11:3531,2021.

533

BioResource Center
Director
Tetsuo Ushiku, M.D., Ph.D. (Professor, Department of Pathology and Diagnostic Pathology)

Deputy Director
Katsutoshi, Oda, M.D., Ph.D. (Professor, Division of Integrative Genomics)

Staff
Aya Shinozaki-Ushiku, M.D., Ph.D. (Associate Professor, Division of Integrative Genomics)

Homepagehttps://www.h.u-tokyo.ac.jp/patient/depts/bio-resource/

Introduction and Organization
A wide variety of clinical and scientific research is
being conducted at The University of Tokyo Hospitaland Faculty of Medicine. When using samples obtained
from patients through surgery and laboratory tests,
researchers of each department have obtained informed
consent for the research and stored the samples in theirown laboratory. To utilize valuable resources more
effectively, the center specialized in collecting andstoring samples is needed. The University of Tokyo
Hospital is one of the core hospitals to promote cancer
genomic medicine in Japan and is required to equip
biobank to store tissue samples of multiple organs.
In these settings, a working group has started to workon the establishment of BioResource Center since 2020.
Members from the Departments of Clinical Genomics,
Pathology, Clinical Laboratory and Surgery, as well as
experts in basic medical research, discussed how to
inform and obtain consent of the patients, details oftissue sampling and storing protocols, and the processof utilizing samples in medical research. After theapproval by Hospital Executives, BioResource Center
was established as one of the Clinical ResearchServices of the University of Tokyo Hospital on Apr 1,
2021. This BiorResource Center Project was also
approved by Research Ethics Committee of the Facultyof Medicine on Aug 16, 2021.
Samples, clinical information, and research data withwritten informed consent of the patients are stored in
the center and are utilized in the research approved by

Research Ethics Committee. Staffs of the center andrepresentatives of clinical departments also hold acommittee to review the research protocols to check
whether the use of the stored samples is appropriate.

Clinical activities
Three doctors (director, deputy director and a staff) andtwo project academic specialists are in charge of theactivity. We work together with Department of Surgery,
Pathology, Clinical Laboratory and Surgical Center inobtaining patients’ consent and collecting samples.
Members of the Office of Research Support also
support us in the management of the center.
In FY2021, we worked on the sampling protocols,developed a system and a database to collect the
information of patients’ consent and stored samples,and set up a laboratory. Sampling of peripheral bloodand tissues started in March 2022.
BioResource Center freezes and stores DNA andplasma extracted from peripheral blood and paired
normal/tumor tissues. Sample information such as
patient’s age, sex and cancer type are also collected.
The center will cover patients of Internal Medicine andpediatric in the future.

Teaching activities
Research activities
In FY2021, we focused on the establishment of the534

center. We hope to expand our activities in education
and research in the coming year.

References
None

535

Clinical Research Promotion
CenterProfessor, Director
Takashi Moritoyo M.D., Ph.D.

Associate Professor, Vice Director
Tatsuya Maruyama, M.D., Ph.D.

Project Lecturer
Kosuke Kashiwabara, Ph.D.

Assistant Professor
Takuya Kawahara, Ph.D., Mihoko Shibuya, M.D., Ph.D., Mariko Inoue, M.D. , Ph.D.

Project Assistant Professor
Miki Ohta, M.D., Ph.D., Ryo Matsuoka, M.D., Ph.D.

Homepagehttps://www.h.u-tokyo.ac.jp/english/centers-services/clinicalresearch-division/clinical-research-promotion-center/index.html

History and Organization
The Clinical Research Promotion Center was
established in 2019. It originated from Clinical Trial
Managing Center, which was established in 1998, andsubsequently the former Clinical Research Center,
which was established in 2001. Currently, it belongs to
the Clinical Research Services of the hospital andprovides supports not only for clinical trials but also forinvestigator-initiated (independent) clinical studies.
However, given the increasing diversity and volume ofclinical research conducted in the University of Tokyo
Hospital, demand mounted for the structural
framework to provide support for multi-centercollaborative studies, research on new technology inevidence-based medicine and translational research etc.
In response to such diversified demands, the former
Clinical Research Center was reorganized in April 2010
into the Clinical Research Support Center, enablingstrengthened support and expeditious promotion ofclinical research.
The Center at the beginning consisted of Site

Coordinating Unit, roughly equivalent to the former
Clinical Research Center, and Central Coordinating
Unit, which provides coordinating functions forresearch such as multicenter trials.
Site Coordinating Unit is comprised of the[Institutional Review Board (IRB) Secretariat
Division] [Investigational Drug/Information Control
Division] and [Clinical Research Coordinator
Division], each charged with IRB secretarial affairs,
management of drugs used in the conduct of clinicalresearch and provide assistance with safety information
reporting, and clinical research coordination activities.
In addition to the existing Consultation Division, newdivisions such as Operation Division, Biostatistics
Division, Data Management Division, Monitoring
Division and Safety Information Division andOperation Division have been added to the Central
Coordinating Unit.
In 2011, the Center was selected as an MHLW-funded
Center of Excellence for early stage and exploratory
clinical trials of drugs for psychiatric and neurological536

diseases, enabling the Center to reinforce the staff andto be equipped with Phase 1 Unit that can conduct
Phase I first-in-human clinical trial. Thus, the third unit,i.e., P1 Unit was established in May 2012 with 13 beds
exclusively used for clinical studies, making it possible
to provide seamless support to the complete clinicaldevelopment process.
We revised rules and procedures in compliance withthe “Ethical Guidelines for Medical and HealthResearch Involving Human Subjects” that came into
effect in April 2015 and examined the realignment offunctions related to clinical research aimed atstrengthening governance functions of the Universityof Tokyo Hospital. In January 2015, we established
Clinical Research Governance Division and later
Office of Clinical Quality Assurance & Compliance
was created independently of the Clinical Research
Support Center responsible for conducting quality
assurance audits. Also, with the aim of improving thequality of clinical research in clinical departments, we
appointed 1-2 to staff from each clinical department toserve as concurrent clinical instructors, thereby
strengthening the supervision and monitoring system inthe departments.
In April 2016, ethical review process of specificclinical trials (involving invasion and intervention) wastransferred to the Faculty of Medicine IRB to ensuretransparency of clinical research. IRB for evaluating
industry-initiated and investigator-initiated clinical
trials was newly established in the hospital. With
respect to the IRB’s secretarial and administrative
duties, the Center will continue to take responsibilities.
Moreover, an Specific Clinical Research Steering
Committee was established under the hospital director
and external audit committee to seek external
evaluation. In addition, we integrated clinical research
management system by strengthening management ofconflicts of interest, created educational environment
for clinical research personnel, formed collaboration
with the Clinical Evaluation and Safety Division tostrengthen safety management system. As a result, theUniversity of Tokyo Hospital received accreditation asa core clinical research hospital under Medical Care
Act in March 2016.
Based on the enforcement of the Act on ensuring the
Safety of Regenerative Medicine, the Certified Special
Committee for Regenerative Medicine was establishedat the Central Administrative Office of the university,
and Clinical Research Support Center undertook
responsibilities for secretarial and administrative
affairs.
In addition, in order to enhance the functions in which
the Clinical Research Support Center was widely
involved in 2015, Education and Training Division,
Clinical Trial Implementation Division and University
Hospital Network Promotion Division were establishedoutside the unit. In fiscal year 2017, we further
integrated safety information functions of the Site
Coordinating Unit and the Central Coordinating Unitand established a new Safety Information Management
Division out the unit. The division remaining in the Site
Coordinating Unit was named as the Investigational
DrugManagement
Division.
Furthermore,
Consultation Division was relocated outside the unit. In
2017, The Regulatory Strategy Division was alsoestablished within the Central Coordinating Unit. In
order to comply with the Clinical Trials Act that was
enforced in April 2018, we established ClinicalResearch Site Secretariat, enacted general andindividual rules to respond to the act and started
operation.
Furthermore, in order to clarify that it is anorganization that promotes clinical research, the Center
was renamed as Clinical Research Promotion Center in
December 2019. The Center was reorganized into 8
departments.
<Investigator-Initiated Clinical Trials Promotion
Department>
The department is responsible for: (1) secretariat
duties for investigator-initiated clinical trials, advanced
medical treatment, patient-proposed healthcare
services and regenerative medicine; (2) Support forphysicians and others in formulating development
strategies for clinical trials, advice on study design, andsupport for pharmaceutical affairs, funding, intellectual
property, and industry-academia collaborations; (3)Support for the promotion of investigator-initiatedclinical trials conducted by physicians and others; (4)Monitoring, data management and data analysis
required to ensure the quality of investigator-initiatedclinical studies; (5) Collecting and reporting on safety
information related to investigator-initiated clinical
trials and providing advice to physicians and others on
the safe conduct of clinical trials.

537<Industry-Initiated Clinical Trials Promotion
Department>
The department is responsible for: (1) Supporting thesafe and smooth implementation of industry-initiatedclinical trials; (2) CRC operations, study drug
management, and clinical psychological examinations.
<IRB Office>The office is responsible for: (1) Managing theInstitutional Review Board (IRB) and coordinatingwith related departments; (2) Providing support forphysicians and others who wish to be reviewed by the
IRB.
<Dedicated Clinical Trial Ward Department (P1unit)>The department is responsible for: (1) The safe andsmooth conduct of clinical trials related topharmaceuticals and medical devices; (2) the
recruitment of human subjects.
<Medical Safety and Personal Information
Management Department>
The department is responsible for: (1) Management ofsafety reports and collection and reporting of safety
information; (2) Management of personal information.
<Planning, Strategy and Management Department>
The department is responsible for: (1) Planning for
responding to authorities, acquisition of funds for
projects and expansion of the Center's functions; (2)Management of the Center's budget, personnel anddocuments; (3) General management of the Center's
information system, including information security; (4)Education and training for and provision of information
to physicians and others who wish to conduct clinicalresearch; (5) Management of the progress of clinicalresearch conducted by physicians and others andsupported by the Center.
<Network Promotion Department>
The department is responsible for: (1) Secretariat
duties for the National University Hospital ClinicalResearch Promotion Initiative joined by 45 hospitals of
42 national universities; (2) Secretariat duties for the
University Hospital Clinical Trial Alliance joined by 8
universities and 9 hospitals in the Kanto-Koshinetsu
region, a network of university hospitals engaged inclinical research.
<Clinical Trials Patient Counseling Department>
The department is responsible for providing
consultation and public relations services for patients

who would like to use advanced medical care.

Clinical Research Promotion
Activities
The Clinical Research Promotion Center provides
wide range of support from pre-application
consultation, secretariat for the IRB to supporting theimplementation and reporting of clinical trials. In 2002,
during the time of the Clinical Trials Department, theCenter began providing assistance for investigatorinitiated clinical trials evaluating therapeutic drugs andstudies involving unapproved drugs in addition toconventional clinical trials (from 2015 use ofunapproved drugs in clinical research was transferred
to Research Ethics Committee of Graduate School of
Medicine and School of Medicine, and from 2018, it
was moved to Evaluation Committee on Unapproved
News Drugs). To further improve the quality of these
supports we decided to adopt ICH-GCP guidance andcomplied with the guidelines, procedure manuals,
styles and guidance etc. From 2009, we have been
providing support for all invasive and interventional
clinical research.
For industry-initiated clinical trials, we hold apreliminary hearing session (called “protocolpresentation”) in order to shorten the period fromapplication to approval and enhance the content ofreview. As a result, we could avoid re-review by the
IRB due to lack of information.
Since 2002, Clinical research coordinators (CRC) of
the Center have been supporting all clinical trials forapproval and post marketing trials. We started tosupport in part investigator-initiated research from2004. We started providing CRC support toinvestigator-initiated research on a beneficiary-paysbasis from 2005 and clinical pharmacology studies inhealthy volunteers from 2012. CRCs exclusively
involved in investigator-initiated research, have been
employed as needed. CRC support for Advanced
Medical Care Program B which University of Tokyo
Hospital participated as a head investigational site wasinitiated in 2017.
As part of patient awareness activities, we continued
updating the patient homepage, prepared leaflets anddistributed them at outpatient reception counters. The
leaflets contain information about research currently

538

recruiting participants. In addition, Clinical Trial
Patient Consulting Room provides consultation topatients or their families participating in clinical trials
or who are considering to enroll in a clinical trial inclose cooperation with the Patients Relations andClinical Ethics Center, Cancer Consulting and Support
Center, Department of Medical Community Network
and Office of Medical Accounting.
In order to support the promotion of investigatorinitiated clinical trials conducted by physicians etc. theCenter has been implementing the system successively
partly supported by the MHLW-funded Early-Stageand Exploratory Clinical Trial Project that started in
2011. In order to comply with the "Ethical Guidelines
for Medical and Health Research Involving Human
Subjects enacted in 2014", we classified clinicalresearch according to guidelines, validation studies andexploratory studies and started accepting all assistancerequests for validation studies, starting from May 2015.
Moreover, since clinical departments were placed incharge of monitoring and data management of all
exploratory
studies,theCenterundertook
responsibility for supervision of the quality control(QC). The Center manages SAE (severe adverse event)reporting and supports various safety reporting in orderto ensure that clinical studies are conducted safely. Oneof the major achievements is the investigator-initiatedclinical trial of the pediatric ventricular assist device;
the trial was initiated in February 2012, applied forregulatory approval in November 2014, and marketing
approval was received in June 18, 2015.
Since its establishment in May 2012, the Phase 1 Unit
has undertaken various preparations to respond to earlyphase clinical research, such as development of SOP
program, procedure manuals, establishment of inhouse collaboration system, on-the job training for staff
and the system for recruiting health volunteers. P1 unit
conducted its very first clinical study in October 2012.
In September 2018 the unit was relocated as a newward with augmented 21 beds exclusively aimed forclinical trial on the 12th floor of the Inpatient Building
B, which was newly constructed in January 2018.

<University Hospital Clinical Trial Alliance>
University Hospital Clinical Trial Alliance (UHCT
Alliance) comprised of 6 national university hospitals(The University of Tokyo, Niigata University, Gunma

University, Tsukuba University, Tokyo Medical and
Dental University and Chiba University) located in thecentral part of Japan was established in February 2006.
In February 2007 Shinshu University and in February
2013 Yamanashi University joined the Alliance as the
7th and 8th member university, respectively. And in
February 2015, the Institute of Medical Science theUniversity of Tokyo joined the Alliance as the 8th
member university 9 hospitals.
As part of the Alliance activities the University ofTokyo developed a clinical research support system
UHCT ACReSS jointly with Fujitsu and started
operation in 2011, to support clinical researchers in thequality and project management. UHCT ACReSS caneasily be customized by researchers. Currently, we areconsidering cloud computing and expanding its use toresearchers other than Alliance members.
In addition, we developed curriculum called
CREDITS (Continuous Systematic Education &Training Curriculum for Clinical Researchers andSpecialists) jointly with the Education and Training
Division in 2015. Currently, we are expanding the use
outside the alliance members.
Activities between the UHCT Alliance and the
University of Tokyo Translational Research (TR) based
regional network started in 2015, as seeds development
project of Alliance members.

<National University Hospital Clinical Research
Initiative>
In October 2012, we launched National University
Hospital Clinical Research Initiative (NUH-CRI). The
administrative affairs of the Initiative has been
supported by the secretariat located within the
University of Tokyo Hospital since the preparatory
meeting in July 2012. The initiative considered sharing
education curriculum as one of the common
educational programs of national university hospitals
nationwide. In 2016, the curriculum was provided toeach university hospital by the National University
Hospital Council of Japan. Feasibility assessment
system was developed for investigator-initiated clinicalstudy to support the promotion of clinical trials
conducted at the National University Hospitals.

539

Education/Training
The Center has been accepting M3/M4 students fortraining course in ‘Clinical Clerkship’ since it become
mandatory in 2013. From 2017, we have been offeringsystematic lectures on “Clinical Research” for M2
medical students. In addition, we have been accepting
junior resident physicians for training as a part of the
M.D. residency-training program.
Education and Training Division was established in2015 and since then it has been providing education andtraining for students and researchers. In particular, wehave developed curriculum called CREDITS(Continuous Systematic Education & Training
Curriculum for Clinical Researchers and Specialists)
jointly with UHCT Alliance.
Clinical instructor system was established in 2015, in
which physicians recommended by each clinicaldepartment hold an additional position at the ClinicalResearch Promotion Center concurrently with theirdepartment, centrally manage information on clinicalresearch conducted in their own departments and holdregular training sessions to disseminate information on
education and training programs.
The University of Tokyo Hospital has conductedannual CRC training program for national, public andprivate university hospitals since 2010, commissionedby the Ministry of Education, Culture, Sports, Scienceand Technology. As a part of the Japan Agency for
Medical Research and Development (AMED) project,training workshop for clinical research personnel has
been held since 2017, sponsored by the University ofTokyo.
Furthermore, in response to the shortage ofbiostatisticians, biostatistics and bioinformatics course
was established by AMED, at the university hospital.
In 2018, master’s course was also established within
the Graduate School of Interdisciplinary Information
Studies and the Clinical Research Promotion Centerhas established a system to conduct practical training
for course participants.

Research Activities
In April 2007, with the cooperation of the Biostatistics
Department, the Center launched the Clinical Trial
Data Management course (endowed course).
As of fiscal 2020, the Center was involved inscientific meetings, which include The Japan Societyof Clinical Pharmacology and Therapeutics,
Conference on CRC and Clinical Trials, etc. As for
publications such as academic papers, 30 papers were
produced (29 papers in English and 1 paper inJapanese).

Publications
1)

2)

3)

4)

5)

Sotomi Y, Kozuma K, Kashiwabara K, Higuchi Y,
Ando K, Morino Y, Ako J, Tanabe K, Muramatsu
T, Nakazawa G, Hikoso S, Sakata Y; OPTIMA-AF
Investigators. Randomised controlled trial toinvestigate optimal antithrombotic therapy inpatients with non-valvular atrial fibrillation
undergoing percutaneous coronary intervention: astudy protocol of the OPTIMA-AF trial. BMJ
Open. 11, e048354, 2021
Ebata S, Yoshizaki A, Fukasawa T, YoshizakiOgawa A, Asano Y, Kashiwabara K, Oba K,
Shinichi Sato. Increased red blood cell distribution
width in the first year after diagnosis predicts
worsening of systemic sclerosis-associatedinterstitial lung disease at 5 years: a pilot study.
Diagnostics. 11, article 2274, 2021
Kaibori M, Yoshii K, Kashiwabara K, Kokudo T,
Hasegawa K, Izumi N, Murakami T, Kudo M,
Shiina S, Sakamoto M, Nakashima O, Matsuyama
Y, Eguchi S, Yamashita T, Takayama T, Kokudo N,
Kubo S. Impact of hepatitis C virus on survival inpatients undergoing resection of intrahepaticcholangiocarcinoma: Report of a Japanesenationwide survey. Hepatology Research. 51,
890–901, 2021
Ebata S, Yoshizaki A, Oba K, Kashiwabara K,
Ueda K, Uemura Y, Watadani T, Fukasawa T,
Miura S, Yoshizaki-Ogawa A, Asano Y, Okiyama
N, Kodera M, Hasegawa M, Sato S. Safety andefficacy of rituximab in systemic sclerosis(DESIRES): a double-blind, investigator-initiated,
randomised, placebo-controlled trial. Lancet
Rheumatology. 3, E489–E497, 2021
Koyanagi H, Kitamura A, Nakagami G,
Kashiwabara K, Sanada H, Sugama J. Local
wound management factors related to biofilm
reduction in the pressure ulcer: A prospective

540

observational study. Japan Journal of Nursing
Science. 18, e12394, 2021
6) Umeda M, Ota Y, Kashiwabara K, Hayashi N,
Naito M, Yamashita T, Mukai H, Nakatsukasa K,
Amemiya T, Watanabe K, Hata H, Kikawa Y,
Taniike N, Yamanaka T, Mitsunaga S, Nakagami
K, Adachi M, Kondo N, Shibuya Y, Niikura N.
Oral care and oral assessment guide in breast
cancer patients receiving everolimus andexemestane: subanalysis of a randomized
controlled trial (Oral Care-BC). Annals ofTranslational Medicine. 9, 535, 2021
7) Tateishi R, Matsumura T, Okanoue T, Shima T,
Uchino K, Fujiwara N, Senokuchi T, Kon K,
Sasako T, Taniai M, Kawaguchi T, Inoue H,
Watada H, Kubota N, Shimano H, Kaneko S,
Hashimoto E, Watanabe S, Shiota G, Ueki K,
Kashiwabara K, Matsuyama Y, Tanaka H, Kasuga
M, Araki E, Koike K, and LUCID study
investigators. Hepatocellular carcinoma development in diabetic patients: a nationwide survey inJapan. Journal of Gastroenterology. 56, 261–273,
20218) Nakatsukasa K, Niikura N, Kashiwabara K,
Amemiya T, Watanabe K, Hata H, Kikawa Y,
Taniike N, Yamanaka T, Mitsunaga S, Nakagami
K, Adachi M, Kondo N, Shibuya Y, Hayashi N,
Naito M, Yamashita T, Umeda M, Mukai H, Ota Y.
Secondary endpoints analysis in patients withestrogen receptor-positive metastatic breast
cancer treated with everolimus and exemestane
enrolled in Oral Care-BC. BMC Cancer. 21, 34,20219) Niikura R, Aoki T, Kojima T, Kawahara T,
Yamada A, Nakamura H, Inoue K, Morikoshi E,
Migita R, Shimizu T, Kojima T, Koike K. Natural
history of upper and lower gastrointestinal
bleeding in hemodialysis patients: A dual-center
long-term cohort study. J Gastroenterol Hepatol.
36:112-117, 2021
10) Bae SK, Akamatsu N, Ichida A, Maki H, Nishioka
Y, Kawahara T, Hoshikawa M, Nagata R, Mihara
Y, Kawaguchi Y, Ishizawa T, Arita J, Kaneko J,
Tamura S, Hasegawa K. Risk factors for hepatitis
B virus recurrence after living donor livertransplantation: A 22-year experience at a single
center. Biosci Trends. 14:443-449, 2021

11) Kurokawa R, Hagiwara A, Amemiya S, Gonoi W,
Fujita N, Kurokawa M, Yamaguchi H, Nakai Y,
Ota Y, Baba A, Kawahara T, Abe O. Imatinibinduced pancreatic hypertrophy in patients withgastrointestinal stromal tumor: Association withoverall survival. Pancreatology. 21:246-252, 2021
12) Adachi Y, Kiyosue A, Ando J, Kawahara T,
Kodera S, Minatsuki S, Kikuchi H, Inaba T,
Kiriyama H, Hirose K, Shinohara H, Saito A,
Fujiwara T, Hara H, Ueda K, Sakakura K, Hatano
M, Harada M, Takimoto E, Akazawa H, Morita H,
Momomura SI, Fujita H, Komuro I. Factors
associated with left ventricular reverse
remodellingafter
percutaneous
coronary
intervention in patients with left ventricularsystolic dysfunction. Sci Rep. 11:239, 2021
13) Fujimoto C, Kawahara T, Kinoshita M, Ichijo K,
Oka M, Kamogashira T, Sugasawa K, Yamasoba
T, Iwasaki S. Minimally important differences for
subjective improvement in postural stability inpatients with bilateral vestibulopathy. Neurosci
Lett. 747:135706, 2021
14) Arai J, Niikura R, Hayakawa Y, Kawahara T,
Honda T, Hasatani K, Yoshida N, Nishida T,
Sumiyoshi T, Kiyotoki S, Ikeya T, Arai M, Suzuki
N, Tsuji Y, Yamada A, Kawai T, Koike K. Use of
Antibiotics and Probiotics Reduces the Risk of
Metachronous Gastric Cancer after Endoscopic
Resection. Biology (Basel). 10:455, 2021
15) Niikura R, Fujishiro M, Nakai Y, Matsuda K,
Kawahara T, Yamada A, Tsuji Y, Hayakawa Y,
Koike K. International Observational Survey of
the Effectiveness of Personal Protective
Equipment during Endoscopic Procedures
Performed in Patients with COVID-19. Digestion.
102:845-853, 2021
16) Arai J, Niikura R, Hayakawa Y, Sato H, Kawahara
T, Honda T, Hasatani K, Yoshida N, Nishida T,
Sumiyoshi T, Kiyotoki S, Ikeya T, Arai M, Suzuki
N, Tsuji Y, Yamada A, Koike K. Nonsteroidal
anti-inflammatory drugs prevent gastric cancer
associated with the use of proton pump inhibitors
after Helicobacter pylori eradication. JGH Open.
5:770-777, 2021
17) Taira N, Sawaki M, Uemura Y, Saito T, Baba S,
Kobayashi K, Kawashima H, Tsuneizumi M,
Sagawa N, Bando H, Takahashi M, Yamaguchi M,

541

Takashima T, Nakayama T, Kashiwaba M,
Mizuno T, Yamamoto Y, Iwata H, Ohashi Y,
Mukai H, Kawahara T, RESPECT Study Group.
Health-Related Quality of Life With Trastuzumab
Monotherapy Versus Trastuzumab Plus Standard
Chemotherapy as Adjuvant Therapy in Older
Patients With HER2-Positive Breast Cancer. J
Clin Oncol. 39:2452-2462, 2021
18) Hagiwara Y, Sawaki M, Uemura Y, Kawahara T,
Shimozuma K, Ohashi Y, Takahashi M, Saito T,
Baba S, Kobayashi K, Mukai H, Taira N. Impact
of chemotherapy on cognitive functioning in older
patients with HER2-positive breast cancer: a substudy in the RESPECT trial. Breast Cancer Res
Treat. 188:675-683, 2021
19) Shiba K, Kawahara T.Using Propensity Scores for
Causal Inference: Pitfalls and Tips. J Epidemiol.
31:457-463, 2021
20) Kurokawa R, Inui S, Gonoi W, Nakai Y, Ishida M,
Watanabe Y, Kubo T, Amano Y, Okamoto K,
Kage H, Harada S, Tanaka G, Kawahara T,
Nagase T, Moriya K, Abe O. Standardized
reporting systems of chest computed tomography
in a population with low coronavirus disease 2019prevalence: A retrospective comparative study.
Heliyon. 7:e07743, 2021
21) Fujimoto C, Kinoshita M, Ichijo K, Oka M,
Kamogashira T, Sugasawa K, Kawahara T,
Yamasoba T, Iwasaki S. Cervical Vestibular
Evoked Myogenic Potentials That Are Absent at
500 Hz But Present at 1000 Hz Are Characteristicof Endolymphatic Hydrops-Related Disease. Ear
Hear. 42:1306-1312, 2021
22) Shiba K, Kawahara T, Aida J, Kondo K, Kondo N,
James P, Arcaya M, Kawachi I. Causal Inferencein Studying the Long-Term Health Effects ofDisasters: Challenges and Potential Solutions. Am
J Epidemiol. 190:1867-1881, 2021
23) Mukai H, Uemura Y, Akabane H, Watanabe T,
Park Y, Takahashi M, Sagara Y, Nishimura R,
Takashima T, Fujisawa T, Hozumi Y, Kawahara
T.Anthracycline-containing regimens or taxane
versus S-1 as first-line chemotherapy for metastatic breast cancer. Br J Cancer. 125:1217-1225,
202124) Nakayama A, Morita H, Kawahara T, Itoh H,
Komuro I. Association between testosterone andlipid profiles under statin therapy and its clinicalimpact on the cardiovascular event risk. Heart
Vessels. 36:1794-1803, 2021
25) Ohta, M. Causality assessment between reported
fatal cerebral haemorrhage and suspected drugs:
developing a new algorithm based on the analysisof the Japanese Adverse Event Report (JADER)
database and literature review. European Journalof Clinical Pharmacology. 77: 1443-1452, 2021
26) Kadowaki H, Ishida J, Akazawa H, Yagi H, SagaKamo A, Umei M, Matsuoka R, Liu Q, Matsunaga
H, Maki H, Sato Y, Kume H, Komuro I. Axitinib
Induces and Aggravates Hypertension Regardlessof Prior Treatment With Tyrosine Kinase
Inhibitors. Circ Rep. 3:234-240, 2021
27) Katsushika S, Kodera S, Nakamoto M, Ninomiya
K, Kakuda N, Shinohara H, Matsuoka R, Ieki H,
Uehara M, Higashikuni Y, Nakanishi K, Nakao T,
Takeda N, Fujiu K, Daimon M, Ando J, Akazawa
H, Morita H, Komuro I. Deep Learning Algorithm
toDetectCardiac
Sarcoidosis
From
Echocardiographic Movies. Circ J. 86:87-95, 2021
28) Katsushika S, Kodera S, Nakamoto M, Ninomiya
K, Inoue S, Sawano S, Kakuda N, Takiguchi H,
Shinohara H, Matsuoka R, Ieki H, Higashikuni Y,
Nakanishi K, Nakao T, Seki T, Takeda N, Fujiu K,
Daimon M, Akazawa H, Morita H, Komuro I. The
Effectiveness of a Deep Learning Model to Detect
Left Ventricular Systolic Dysfunction from
Electrocardiograms. Int Heart J. 62:1332-1341,
2021
29) Umei M, Akazawa H, Saga-Kamo A, Yagi H, Liu
Q, Matsuoka R, Kadowaki H, Shindo A,
Nakashima A, Yasuda K, Suzuki K, Komuro I.
Oral Administration of Euglena Gracilis Z
Alleviates Constipation and Cardiac Dysfunction
in a Mouse Model of Isoproterenol-Induced Heart
Failure. Circ Rep. 4:83-91, 2021

542

Division of Tissue Engineering
Director & Professor
Kazuto Hoshi, M.D., Ph.D.

Vice Director
Atsuhiko Hikita, M.D., Ph.D.

Project Professor
Makoto Komura, M.D., Ph.D.,

Project Associate Professors
Atsuhiko Hikita, M.D., Ph.D.,
Kazumichi Yonenaga, D.D.S., M.D., Ph.D, Yasunori Omata, M.D. Ph.D.

Project Lecturer
Yukiyo Asawa, D.V.M., Ph.D. , Ono Sachiko, D.D.S., Ph.D., Asuka Terashima, Ph.D.

Research Associates
Itai Shunsuke, D.D.S., Ph.D.

Homepage

http:// square.umin.ac.jp/t-e/

Introduction and Organization
Division of Tissue Engineering was established as a
special medical office in The University of Tokyo
Hospital, in October 2001 and has a fully equipped 800
m2 laboratory on the 8th floor of the In-patient Ward B.
In May 2016, it moved to Molecular and Life
Innovation building. Division of Tissue Engineering
consists of Department of Bone & Cartilage
Regenerative Medicine, Department of Tissue Stemcell/Life Dentistry and Department of Eat-loss
Medicine. Researchers assigned to each department are
conducting research with many graduate students. The
researchers continue their studies to make the center
function as a translational research center.
Tie-up with companies, technical transfer, patenting developed technologies, producing materials fortreatment at a GMP level, safety evaluation studies andorganization for clinical trials are necessary in order torealize regenerative medicine, which is now recognized
as a national project. As foundation and operation ofventure companies as well as industry-universitygovernment cooperation is essential to the success, it
seems that state-level efforts are necessary. It is
expected that broad progress in tissue engineering
technologies and regenerative medicine contributes totreatment and drug discovery of all medical fields
regardless of specialties.
October, 2001 Division of Tissue Engineeringfounded as a special medical office in the University ofTokyo Hospital.
June, 2002 Department of Corneal Tissue Engineering founded by a donation from HOYA health care CO.,Ltd.
July, 2002 Department of Vascular Regeneration
founded by a donation from Daiichi PharmaceuticalCo., Ltd.
July, 2002 Department of Bone & Cartilage
Regenerative Medicine founded by a donation from
TAKEDA Chemical Industries., Ltd.
September, 2002 Department of Regeneration
Medicine for Hematopoiesis founded by a donation

543

from KIRIN Brewery Co., Ltd.
November, 2002 Department of Clinical Renal
Regeneration founded by a donation from MOCHIDA
Pharmaceutical Co., Ltd.
November, 2002 Department of MENICON
Cartilage & Bone Regeneration founded by a donationfrom MENICON Co., Ltd.
March, 2003 The Cell Processing Center set up on
the 8th floor of the In-patient Ward B.
June, 2005 Department of Corneal Tissue Regeneration was renewed by a donation from AMNIOTEC Co., Ltd.
July, 2005 Department of Bone & Cartilage
Regenerative Medicine was renewed by a donationfrom TAKEDA Chemical Industries Co., Ltd.
September, 2005 Department of Regeneration
Medicine for Hematopoiesis was renewed by adonation from KIRIN Brewery Co., Ltd.
November, 2005 Department of Clinical Renal
Regeneration was renewed by a donation fromMOCHIDA Pharmaceutical Co., Ltd.
November, 2005 By a donation from FUJISOFTABC Co., Ltd. Department of MENICON Cartilage &Bone Regeneration was renewed to Department of Fuji
Software ABC Cartilage & Bone Regeneration.
January, 2007 Laboratory for Pediatric Regenerative Medicine was founded by department of pediatricsurgery.
July, 2007 Department of Bone & Cartilage
Regenerative Medicine was renewed by a donationfrom Eli Lilly Japan K.K.
March, 2012 Department of Advanced Nephrol- ogy
and Regenerative Medicine founded by a donationfrom Zenjinkai.
April, 2016 The Cell Processing & Banking Centerset up on the 4th floor of the Molecular & Life
Innovation Building.
November 2017 Change of the department name:
Department of Cartilage & Bone Regeneration became
Department of Cell & Tissue Engineering.
July, 2018 Department of Bone & Cartilage
Regenerative Medicine was renewed by a donationfrom Avenue Cell Clinic, Kaneka Corporation, Rohto
Pharmaceutical Co., Ltd. and Nichirei Corporation.
November, 2019 Department of Tissue Stemcell/Life Dentistry established by Dental assist Co., Ltd,
Fuke hospital, Sashiogi Hospital, Ikegami Home Clinic

and Inotec Co., Ltd.
April, 2020 Department of Eat-loss Medicine wasfounded by a donation from ITOEN ltd.
October, 2020 Department of Cell & Tissue
Engineering was terminated.

Research activities
As for bone and cartilage regeneration, we areresearching and developing the treatment of
osteoarthritis using human adipose stem cells (ASCs)
from the renewal of the department in 2018. To clarify
the protective effects of human ASCs for cartilage more
precisely, we are planning to establish the assay system
for the knee pain of mouse. We are also developing theculture medium by which highly-functional humanmesenchymal cells can be amplified stably andeffectively. We are also working on basic research for(1) elucidation of molecular mechanisms underlying
osteoarthritis（2）clarification of the roles of tissue stem
cells in the homeostasis of joints and pathogenesis ofosteoarthritis. In addition, for the realization of boneregeneration, we are trying to apply a nanosheet which
can induce osteogenesis. Now we are testing its
effectiveness in large animals.
In addition, to produce regenerated cartilage andbone with high safety and usefulness, to realize
production system and establish practical quality
control and to promote the application of regenerated
cartilage and bone, we are conducting research on
development of novel scaffolds in cartilage and boneregeneration, development of 3-D reconstruction
system for regenerated tissues, evaluation on
biochemical and biophysical properties of regenerated
tissues in vivo and clinical trials and application ofregenerated cartilage and bones.
In the department of tissue stem cells/ life dental
science, we are doing research about engineered airway,
dental pulp stem cells and umbilical cord stem cells. In
addition, we investigate the mechanism of the selfgeneration by the tissue encapsulating the mold (BIOTUBE).
In the department of Eat-loss medicine, in order tosupport "eating," which is the foundation of human life,

544

we are conducting research to systematize thediagnosis, prevention, and treatment of "eating" as an
academic discipline by approaching the problem of
persistent inability to eat from the oral region, so thatmany people can live a full, healthy life.

Clinical Studies
Of particular note is clinical studies started as a resultof basic research. In Department of Bone & Cartilage
Regenerative Medicine, a clinical study on bone
implants into non-loading parts (IRB approval number#1310) was conducted on 10 patients successfully anda large-scale clinical trial was started across the nation.
In project for cartilage regeneration, an investigatorinitiated clinical trial “A clinical trial for the validationof safety and efficacy of the implant-type tissueengineered cartilage using autologous cells” wascarried out. In addition, a clinical study of treatment for
temporomandibular joint disorder taking advantage ofanti-inflammatory and tissue repairing abilities ofadipose stem cells has been also approved.
As stated above, we are proceeding translational
research aiming at clinical application of tissue
engineering and regenerative medicine. Contribution to
the Hospital

Contribution to the Hospital
Division of Tissue Engineering, as a cooperative
research facility in the Hospital, opens expensive
special machines that each laboratory cannot afford toequip with, such as a confocal laser scanningmicroscope, a cell analyzer and a cell sorter to the
Hospital staff, letting them use with cost sharing.
Various departments are conducting research using thisfacility.

References
1.

2.

Histochemical and Morphometrical Analyses of
Scarless Wound Healing in Mouse Fetal Model.
Kawakami H, Nishizawa S, Hikita A, Hoshi K.
Tokai J Exp Clin Med. 2021 Apr 20;46(1):33-43.
Different phenotypes and chondrogenic responsesof human menstrual blood and bone marrowmesenchymal stem cells to activin A and TGF-β3.
Uzieliene I, Bagdonas E, Hoshi K, Sakamoto T,

Hikita A, Tachtamisevaite Z, Rakauskiene G,
Kvederas G, Mobasheri A, Bernotiene E. Stem
Cell Res Ther. 2021 Apr 29;12(1):251.
3. Mesenchymal stromal cells in the bone marrowniche consist of multi-populations with distinct
transcriptional and epigenetic properties.
Kanazawa S, Okada H, Hojo H, Ohba S, Iwata J,
Komura M, Hikita A, Hoshi K. Sci Rep. 2021 Aug
4;11(1):15811.
4. M1-like macrophage contributes to chondrogenesis in vitro. Miyamoto Y, Kubota K, Asawa Y,
Hoshi K, Hikita A. Sci Rep. 2021 Oct
29;11(1):21307.
5. Requirement of direct contact betweenchondrocytes and macrophages for the maturationof regenerative cartilage. Kanda K, Asawa Y, Inaki
R, Fujihara Y, Hoshi K, Hikita A. Sci Rep. 2021
Nov 18;11(1): 22476.
6. A new method of primary engineering ofesophagus using orthotopic in-body tissue
architecture. Suzuki K, Komura M, Obana K,
Komura H, Inaki R, Fujishiro J, Suzuki K,
Nakayama Y. J Pediatr Surg. 2021 Jul;56(7):1186-1191.
7. Significant cases of central cusps, enamel pits, andoral fibromas in tuberous sclerosis complex. Taga
T, Yonenaga K, Eno Y, Yasumitsu T, Hatano T,
Matsuo A, Takato T. Odontology. 109(1) 279 - 283
2021
8. Association between the Mallampati score andmaximal mouth opening in patients with
obstructive sleep apnea. Yonenaga K, Taga H, Eno
Y, Watanabe M, Matsuo A, Itai S, Ono S, Takato
T. Oral Science International 18(2) 116-119 2021
9. A comparative randomized, open-label, multicenter study of the efficacy and safety of
miconazole mucoadhesive tablets and miconazole
gel in the treatment of Oropharyngeal Candidiasis[Translated article]. Tsuyoshi Takato, Yoshimasa
Kitagawa, Yoshiaki Kamikawa, Hiromitsu
Kishimoto, Seiji Nakamura, Takahide Komori,
Daichi Chikatsu, Yoshiyuki Mori, Hideki Tanzawa,
Akira Katakura, Akihiro Kanekawa, Masahiro
Umeda, Akinori Gomi, Kazumichi Yonenaga.
Medical Mycology Journal 62(1) 11 - 19 2021
10. Swallowing evaluation by the Kuchikara Taberu
Balance Chart and videoendscopic examination

545

11.

12.

13.

14.

15.

16.

reveals that respiratory conditions, chewing, andposition are strongly related to dysphagia.
Tonosaki K, Yonenaga K, Ono S, Itai S, Oyama S,
Mizuno T, Watanabe R, Hoshi K Odontology
109(2) 448-454 2021
Transcription Factor Hematopoietically Expressed
Homeobox Protein (Hhex) Negatively Regulates
Osteoclast Differentiation by Controlling CyclinDependent Kinase Inhibitors. Watanabe H, Okada
H, Hirose J, Omata Y, Matsumoto T, Matsumoto
M, Nakamura M, Saito T, Miyamoto T, Tanaka S.
JBMR Plus. 2022 Feb 14;6(4):e10608.
Inflammatory Arthritis and Bone Metabolism
Regulated by Type 2 Innate and Adaptive
Immunity. Omata Y, Frech M, Saito T, Schett G,
Zaiss MM, Tanaka S. Int J Mol Sci. 2022 Jan 20;
23(3):1104.
Btn2a2 Regulates ILC2-T Cell Cross Talk in Type2 Immune Responses. Frech M, Omata Y,
Schmalzl A, Wirtz S, Taher L, Schett G, Zaiss MM,
Sarter K. Front Immunol. 2022 Jan 25;13:757436.
Regulation of osteoarthritis development by
ADAM17/Tace in articular cartilage. Kaneko T,
Horiuchi K, Chijimatsu R, Mori D, Nagata K,
Omata Y, Yano F, Inui H, Moro T, Tanaka S, Saito
T. J Bone Miner Metab. 2022 Mar;40(2):196-207.
Lubricin Contributes to Homeostasis of Articular
Cartilage by Modulating Differentiation ofSuperficial Zone Cells. Maenohara Y, Chijimatsu
R, Tachibana N, Uehara K, Xuan F, Mori D,
Murahashi Y, Nakamoto H, Oichi T, Chang SH,
Matsumoto T, Omata Y, Yano F, Tanaka S, Saito T.
J Bone Miner Res. 2021 Apr;36(4):792-802.
Involvement of Transient Receptor Potential
Vanilloid Channel 2 in the Induction of Lubricin
and Suppression of Ectopic Endochondral
Ossification in Mouse Articular Cartilage.
Nakamoto H, Katanosaka Y, Chijimatsu R, MoriD, Xuan F, Yano F, Omata Y, Maenohara Y,
Murahashi Y, Kawaguchi K, Yamagami R, Inui H,
Taketomi S, Taniguchi Y, Kanagawa M, Naruse K,
Tanaka S, Saito T. Arthritis Rheumatol. 2021 Aug;73(8):1441-1450.

【Book】

546

Cooperative Unit of Medicine andEngineering Research
Organization
The University of Tokyo Hospital
Cardiovascular Medicine, Nutrition and Metabolism, Surgical Oncology, Vascular Surgery,
Artificial Organ and Transplantation, Cardiac Surgery, Thoracic Surgery, Neurosurgery,
Urology, Orthopaedic Surgery, Oral and maxillofacial Surgery, Radiology, Tissue
Engineering Unit, Department of Clinical Epidemiology & Systems, Bone & Cartilage
Regenerative

Medicine,

Cartilage

of

Bone

Regeneration,

Department

ofImmunotherapeutics (Medinet), Division of Science for Joint Reconstruction

Engineering and Pharmaceutical Research
Chemical System Engineering, Mechanical Engineering, Precision Engineering, Quantum
Engineering and System Science, Nuclear Engineering and Management, Chemistry andBiotechnology, Material Engineering, Information Science and Technology, Frontier
Sciences, Pharmaceutical Sciences Laboratory of Chemistry and Biology, Center for Disease
Biology and Integrative Medicine, Center for Disease Biology and Integrative Medicine
Regenerative Medical Engineering, Center for Disease Biology and Integrative Medicine
Clinical Biotechnology, Research Center for Advanced Science and Technology, Institute ofIndustrial Science

Introduction and Organization
The application of an advanced bioscience to a newtechnical development of clinical medicine has
become an important subject for research in the 21st
century. We’ve established Cooperative Unit ofMedicine and Engineering Research at The Universityof Tokyo Hospital to create a new research andeducation center, which cross-sectionally unites
medicine with engineering research for the development of a next generation medical technology.
2002 June. The establishment of Cooperative Unitof Medicine and Engineering Research was approvedby a hospital administration committee as a special

practice unit that belongs to The University of Tokyo
Hospital.
2002 September. A steering committee of Cooperative Unit of Medicine and Engineering Research
was organized by representative members of relevant
clinical departments. The committee made a decisionof the following basic principles; recruitment for theparticipation to this unit should be, as a general rule,
an open call for a joint project of clinical department
and engineering or pharmaceutical research group in
The University of Tokyo, an equipment/administration
expense of a laboratory should be a responsibility of
the user, and a basic participation period to this unit
should be three years and for the continued

547

participation in the unit, a review and approve of thesteering committee is indispensable.
2002 October. An open call for participants to thisunit started. There were 18 applications and thesteering committee approved all projects after review.
A liaison conference of Cooperative Unit of Medicine
and Engineering Research was organized by arepresentative member of each project. Configurationof each project in a space of 554.4m2 that is consistedof a portion of the first floor and the basement of an
administration building came to a decision by theconference.
2003 May. The construction of Cooperative Unit ofMedicine and Engineering Research was completed.
The cost of the construction was shared by theparticipation groups.
2003 May 22. The first research meeting of
Cooperative Unit of Medicine and Engineering
Research took place and research activities started.
2004 September 3. The second research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2005 September 13. The third research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2006 December 21. The fourth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2007 December 13. The fifth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2009 December 3. The sixth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2011 February 2. The seventh research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2011 December 17. The eighth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place2013 January 25. Development forum of advanced
medical seeds took place
2014 January 24. Development forum of advanced
medical seeds took place
2015 January 22. Development forum of advanced
medical seeds took place
2016 February 2. Development forum of advanced

medical seeds took place2017 February 2. Development forum of advanced
medical seeds took place2018 February 1. Development forum of advanced
medical seeds took place2018 October. Each lab was moved from the thefirst floor and the basement of an administrationbuilding, based on the decision of redistribution of
hospital facility
2019 February 18. Development forum of advanced
medical seeds took place2020 January 21. Development forum of advanced
medical seeds took place
2021 February 10. Development forum of advanced
medical seeds took place
2022 February 4. Development forum of advanced
medical seeds took place

Research activities
Development of Advanced Stereotactic Radiation
Cancer Therapy System
Department of Radiology
Nuclear Professional School, Department of Nuclear
Engineering and Management
Department of Chemical System Engineering
High Precision Stereotactic X-ray Cancer Therapy
System. Development of Advanced Compact Electron
Linear Accelerator for Cancer Inspection and Therapy
The aim of this research is to apply the in-vivo
visualization technique developed by our group in
high-precision radiation therapy and to develop the
motion prediction system for a real-time
tumor-tracking radiation therapy. For the visualizationof the treatment area during treatment, afour-dimensional cone-beam computed tomography(4D CBCT) reconstruction algorithm is developed bytaking the anatomy or tumor motion analysis into
account. In-treatment 4D CBCT requires the
projection images acquired during treatment. The
projection images are analyzed online, and comparedwith the reprojection images from the treatment
planning CT or registration CT. The time lag due tothe analysis can be compensated by the prediction
using a multi-channel singular spectrum analysis. Thissystem will remove a delay problem during thereal-time tumor-tracking radiation therapy, and will

548

provide a safer radiation therapy than the current ones
because this will be able to detect an irregularbreathing motion of the tumor.
Research and development of micro-neurosurgicalrobotic systems
Department of Neurosurgery, The University of Tokyo
Hospital
Mitsuishi Laboratory, Department of MechanicalEngineering, School of Engineering
Development of micro-neurosurgical robotic systems
and advanced microscopic image processing forautonomous surgical task recognition.
Development of Support Systems for Risk
Reduction in the Clinical Process
Chemical System Engineering
Center for Epidemiology and Preventive Medicine
Our specific targets are research and education on the
integration of biological and clinical information
including genome. In particular, we focus onestablishment of personalized medicine as translational research, selection of drug targets by proteomics,
interpretation of transcriptional regulations and drug
development by targeting transcriptional factors inmetabolic and cardiovascular diseases. Also, analysesof genomic functions, clinical safety monitoring by
clinical database and assessments of clinicalinformation systems are conducted.
Project of Neutron Capture Therapy & Innovationof DDS for Cancer
Department of Cardiothoracic Surgery, Graduate
School of Medicine
Institute of Engineering Innovation, School ofEngineering
Department of Bioengineering, School of Engineering
In order to control and eliminate human cancers, wedevelop the neutron capture therapy (NCT) using
small neutron accelerator equipped to hospital andalso aim to augment cancer therapy combined withapproaches of Drug Delivery System. We develop thetumour specific drug delivery systems entrappedboron or gadolinium compounds as neutron capture
agents (WOW emulsion, Nano-micelle, Cationic
Polyplex).

Development of adhesion barrier materials using a
new animal model of liver-peritoneal adhesion
Artificial Organ and Transplantation Division,
Department of Surgery, Graduate School of Medicine,
University of Tokyo
Hepato-Biliary-Pancreatic
Surgery
Division,
Department of Surgery, Graduate School of Medicine,
University of Tokyo
Organs and Biosystems Engineering Laboratory,
Institute of Industrial Science, The University of Tokyo
Division of Biomedical Equipment and Biomaterials,
Center for Disease Biology and Integrative Medicine,
Graduate School of Medicine, The University of Tokyo
Department of Chemical System Engineering,
Graduate School of Engineering, The University ofTokyo
Department of Bioengineering, Graduate School ofEngineering, The University of Tokyo
Adhesions between liver and other organs are an
important issue in the cases of second surgeries suchas hepatic resection. Adhesions extend operative
duration; in addition, they increase the risk ofsurgeries. Thus, it is important to avoid adhesions at afirst surgery. However, no one report both the animalmodel and adhesion barrier materials of liver adhesion.
We try to develop a new adhesion model by hepatic
resection, instead of a usual peritoneal abrasion model.
Also, we develop new materials for preventing theadhesions.
Development of gene therapy of cardiovasculartherapy by polymeric micelles.
Department of Vascular Surgery, Division of Tissue
Engineering, The University of Tokyo Hospital
Kataoka Laboratory, Department of Materials Scienceand Engineering, Graduate School of Engineering,
The University of Tokyo
To achieve effective and safe in vivo gene therapy ofcardiovascular and vascular diseases, we aredeveloping non-viral gene vectors based on
nano-scaled polymer assemblies (polymeric micelles).
Polymeric micelles, which are spontaneously formed
from block copolymers, have a core containing
packaged genes surrounded by biocompatible poly
(ethylene glycol) (PEG) palisades, and a variety ofpilot molecules can be installed on the surface ofpolymericmicelles.
This"virus-mimicking"

549

nanoparticles might achieve efficient gene transfer tothe targeted tissues or cells because of protection of
the loaded DNA from nuclease attack, their lowered
non-specific interaction with proteins and cells andfacilitated internalization by the targeted cells throughspecific interaction of the pilot molecules. Currently,
our research has been focused on in vivo gene transfer
to artery walls and muscles using polymeric micelles
incorporated genes.

7.

8.

References (in 2021)
1.

2.

3.

4.

5.

6.

Hanada K, Hoshina K, Iwakiri T, Akai T,
Miyahara K, Isaji T, Takayama T, Yamamoto S. A
comparison of subjective clinical and objective
judgement of abdominal aortic aneurysm
morphology. Int Angiol 2021;40:138-142.
Okata S, Hoshina K, Miyahara K, Matsukura M,
Akai T, Isaji T, Takayama T. High aneurysm wallenhancement values are associated with late sacshrinkage after endovascular repair of abdominal
aortic aneurysms. Medicine(Baltimore) 2021 Jan
15;100:e24133.
Hoshina K, Kato M, Ishimaru S, Michihata N,
Yasunaga H, Komori K; Japanese Committee for
Stentgraft Management (JACSM). Impact of theurgency and the landing zone on rates of inhospital death, stroke, and paraplegia following
thoracic endovascular aortic repair in Japan. J
Vasc Surg 2021; S0741-5214(21)00142-7
Matsuura S, Takayama T, Yuhn C, Oshima M,
Shirasu T, Akai T, Isaji T, Hoshina K. Carotid
stump pressure and contralateral internal carotid
stenosis ratio during carotid endarterectomies:
1D-0D hemodynamic simulation of cerebral
perfusion. Ann Vasc Dis 2021;14:39-45.
Hoshina K, Komori K, Kumamaru H, Shimizu H.
The Outcomes of endovascular aneurysm repair
in Japan in 2017: A Report from the JapaneseCommittee for Stentgraft Management. 2021;25;
14:92-98.
Sugawara M, Hoshina K, Chigira M, Suzuki H,
Daimon M, Takayama T, Ono Y, Yatomi Y.
Usefulness of duplex ultrasonography to detectcollagen sponge misplacement into the arterial
lumen during the use of Angio-Seal: A case

9.

10.

11.

12.

13.

report. SAGE Open Med Case Rep 2021;9:2050313X211004818
Matsuura S, Takayama T, Oyama TG, Oyama K,
Taguchi M, Endo T, Akai T, Isaji T, Hoshina K. A
Radiation-crosslinked gelatin hydrogel that
promotes tissue incorporation of an expanded
polytetrafluoroethylene vascular graft in rats.
Biomolecules 2021;11:1105.
Iida T, Murono K, Shiratori H, Nozawa H, Kawai
K, Sasaki K, Emoto S, Kishikawa J, Ishii H,
Yokoyama Y, Abe S, Nagai Y, Anzai H, Sonoda H,
Takayama T, Hoshina K, Ishihara S. Impact ofinferior mesenteric artery occlusion on the calibreof collateral arteries of the colon. Anticancer Res
2021;41: 5189-5193.
Hoshina K, Komori K, Kumamaru H, Shimizu H.
The outcomes of thoracic endovascular aortic
repair in Japan in 2017: A report from theJapanese Committee for Stentgraft Management.
Ann Vasc Dis 2021;14:281-288.
Mo M, Hirokawa M, Satokawa H, Yasugi T,
Yamaki T, Ito T, Onozawa S, Kobata T, Shirasugi
N, Shokoku S, Sugano N, Sugiyama S, Hoshina
K, on behalf of guideline committee JapaneseSociety of Phlebology, Ogawa T, on behalf ofguideline committee of endovenous treatment forvaricose veins. Supplement of clinical practiceguidelines for endovenous thermal ablation forvaricose veins: Overuse for the inappropriate
indication. Ann Vasc Dis 2021:14:323-327.
Horio K, Marinho MM, Harada K, Muto J,
Nakatomi H, Saito N, Morita A, Watanabe E,
Mitsusishi M. “The effects of Grid Size for
Automatic Suture Thread, Detection with an
Image Classifier”, The 17th Asian Conference on,
Computer Aided Surgery (ACCAS2021), pp.102103, Online, December 10, 2021.
Arvind K. Chandel S, Shimizu A, Hasegawa K,
Ito T. "Advancement of biomaterial-based
postoperative adhesion barriers" Macromolecular
Bioscience, 2021, 2000395 DOI:10.1002/mabi.
202000395
大木悠一朗、伊藤大知 “「生体直交型反応を用いたインジェクタブルハイドロゲル」” 日
本薬学会誌ファルマシア, 2021, 57(11), 10251029 https://doi.org/10.14894/faruawpsj.57.11_
1025

550

14. Yanagie H, Fujino T, Yanagawa M, Terao T,
Imagawa T, Fujihara M, Morishita Y, Mizumachi
R, Murata Y, Dewi N, Ono Y, Ikushima I,
Seguchi K, Nagata M, Nonaka Y, Furuya Y, Hisa
T, Nagasaki T, Arimori K, Nakashima T, Sugihara
T, Kakimi K, Ono M, Nakajima J, Eriguchi M,
Higashi S, Takahashi H.: Tumor Growth Suppression With Novel Intra-arterial Chemotherapy
Using Epirubicin-entrapped Water-in-oil-in-water
Emulsion In Vivo.. In Vivo. 2021 Jan-Feb;35(1):239-248.
doi:10.21873/invivo.12252.
PMID:
33402470
15. Yanagie H, Yanagawa M, Morishita Y, Shinohara
A, Dewi N, Nonaka Y, Furuya Y, Mizumachi R,
Murata Y, Nakamura H, Suzuki M, Sakurai Y,
Tanaka H, Masunaga S, Ono K, Sugihara T,
Nashimoto M, Yamauchi H, Ono M, Nakajima J,
Takahashi H. : Suppression of Tumor Growth in a
Rabbit Hepatic Cancer Model by Boron Neutron
Capture Therapy With Liposomal Boron Delivery
Systems. In Vivo. 2021 Nov-Dec;35(6):3125-3135.
doi: 10.21873/invivo.12607. PMID: 34697143

551

Genomic Research Support Center(GresCent)
Director & Professor
Yutaka Osuga, M.D., Ph.D.

1. Organization
Genomic Research Support Center was establishedin 2017 to support appropriate and harmonious
achievements of advanced genomic researches at the
University of Tokyo Hospital. Genomic Research
Support Center deals with cancer, life-style disease,
hereditary disorders, and so on. This center is directedby Professor Yutaka Osuga. Experts of these fields,
including Associate Professor Nobuhiro Shojima,
participate in the activities as follows; (1) large scale
analysis of genomes utilizing next generation
sequencers and establishment of pipelines of genome
informatic analysis, (2) elucidation of hereditary
factors and pathogenesis of various diseases, (3)integrated research and education of genomic andclinical information, (4) analysis of polymorphismand mutation of genes involved in susceptibility andresponse to treatment in various diseases such as lifestyle disease, and (5) establishment of database andintegrated data mining of associated clinicalinformation.

2. Activities
In collaboration with RIKEN, we have identified
genetic variations conferring susceptibility to type 2
diabetes, myocardial infarction and renal dysfunctionin the Japanese population from the genome-wide
association study (GWAS) results. We identified type2 diabetes – associated loci, including missense
variants in genes related to insulin secretion (GLP1R).
To examine type 2 diabetes risk in East Asian
individuals, our team carried out a meta-analysis of
GWAS data from over 400,000 individuals. We

identified 61 loci that are newly implicated in
predisposition to type 2 diabetes. (Nature 582, 240245, 2020).
In collaboration with the Osaka University, RIKEN
and BioBank Japan, we have identified genetic
variations conferring susceptibility to deep-phenotype(diseases, biomarkers and medication usage). To
expand an atlas of genetic associations in nonEuropean populations, we conducted 220 deepphenotype genome-wide association studies in
BioBank Japan, by incorporating past medical history
and text-mining of electronic medical records (Nature
Genetics, 53, 1415-1424, 2021). Meta-analyses with
the UK Biobank and FinnGen identified new loci,which improved the resolution of the genomic map ofhuman traits. We performed statistical decompositionof matrices of phenome-wide summary statistics andidentified latent genetic components.
In collaboration with the Osaka University, RIKEN
and BioBank Japan, we assembled an ancestrally
diverse collection of GWAS of type 2 diabetes
through the UK Biobank, AGEN T2D and the
Diabetes Meta-Analysis of Trans-Ethnic association
studies (DIAMANTE) Consortium. Multi-ancestry
GWAS meta-analysis identified multiple lociattaining stringent genome-wide significance, whichwere delineated to multiple distinct association
signals (Nature Genetics, 5, 560-572, 2021). As
expected, ancestry-specific genetic risk score (GRS)
performed best in test GWAS from their respective
ancestry group. Multi-ancestry meta-analysis
maximizes power to detect association signals that areshared across ancestry groups. By modelingheterogeneity in allelic effects across ancestries, our552

meta-regression approach can also allow for
association signals that are driven by ancestryspecific causal variants, although power will belimited by the sample size available in that ancestry
group.
In collaboration with the Osaka University, RIKEN
and BioBank Japan, we profiled serum metabolites of
persons with type 2 diabetes with both diabetic
retinopathy and diabetic kidney diseases using acomprehensive non-targeted metabolomics approachwith mass spectrometry. We compared the abundanceof the serum metabolites between the persons with
type 2 diabetes with multiple complications andwithout any complications, identifying fivemetabolites, including N-acetylneuraminic acidsignificantly increased in those with the complications.
Our metabolome analysis identified the serum
metabolite features of the persons with type 2 diabetes
with the complications, which could potentially be
used as biomarkers.
We conducted whole genome sequence andanalyzed the sequence data of over 2,000 subjects
with type 2 diabetes in collaboration with the Osaka
University, RIKEN and BioBank Japan. We aredeveloping the methods to predict diabetic
complications and deterioration of diabetes bybioinformatics algorithms including the Penalized
regression method, often used in machine learningand public OmiX database.
In collaboration with Department of Clinical
Genomics, we supported the meetings and expertpanel regarding cancer and rare diseases. We hadclinical and genomic WEB conference with hospitals
related to cancer treatment.
We shared genomic data with researchers abouttype 2 diabetes association study, Set3 (121,950
controls, 18,688 cases) and Set4 (7,065 controls,
2,483 cases) through national bioscience databasecenter, NBDC (https://humandbs.biosciencedbc.jp/
hum0014-v18#diabet3).
We made paper to inform for the participants of theresearch on ‘Realization of personalized medicine for
Metabolic syndrome related disease.’ in collaboration
with research ethics support center.
We used panel analysis applying next-generation
sequencer and revealed the genetic diagnosis on

extreme phenotypes of diseases related to life-styles
including, maturity onset diabetes of the young andlipodystrophy and predicted the prognosis andselected effective therapies.

3．References
1.

2.

3.

4.

Sakaue S, Kanai M, Tanigawa Y, Karjalainen J,
Kurki M, Koshiba S, Narita A, Konuma T,
Yamamoto K, Akiyama M, Ishigaki K, Suzuki A,
Suzuki K, Obara W, Yamaji K, Takahashi K, Asai
S, Takahashi Y, Suzuki T, Shinozaki N,
Yamaguchi H, Minami S, Murayama S,
Yoshimori K, Nagayama S, Obata D,
Higashiyama M, Masumoto A, Koretsune Y;
FinnGen, Ito K, Terao C, Yamauchi T, Komuro I,
Kadowaki T, Tamiya G, Yamamoto M, Nakamura
Y, Kubo M, Murakami Y, Yamamoto K,
Kamatani Y, Palotie A, Rivas MA, Daly MJ,
Matsuda K, Okada Y. A cross-population atlas ofgenetic associations for 220 human phenotypes.
Nat Genet. 2021 Oct;53(10):1415-1424. doi:
10.1038/s41588-021-00931-x. Epub 2021 Sep 30.
PMID: 34594039.
Sone K, Toyohara Y, Taguchi A, Miyamoto Y,
Tanikawa M, Uchino-Mori M, Iriyama T,
Tsuruga T, Osuga Y. Application of artificial
intelligence in gynecologic malignancies: A
review. J Obstet Gynaecol Res. 2021, Aug;47(8):2577-2585. doi: 10.1111/jog.14818. Epub 2021
May 10. PMID: 33973305.
Hosoe J, Kawashima-Sonoyama Y, Miya F,
Kadowaki H, Suzuki K, Kato T, Matsuzawa F,
Aikawa SI, Okada Y, Tsunoda T, Hanaki K,
Kanzaki S, Shojima N, Yamauchi T, Kadowaki T.
Genotype-Structure-Phenotype Correlations of
Disease-Associated
IGF1R Variants
andSimilarities to Those of INSR Variants. Diabetes.
2021 Aug;70(8):1874-1884. doi: 10.2337/db201145. Epub 2021 Jun 1. PMID: 34074726.
Hosoe J, Suzuki K, Miya F, Kato T, Tsunoda T,
Okada Y, Horikoshi M, Shojima N, Yamauchi T,
Kadowaki T. Structural basis of ethnic-specificvariants of PAX4 associated with type 2 diabetes.
Hum Genome Var. 2021 Jul 5;8(1):25. doi:
10.1038/s41439-021-00156-8. PMID: 34226521;
PMCID: PMC8257626.

553

5.

6.

Imamura M, Takahashi A, Matsunami M,
Horikoshi M, Iwata M, Araki SI, Toyoda M,
Susarla G, Ahn J, Park KH, Kong J, Moon S,
Sobrin L; International Diabetic Retinopathy andGenetics CONsortium (iDRAGON), Yamauchi T,
Tobe K, Maegawa H, Kadowaki T, Maeda S.
Genome-wide association studies identify two
novel loci conferring susceptibility to diabetic
retinopathy in Japanese patients with type 2
diabetes. Hum Mol Genet. 2021 May 17;30(8):716-726. doi: 10.1093/hmg/ddab044. Erratum in:
Hum Mol Genet. 2022 Jul 7;31(13):2294. PMID:
33607655; PMCID: PMC9022108.
Mahajan A, Spracklen CN, Zhang W, Ng MCY,
Petty LE, Kitajima H, Yu GZ, Rüeger S, Speidel
L, Kim YJ, Horikoshi M, Mercader JM, Taliun D,
Moon S, Kwak SH, Robertson NR, Rayner NW,
Loh M, Kim BJ, Chiou J, Miguel-Escalada I,
Della Briotta Parolo P, Lin K, Bragg F, Preuss
MH, Takeuchi F, et al. Multi-ancestry genetic
study of type 2 diabetes highlights the power ofdiverse populations for discovery and translation.
Nat Genet. 2022 May;54(5):560-572. doi:
10.1038/s41588-022-01058-3. Epub 2022 May
12. PMID: 35551307; PMCID: PMC9179018.

554

Advanced Medical Center forHeart Failure
Director, Associate Professor
Masaru Hatano, M.D.,Ph.D.

Vice Director
Masahiko Ando, M.D., Ph.D.

Homepage https://www.h.u-tokyo.ac.jp/patient/depts/shinfuzen/
Introduction and Organization
Advanced medical center for heart failure
collaborates with a wide range of university hospitals
and core regional medical institutions to accept patients
who require heart transplantations of ventricular assist
device (VAD) implantation. In addition to
cardiovascular medicine and cardiovascular surgery,the center provides medical care with a heart teamconsisting of recipient transplant coordinators,
pharmacists, medical engineers and physical therapists.
In addition to such medical cooperation efforts, thecenter is also responsible for training heart failure
specialists and other specialized staff by accepting
trainees.

Clinical activities
Target diseases include idiopathic cardiomyopathies
such as dilated cardiomyopathy and hypertrophic
cardiomyopathy, various types of secondary
cardiomyopathy, and all causes of heart failure
regardless of underlying disease
・Heart transplantation : Performed 186
Heart tansplantation to date (as of 31 Aug 2022), thelargest number in Japan・ Ventricular Assist Device (VAD): The center canemploy all types of VADs approved in Japan,
making it possible to choose the most suitablemodel according to each patient’s physical and heart
failure condition. It is also recognized as a facility
that can perform destination therapy.

・ Drug therapy for heart failure: The center has
extensive experience in the use of heart failuredrugs, including those that have been in recent years.
・Introduction of Vyndaqel for cardiac amyloidosis:
The center has been certified to prescribe Vyndaqelby The Japanese Circulation Society and havealready gained a significant amount of experience
with the drug.
・ HeartSeet: The center participates in a postmarketing clinical trial of HeartSeet, a skeletal
myoblast sheet to be transplanted onto the surfaceof the heart.

Teaching and Research activities
In addition to medical care, we accept training in
advanced heart failure management from medical
facilities nationwide and play an important role intraining heart failure specialists and specialized staff.
We are also focusing on research and in addition todisseminating many research results, we are promoting
translational research that bridges basic research andclinical practice. In addition, while treating a large
number of heart failure patients, we are also striving toestablish optimal prevention and treatment strategy(precision medicine) that consider individual
differences.

References1.

Fujiwara T, Takeda N, Hara H, Ishii S, Numata G,
Tokiwa H, Maemura S, Suzuki T, Takiguchi H,

555

2.

3.

4.

5.

6.

7.

Kubota Y, Seo K, Sakata A, Nomura S, Hatano M,
Ueda K, Harada M, Toko H, Takimoto E, Akazawa
H, Nishimura S, Komuro I . Three-Dimensional
Visualization of Hypoxia-Induced Pulmonary
Vascular Remodeling in Mice.. Circulation. 2021;
144(17):1452-1455.
Ide T, Kaku H, Matsushima S, Tohyama T, Enzan
N, Funakoshi K, Sumita Y, Nakai M, Nishimura K,
Miyamoto Y, Tsuchihashi-Makaya M, Hatano M,
Komuro I, Tsutsui H; JROADHF Investigators.
Clinical Characteristics and Outcomes of
Hospitalized Patients With Heart Failure From theLarge-Scale Japanese Registry Of Acute
Decompensated Heart Failure (JROADHF). Circ J.
2021;85(9):1438-1450.
Kaneko H, Kiriyama H, Kamon T, Itoh H, Kodera
S, Fujiu K, Daimon M, Morita H, Hatano M,
Komuro I. Percutaneous Mitral Valve Intervention
Using MitraClip for Functional Mitral
Regurgitation and Heart Failure. Int Heart J. 2021;
62(1):4-8.
Bujo C, Amiya E, Hatano M, Tsuji M, Maki H,
Ishida J, Ishii S, Narita K, Endo M, Ando M,
Shimada S, Kinoshita O, Ono M, Komuro I.
Association between infectious event and de novo
malignancy after heart transplantation. Heart
Vessels. 2021;36(4):499-508.
Ishiwata J, Daimon M, Nakanishi K, Sugimoto T,
Kawata T, Shinozaki T, Nakao T, Hirokawa M,
Sawada N, Yoshida Y, Amiya E, Hatano M, Morita
H, Yatomi Y, Komuro I. Combined evaluation ofright ventricular function using echocardiography
in non-ischaemic dilated cardiomyopathy. ESC
Heart Fail. 2021 ;8(5):3947-3956.
Bujo C, Amiya E, Hatano M, Ishida J, Tsuji M,
Kakuda N, Narita K, Saito A, Yagi H, Ando M,
Shimada S, Kimura M, Kinoshita O, Ono M,
Komuro I. Long-Term renal function after
implantation of continuous-flow left ventricularassist devices: A single center study. Int J Cardiol
Heart Vasc. 2021;37:100907.
Tsuji M, Amiya E, Bujo C, Hara T, Saito A,
Minatsuki S, Maki H, Ishida J, Hosoya Y, Hatano
M, Imai H, Nemoto M, Kagami Y, Endo M,
Kimura M, Ando M, Shimada S, Kinoshita O, Ono
M, Komuro I. Carbon Monoxide Diffusing
Capacity Predicts Cardiac Readmission in Patients

8.

9.

10.

11.

12.

13.

Undergoing Left Ventricular Assist Device
Implantation in Japan. ASAIO J. 2021;67(10):1111-1118.
Goto K, Uehara M, Okamoto K, Takeda N, Morita
H, Hatano M, Komuro I. The therapeutic dilemmaof immunosuppressive drugs for refractory
cardiac sarcoidosis in COVID-19 infection. ESC
Heart Fail. 2021;8(6):5577-5582.
Minatsuki S, Kiyosue A, Shimizu Y, Tanikawa I,
Murasawa T, Hirose K, Saito A, Yagi H, Takeda N,
Hatano M, Ando J, Komuro I. A Novel Techniqueof Balloon Pulmonary Angioplasty for theTreatment of Total Occlusion Lesions. CJC Open.
2021;3(12):1513-1515.
Tamura Y, Kumamaru H, Abe K, Satoh T, Miyata
H, Ogawa A, Tanabe N, Hatano M, Yao A, Tsujino
I, Fukuda K, Kimura H, Kuwana M, Matsubara H,
Tatsumi K; Japan Pulmonary Hypertension
Registry (JAPHR) Network. Improvements in
French risk stratification score were correlatedwith reductions in mean pulmonary arterypressure in pulmonary arterial hypertension: asubanalysis of the Japan Pulmonary Hypertension
Registry (JAPHR). BMC Pulm Med. 2021;21(1):28.
Dai Z, Uehara M, Amiya E, Hatano M, Komuro I.
Acute cellular rejection after heart transplantationand its remission visualized by cardiac magnetic
resonance. Eur Heart J Case Rep. 2021;5(3):ytab085.
Ikawa T, Miyagawa T, Fukui Y, Minatsuki S, Maki
H, Inaba T, Hatano M, Toyama S, Omatsu J, Awaji
K, Norimatsu Y, Watanabe Y, Yoshizaki A, Sato S,
Asano Y. Association of serum CCL20 levels withpulmonary vascular involvement and primarybiliary cholangitis in patients with systemicsclerosis. Int J Rheum Dis. 2021;24(5):711-718.
Adachi Y, Kiyosue A, Ando J, Kawahara T,
Kodera S, Minatsuki S, Kikuchi H, Inaba T,
Kiriyama H, Hirose K, Shinohara H, Saito A,
Fujiwara T, Hara H, Ueda K, Sakakura K, Hatano
M, Harada M, Takimoto E, Akazawa H, Morita H,
Momomura SI, Fujita H, Komuro I. Factors
associated with left ventricular reverse remodelling after percutaneous coronary intervention inpatients with left ventricular systolic dysfunction.
Sci Rep. 2021;11(1):239.

556

14. Minatsuki S, Takahara M, Kiyosue A, Kodera S,
Hatano M, Ando J, Kohsaka S, Ishii H, Shinke T,
Amano T, Ikari Y, Komuro I; J-SHD and J-PCIInvestigators. Characteristics and in-hospitaloutcomes of patients undergoing balloon
pulmonaryangioplastyforchronic
thromboembolic pulmonary hypertension: a timetrend analysis from the Japanese nationwide
registry. Open Heart. 2021;8(2):e001721.
15. Kakuda N, Amiya E, Hatano M, Maki H, Bujo C,
Tsuji M, Narita K, Fujita K, Ishida J, Ono M,
Komuro I. Case Report: A Case of Acute Cellular
Rejection Due to Atopic Dermatitis Exacerbation
3 Years After Heart Transplantation. Front
Immunol. 2021;12:630051.
16. Kadowaki H, Ishida J, Uehara M, Ishizuka M,
Kiyosue A, Hatano M, Shimada S, Ono M,
Akazawa H, Komuro I. Detection of ProfoundMyocardial Damage by Cardiac MRI in a Patientwith Severe Cardiotoxicity Induced by AntiHER2 Therapy. Int Heart J. 2021;62(6):1436-1441.
17. Yasunaga M, Yasuda Y, Honda A, Maki H,
Toyama K, Masamoto Y, Bujo C, Amiya E, Hatano
M, Ono M, Komuro I, Kurokawa M.Successfultreatment of EBV-related lymphoproliferative
disease after heart transplantation with autologous
hematopoietic stem cell transplantation despitetransient heart failure associated with engraftment
syndrome. Ann Hematol. 2021 ;100(4):1097-1100.
18. Hatano M, Jimba T, Fujiwara T, Tsuji M, Bujo C,
Ishida J, Amiya E, Kinoshita O, Ono M. Lateonset right ventricular failure after continuousflow left ventricular assist device implantation:case presentation and review of the literature.
Cardiol. 2022;80(2):110-115.

557

Swallowing Center
Director/Associate Professor
Rumi Ueha, M.D., Ph.D.

Vice Director
Haruhi Inokuchi, M.D., Ph.D. (Department of Rehabilitation Medicine)
Asako Kaneoka, SLP., Ph.D. (Rehabilitation Center)

Homepage http://www.m.u-tokyo.ac.jp/mcm/
Introduction and Organization
A condition in which there is a problem withswallowing food or drink is called a swallowing
disorder. In recent years, advances in medical
technology have increased the lifesaving rate and theaging of society, resulting in an increase in the numberof patients with dysphagia among a wide range of age
groups caused by congenital diseases, stroke,
intractable diseases, malignant tumors and aging. Since
2009, we have been providing medical care for patientswith dysphagia at the University of Tokyo Hospital byorganizing the " Swallowing Support Team" withspecialists in the field of swallowing. To provide more
specialized and multifaceted treatment for dysphagia,
in 2021, the Swallowing Center was established.
At the Swallowing Center, the departments of
Otolaryngology and Head and Neck Surgery,
Rehabilitation Medicine, Oral-Maxillofacial Surgery
and Orthodontics, Geriatric Medicine, Pediatrics,
Pediatric Surgery, Neurology, Clinical Nutrition,
Nursing, and Clinical Laboratory work together as ateam of multidisciplinary specialists including
physicians, speech pathologists, nurses, dietitians,
pharmacists, and dental hygienists, taking a
multifaceted approach to each patient.
The following is a list of departments and divisions thatcollaborate with the Swallowing Center:
1. Otolaryngology and Head and Neck Surgery
2. Rehabilitation Medicine
3. Oral-Maxillofacial Surgery and Orthodontics
4. Geriatric Medicine

5. Pediatrics
6. Pediatric Surgery
7. Neurology
8. Clinical Nutrition Center
9. Nursing Department
10. Pharmaceutical Department
We also hold a bimonthly meeting of the Swallowing
Center to share information and improve problems.

Clinical activities
We have outpatient clinics for patients with dysphagia
at the Department of Otorhinolaryngology and Headand Neck Surgery every Tuesday and Thursday
mornings. For hospitalized patients, we provide more
specialized and multifaceted treatment for dysphagia
caused by a variety of factors in a wide range of age
groups, with physicians and specialists from multiple
departments working as a team. A weekly swallowing
conference is held on Tuesdays to discuss various caseswith a multidisciplinary team.
We also actively perform surgical treatment fordysphagia (to prevent aspiration or to improveswallowing functions) and provides intensive
rehabilitation after surgery to improve swallowing
functions during hospitalization.
The following is a list of swallowing examinations
performed in 2021.
 Videofluorographic swallowing study: 637 cases Videoendoscopic examination of swallowing: 575
cases High-resolution swallowing manometry: 45 cases

558



Swallowing computed tomography: 9 cases

Teaching activities
The center emphasizes educational activities on
feeding and swallowing throughout the hospital andactively organizes E-learning and training sessions.
We participate in undergraduate education as a part ofsystemic lectures and bedside learning by thedepartment of Otolaryngology and Head and Neck
Surgery and Rehabilitation Medicine.
Research activities
Our research field covers a variety of topics related toswallowing. Clinical and basic research activities arehighly encouraged. The clinical research is related toswallowing dynamics and physiology, laryngology,
broncho-esophagology and rhinology and is related tocase research, and clinical statistics.
Basic research is also encouraged to solve essence ofclinical problems and to elucidate basic phenomena or
anatomical and cellular structures. Our research topics
cover:
1. Effects of aspiration prevention surgery on
patients with severe dysphagia
2. Pulmonary inflammatory responses by contrast
agent aspiration
3. Swallowing mechanisms using pathological andelectrophysiological analysis and VR system
4. Esophageal Motility in Neuromuscular Disorders
5. Evaluation of swallowing physiology withpharyngo-esophageal high-resolution manometry
6. Regeneration of vocal fold structure and its
molecular mechanism
7. Gene expression analysis of recurrent respiratory
papillomatosis
8. Pathophysiology of olfactory dysfunction due to
COVID-19
9. Research on preventive rehabilitation for
dysphagia due to chemoradiotherapy for head andneck cancer
10. Pathophysiology of dysphagia after esophageal
cancer surgery
11. Statistical analysis of dysphagia patients using big
data
12. Research on the effect of cervical spine surgery on
swallowing function

References
1.

2.

3.

4.

5.

6.

7.

8.

9.

Kataoka T, Yoshida S, Ueha R. Clicking Sensation
on Swallowing. Jama Otolaryngol. 147(8):762-3.
2021.
Koyama S, Kondo K, Ueha R, Kashiwadani H,
Heinbockel T. Possible Use of Phytochemicals for
Recovery from COVID-19-Induced Anosmia andAgeusia. International journal of molecularsciences. 22(16). 2021.
Koyama S, Ueha R, Kondo K. Loss of Smell andTaste in Patients With Suspected COVID-19:
Analyses of Patients' Reports on Social Media. J
Med Internet Res. 23(4). 2021.
Masuda H, Ueha R, Sato T, Goto T, Koyama M,
Yamauchi A, Kaneoka A, Suzuki S, Yamasoba T.
Risk Factors for Aspiration Pneumonia After
Receiving Liquid-Thickening Recommendations.
Otolaryngology--head and neck surgery: official
journal of American Academy of OtolaryngologyHead and Neck Surgery. doi: 10.1177/
01945998211049114. 2021.
Mori E, Ueha R, Kondo K, Funada S, Shimmura
H, Kanemoto K, Tanaka H, Nishijima H, Otori N,
Yamasoba T, Kojima H. Squamous andRespiratory Metaplasia After Olfactory Mucosal
Resection. Front Neurosci. 15:695653. 2021.
Nativ-Zeltzer N, Ueha R, Nachalon Y, Ma B,
Pastenkos G, Swackhamer C, Bornhorst GM,
Lefton-Greif MA, Anderson JD, Belafsky PC.
Inflammatory Effects of Thickened Water on theLungs in a Murine Model of Recurrent Aspiration.
Laryngoscope. 131(6):1223-8. 2021.
Sato T, Ueha R, Goto T, Yamauchi A, Kondo K,
Yamasoba T. Expression of ACE2 and TMPRSS2
Proteins in the Upper and Lower Aerodigestive
Tracts of Rats: Implications on COVID 19
Infections. Laryngoscope. 131(3):E932-E9. 2021.
Sekiguchi Koyama M, Ueha R, Goto T, Sato T,
Tachibana A, Mizumoto Y, Nito T, Yamasoba T.
Aspiration Prevention Surgery under Local
Anesthesia for Palliative Care in Patients with
Head and Neck Cancer: A Report of Two Cases.
ORL J Otorhinolaryngol Relat Spec. 83(1):52-8.
2021.
Sugaya T, Ueha R, Sato T, Goto T, Yamauchi A,
Yamasoba T. Safety of surgical tracheostomy

559

10.

11.

12.

13.

14.

under continued antithrombotic therapy: A retrospective cohort study. Clinical otolaryngology.
doi: 10.1111/coa.13861. 2021.
Takeuchi M, Ahn J, Lee K, Takaki K, Ifukube T,
Yabu K, Ueha R, Sekino M. Hands-free wearable
electrolarynx using LPC residual waves andlistening evaluation by laryngectomies. Advanced
Biomedical Engineering. 11:68-75, 2021.
Ueha R, Kondo K, Kagoya R, Shichino S,
Shichino S, Yamasoba T. ACE2, TMPRSS2, andFurin expression in the nose and olfactory bulb inmice and humans. Rhinology. 59(1):105-9. 2021
Ueha R, Sato T, Goto T, Koyama M, Yamauchi A,
Mizukami A, Yamasoba T. Effects of Aspiration
Prevention Surgery on the Dynamics of the
Pharynx and Upper Esophageal Sphincter. OTO
Open. 5(4):2473974X211048505. 2021
Ueha R, Sato T, Goto T, Yamauchi A, NativZeltzer N, Mitsui J, Belafsky PC, Yamasoba T.
Esophageal Dysmotility is Common in Patients
With Multiple System Atrophy. Laryngoscope.
131(4):832-8. 2021
Uranaka T, Kashio A, Ueha R, Sato T, Bing H,
Ying G, Kinoshita M, Kondo K, Yamasoba T.
Expression of ACE2, TMPRSS2, and Furin in
Mouse Ear Tissue, and the Implications for SARSCoV-2 Infection. Laryngoscope. 131(6):E2013-E7.
2021.

560

Immune-Mediated Diseases
Therapy Center
Professor
Associate Professor
Hiroko Kanda, M.D., Ph.D.

Lecturer
Associate

Homepage

http://www.m.u-tokyo.ac.jp/patients/depts./menekishikkan/

Introduction and Organization
In many immune diseases, some immune cells andresponses are out of control. “Biologics” have beendeveloped as agents that control the cytokines and cellsurface molecules. In Japan, TNF inhibitors wereintroduced for the first time as "biologics" forrheumatoid arthritis (RA) in 2003. The effect of thesedrugs has been tremendous and has brought about aparadigm shift in RA practice, not only in terms oftreatment goals, but also in terms of treatment
algorithms, revised classification criteria for diagnosis,
and so on. Now, "small-molecule inhibitors" that target
specific molecules of intracellular signal transduction
events have been added, and these drugs, called"molecular targeted therapies," are being developed
one after another. Currently, “Biologics” include 8 TNF
inhibitors, 3 IL-6 inhibitors, 1 CTLA4-Ig, 4 IL-17
inhibitors, 1 IL-12/23 inhibitor, 2 IL-23 inhibitors, 2alpha 4 integrin inhibitors, 2 IL-5 inhibitors, 1 IL-4/13
inhibitor, 1 anti-IgE antibody, 1 IL-1 inhibitor, 2 B-cell
activation inhibitors, 1 typeI IFN inhibitor, 2complement activation inhibitors, 1 nFcR inhibitor, and
5 JAK inhibitors and 1 PDE4 inhibito have been
approved "small-molecule inhibitorss". Target diseases
include not only immunological diseases such as RA,

juvenile idiopathic arthritis, systemic lupus
erythematosus, scleroderma, adult-onset Still's disease,vasculitis, spondyloarthritis, psoriasis and psoriatic
arthritis, inflammatory bowel disease, multiple
sclerosis, neuromyelitis optica, nocturnal paroxysmal
hemochromaturia, Castleman's disease, but also
autoinflammatory diseases, atopic Dermatitis.
Molecularly targeted therapies have shown highefficacy against these diseases and are expected to
avoid long-term administration of corticosteroids.
In 2017, with the expansion of molecular targeted
agents, the “Immune-mediated Diseases Therapy
Center Outpatient Department” was established in theoutpatient consultation division. Due to further
increases in the number of drugs and indications, theCenter was approved as a department of the Graduate
School of Medicine of the University of Tokyo in April
2020. At the same time, the "Immune-mediatedDiseases Therapy Center" was established on the 12th
floor of Inpatient Unit B as an outpatient center toprovide intravenous molecular targeted therapy for all
patients with immune-mediated diseases in theuniversity of Tokyo hospital. There are eight
departments: Allergy and Rheumatology, Dermatology,
Ophthalmology, Orthopaedics surgery and Spinal

561

surgery, Gastroenterology, Colon and Rectal surgery,
Neurology, and Hematology. Together with three
dedicated nurses and two pharmacists, we are working
to make the outpatient clinic a smoother and safer place
to provide molecular targeted therapy. In addition, once
every two months, the immune-mediated diseases
therapy center meeting is held as a forum for
information sharing, where new drug regimens are
discussed and problems are remedied.
The current number of prescriptions for molecularly
targeted agents has more than doubled from 550 in2017 to 1,300 in 2021, with 65% subcutaneous, 30%
intravenous, and 5% oral. As a cross-sectional center,
we would like to deepen our cooperation and aim forsafer operations in the future.

Clinical activities
We have an outpatient clinic at the “ImmuneMediated Therapy Center” every Monday morning,where we provide consultation services for diagnosis
and treatment of immune-mediated diseases, especiallythose related to molecular targeted therapy. The actual
treatment is provided by the attending physician ofeach department, but as mentioned above, intravenous
treatment is centralized at our center.

Teaching activities
As for education for outpatient staff, lectures on eachdisease are held once a year. When a new drug isintroduced, additional lectures related to that drug are
given. Medical students are educated through BSL.

Research activities
We aim to conduct research on the efficacy andsafety of molecular targeted agents for each immunemediated disease by searching for biomarkers andanalyzing medical information, which will lead to theestablishment of precision medicine.

References
1.

Shimizu T, Nagafuchi Y, Harada H, Tsuchida Y,
Tsuchiya H, Hanata N, Tateishi S, Kanda H,
Sumitomo S, Soda H, Yamamoto K, Fujio K.
Decrease peripheral blood memory B cells areassociated with the presence of interstitial lung

2.
3.
4.
5.
6.

disease in rheumatoid arthritis: a case-control
study. Mod Rheumatol. 2021; 31: 127-32
Kanda H. Evaluation of activity for Psoriatic
arthritis. Nippon Rinsho. 2021; 79: 534-539
Kanda H. Safety of tofacitinib for rheumatoid
arthritis. Rheumatology. 2021; 65: 494-501
Kanda H. Cyclosporin in lupus nephritis. Kidneyand dialysis. 2021; 91: 143-6
Kanda H. IgA vasculitis. Kidney and dialysis.
2021; 91: 143-6
Kanda H. Methotrexate in psoriatic arthritis.
Diagnosis and treatment. 2021; 109: 1641-5

562

Medical Community Network andDischarge Planning Center
Associate Professor
Masahiko Sumitani, M.D., Ph.D. (concurrently)

Assistant Profeesor

Homepage https://www.h.u-tokyo.ac.jp/english/centers-services/central-clinicalfacilities/medical-community-network-and-discharge-planning/index.html
Introduction and Organization
In April 1997, plans for the Department of Medical
Social Service and Welfare were initiated by the
University of Tokyo Hospital with the aim ofsupporting inpatients upon discharge. The Department
was officially authorized in April 2000, the firstamong national universities. In April 2005, theDepartment began providing assistance to outpatientsreferred from other hospitals and was renamed theDepartment of Medical Community Network andDischarge Planning. Further, in 2019, the departmentchanged the name to Medical Community Network
and Discharge Planning Center. The Center provides
assistance to outpatients referred from local medical
institutions, to inpatients being discharged to theirhomes, and to inpatients being transferred to local
medical institutions.

Clinical activities
Assistance to patients receiving 9 medica I treatment:
The Department provides assistance to outpatientsreferred from local medical institutions. Our staff
helps patients make appointments and follow procedures to receive medical treatment. The Department
assists new outpatients in arranging general consultations, helps outpatients schedule spedalized treatment,
and provides assistance to patients who have beenreferred to a specific physician.
Assistance to inpatients upon discharge: The
Department provides assistance to patients for whomtransfer to a local medical institution or discharge tohome if need arises.
Many of such patients are highly dependent on
medical care due to the severity of their condition. For
those receiving medical care at home, our department
staff arranges home visits by primary care doctors andnurses. For patients being transferred to local
institutions, our staff provides assistance both togeneral hospitals and hospice care units.
Home Care Support (Home Care Support clinic): Our
Home Care Support Clinic, which offers home care
support to our outpatients, has been running since
Janualy 2003. The clinic supports the implementationand coordination of home care services, and refers
outpatients requesting hospital admission to otherhospitals or facilities.
Consultation by Social Worker (Consultation on
Recuperation): Our consultation service provided bysocial workers has been running since 2012. Oursocial workers mainly consult enquiries regarding
patient recuperation.
Transferring out patients to local institutes: Aiming todefining the distinction of the medical role between
the University Hospital and local institutes andfacilitate transferring our outpatients to them, theproportion of such transferring patients to first-visit
patients keeps more than 80%.

Teaching activities
We educate undergraduate students of the Medical
Social Working and Welfare of other university.

563

Research activities
Our research field covers investigating appropriate
patient numbers for assistance to inpatients upondischarge in the University hospital; and investigating
how to assist working and job in patients with severe
illness.

564

Department of Cancer Resource
CenterChief
Sachiyo Nomura, M.D.,Ph.D.

Associate chief
Takako Wakeda, M.D., Ph.D.

Counseling staff
Yuko Irisawa, RN., Keiko Fukuda, RN., Kunie Wakao, RN.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/gansoudan/

Introduction and Organization
As part of national efforts to address cancer, thegovernment has been establishing a network of“cancer care hub hospitals.” In response to its being
designated as a regional cancer care hub hospital in2008, the University of Tokyo Hospital established theCancer Patient Support Center to provide consultations to cancer patients and their families as well as
residents in neighboring communities with the aim ofleading them to appropriate departments and facilities.

Medical Services
Provision of information if patient contracts cancer
If a person gets cancer, the first thing they need to
do is collect information on cancer. The Cancer
Counseling and Support Center provides information
and booklets on different types of cancer.
Furthermore, the person needs to accurately
understand the doctors’ explanations to select the besttreatment for oneself from the various options
presented by doctors. At the Cancer Counseling andSupport Center, we explain difficult medical terms in
simple language, and we help patients understand theirdoctors’ advice.

Various kinds of advice related to the medical careof cancer
If a person contracts cancer, besides the medical
problem of what kind of treatment to undergo andwhere, there are also issues related to medical carewhen receiving treatment, such as medical expenses,
how to get along after being discharged from hospital,
job, and nursing services. The Cancer Counseling andSupport Center provides patients with advice andsupport so that they can resolve such social worries.
Provision of information on second opinions
The Center provides information on how to get asecond opinion and on facilities that provide second
opinions.
Various kinds of advice related to the appearancechanges caused by cancer treatment
Cancer treatment often causes appearance changes
such as hair loss and skin pigmentation. The center
provides patients with practical advice and support
about wig and cover make-up.
Provision of general information and advice on
cancer
The Center sends out and provides information topeople who do not have cancer but who want to find565

out about cancer, for instance the treatment andscreening for it.

Open hours
If you have any queries, please contact us on
03-5800-9061 between 9am-12noon, 1pm-4pm
weekdays.

Research activities
Our research field covers the relation between
appearance changes caused by cancer therapy andPatients’ quality of life.

Center for Disease Biology andIntegrative Medicine

567

Laboratory of Molecular
Biomedicine for Pathogenesis
Professor
Toru Miyazaki, M.D., Ph.D.

Associate Professor
Satoko Arai, Ph.D.

Assistant Professor
Natsumi Maehara, Ph.D.

Project Associate Professor
Kaori Taniguchi, Ph.D.

Official Website

http://tmlab.m.u-tokyo.ac.jp/

Research
Our laboratory focuses on clarification of thepathogenesis of various diseases and the related
physiological machineries in cellular and molecular
aspects. Based on our technical advantage in genemanipulation via gene knockout and transgenesis, wegive high priorities to in vivo analyses. This willdefinitively contribute to the direct therapeutic
application of our findings. Since our rationale is tochallenge to uncharacterized disease mechanisms andphysiologies, we will not restrict our interest, strategy
or technique employed, in certain specific field.
Rather, we will expand our research area by
establishing different collaborations with a broad
spectrum of researchers. We believe this fits to thepolicy of the CDBIM, which aims the development of
a comprehensive science including the fundamental
and clinical medicines, and the biotechnology. Overall,
we will attempt to discover novel biological insights
rather than to study details of previously characterized
physiologies, by targeting molecules newly identified
by ourselves. Now, we are focusing on the following
major projects.

AIM (Apoptosis Inhibitor of Macrophage) as a masterswitch to various modern diseases.
The rapid change in lifestyles and eating habits intoday’s society are thought to be the cause of various
disorders; metabolic syndrome and lifestyle-relateddiseases increase the risk of developing obesity,
diabetes, and cardiovascular disease; a fatty liver leads
to NASH and liver disease, may result in liver cancer;
autoimmune disease followed by obesity, chronic
renal failure, and Alzheimer’s disease are considered
as well. We hypothesize that such various modern
disorders, seemingly unrelated at first sight, share thecommon underlying pathological condition andmechanism, and the group of molecules exists as themaster switch, regulating the varied conditions.
We found a soluble apoptosis inhibitor factor
largely produced by tissue macrophage, named AIM(apoptosis inhibitor of macrophage). Our recent
studies showed that AIM plays an important role inregulating the pathological condition of the modern
diseases.
AIM is produced by macrophage and largely
presents in bloodstream as a soluble molecule. Once
AIM is incorporated into adipose tissue, it progressionof obesity. However, when this process undergoes

568

effectively and excessively under the obese condition,
oppositely to control the progression of obesity,
chronic inflammation of adipose tissue and insulin
resistance are triggered and Type II diabetes andatherosclerosis are worsen.
Moreover, because AIM binds to IgM in bloodstream, it leads to production of various autoantibodies, especially under the obese condition.
This suggests that the obesity is the cause of
autoimmune disease. Other studies showed that liverdisease, cancer, and kidney disease worsen under low
concentration of AIM. It is suggested that theconcentration of AIM in bloodstream differentiates theoutcome and the risk of getting various diseases.
The project was accepted for Advanced Researchand Development Programs for Medical Innovation,
Leading Advanced Projects for medical innovation(LEAP) 2019 (FY2019-2023), on Japan Agency for
Medical Research and Development (AMED).
Finding the mechanism on the regulation of AIM
activity will shed light on developing a diagnostics
and potential treatments to modern diseases. We will
focus on the details of involvement of AIM to thevarious diseases by generating a mouse model. Also,
cohort study is carried out using and analyzing thehuman specimen, aiming to develop a novel drug
treatment.
Additionally, we worked on the project regarding
the development of novel therapy against theinfectious diseases based on the phagocyticmechanism, founded by Research Program on
Emerging and Re-emerging Infectious Diseases(AMED FY2020-2021).

Lab Activities
We believe that the following three things are essential
for research in medical biology: ideas, strategies, andexperimental techniques. Therefore, the goal of oureducation is to let the students acquire as wide rangeof techniques as possible during their Master/PhD
courses and to cultivate ideas and strategies forresearch during their postdoctoral period. In addition,
since the establishment of our laboratory in 2006, wehave been constructing an international research
environment by regularly organizing a series ofseminars by leading overseas researchers and creating

as many opportunities as possible for young
researchers to have discussions in English, based on
the extensive friendships cultivated by Professor
Miyazaki's long-term overseas research experience. In
addition, we regularly hold joint meetings with
universities in Japan and abroad to exchange eachother's research progression and to explore thedevelopment of research through multifaceted
discussions, as well as to provide opportunities forstudents to present and discuss their research and tointeract with researchers. This year's seminars andmeetings were postponed in view of the situation
under the COVID-19.

Publications
1.

2.

3.

4.

Hasegawa H, Mizoguchi I, Orii N, Inoue S,
Katahira Y, Yoneto T, Xu M, Miyazaki T &Yoshimoto T. IL-23p19 and CD5 antigen-likeform a possible novel heterodimeric cytokine andcontributetoexperimental
autoimmune
encephalomyelitis development. Sci. Rep. 11,5266 (2021).
Lee J Y, Arumugarajah S, Lian D, Maehara N,
Haig A R, Suri R S, Miyazaki T, & Gunaratna L.
Recombinant Apoptosis Inhibitor of Macrophage
Protein Reduces Delayed Graft Function in a
Murine Model of Kidney Transplantation. PloS
One. 16, e0249838 (2021).
Maehara N, Taniguchi K, Okuno A, Ando H,
Hirota A, Li Z, Wang C-T, Arai S, & Miyazaki T.
AIM/CD5L attenuates DAMPs in the injured
brain and thereby ameliorates ischemic stroke.
Cell Rep. 36, 109693 (2021).
Wang C-T, Tezuka T, Takeda N, Araki K, Arai S,& Miyazaki T. High salt exacerbates acute kidney
injury by disturbing the activation of CD5L/
apoptosis inhibitor of macrophage (AIM) protein.
PloS One. 16, e0260449 (2021).

569

Laboratory ofStructural Physiology
Professor
Haruo Kasai, M.D.,Ph.D.

Lecturer
Sho Yagishita, M.D. Ph.D.

Research Associates
Yusuke Iino, M.D. Ph.D.

Homepage

http://www.bm2.m.u-tokyo.ac.jp/

Introduction and Organization

Teaching activities

The Center for Disease Biology and Integrative
Medicine (CDBIM) has been established in 2003, andelected Dr. Kasai as the professor of the Division of
Basic Medical Sciences (2) of CDBIM in July of 2004.
Dr. Kasai was in the National Institute forPhysiological Sciences, and officially took office in the
University of Tokyo in November, 2005. The Kasailaboratory has moved to the first building of Faculty of
Medicine in January, 2006. It belongs to the Section of
Functional Biology in the Graduate School of Medicine.
Its name has been changed from Division of Biophysics
to Laboratory of Structural Physiology in the April,2008. Dr. Kasai has also appointed as a principal
researcher in the International Research Center of
Neurointelligence (IRCN), the Institute of Advanced
Studies of the University of Tokyo since it hasestablished in 2017.10, and the laboratory is
cooperating the activity of IRCN.
The 17 members of our laboratories in the April of
2021 are Haruo Kasai, Sho Yagishita (Lecturer),
Yusuke Iino (Resaerch Associate), Takeshi Sawada(Resaerch Associate), Hasan Ucar (Project Researcher),
Mio Tajiri (Project Researcher), Yuichi Morimoto(Project Researcher), Toshiaki Kume (D4), Hitoshi
Okazaki (D2), Hidefumi Ohmi (M2), and as technicalstaffs, Arisa Kurabayashi, Shizuka Fujii, Yuki Sakata,
Masayoshi Asaumi, Chie Fujinami, Akiko Abe andYumiko Saikachi.

We gave three lectures of physiology forundergraduate students, was responsible for one
student experiment, four lectures of physiology andneuroscience for master course students, organized ten
lectures of the functional biology for graduate students.
The final lecture of Haruo Kasai was held on March 3,2022 for his retirement from Medical School. One
undergraduate student joined the activity of ourlaboratory for free quarter (FQ).

Research activities
Functional imaging is a central theme in modern
biology and medicine. All biological functions involvea multitude of interactions at the molecular, cellular,
and system levels, and it is ultimately desirable toperform molecular and cellular imaging in intact
preparations in which the original in vivo functions arepreserved. We have been exploring two-photon
excitation microscopy with a new type of laser, an
infrared femtosecond-pulse laser, as a means to achieve
this goal. The two-photon microscope has the ability topenetrate deep into tissues and is the only imaging
instrument that allows investigations of intact tissues atthe cellular and molecular levels. Two-photon
microscopy can also be readily combined withmolecular biological and other physiological methods,
and it promises to provide important insight into

570

various biological processes in the coming years. Our
research interests have two main focuses: (1) the
dynamics of synapses in the cerebral cortex and (2)exocytosis in both neurons and secretory cells. We
welcome multidisciplinary collaborations to promote
our research goals and to help to adapt the new
microscopic techniques and lasers to a wide range of
biomedical applications.
(1) Dendritic spines
Dendritic spines are postsynaptic to most excitatory
synapses in the brain, and their structural changes are amajor cellular basis for learning and memory (Kasai, etal. 2010. Spine generation and elimination are robust
processes, even in the adult brain, and spine enlargement and shrinkage play key roles in the plasticity ofdendritic spines. We previously used two-photon
glutamate uncaging to stimulate individual spines anddemonstrated that dendritic spine enlargement underlay
long-term potentiation (LTP) at the level of single
spines (Matsuzaki, Nature 2004). We also reported thatspine shrinkage and elimination can be induced when
glutamate uncaging was paired with action potentials
in the presence of GABAergic inhibition (Hayama,2013). Spine structures are dynamically maintained by
the regulation of actin fibers (F-actins). Cofilin is ahighly abundant actin-regulatory protein, which binds
to and alters the physical properties of F-actin.
Dephosphorylated cofilin at its serine-3 residue (dpcofilin) cleaves F-actin to generate new barbed ends
that are sites for actin polymerization anddepolymerizes F-actin at its pointed end to reduce fiber
length. These bidirectional enzymatic activities ofcofilin are inhibited by its phosphorylation at theserine-3 residue, as phosphorylated cofilin (p-cofilin)
dissociates from F-actin. Thus, the entire lifecycle of Factin is regulated by cofilin. Dendritic spine
enlargement and shrinkage are likely also regulated by
the phosphorylation and dephosphorylation of cofilin1(Noguchi, 2016). We previously showed thatbidirectional structural plasticity is controllable inindividual
spinesbymodulating
cofilinphosphorylation (Hayama,, Kasai, Nat, Neurosci.
2013). We have also made a optic probe which labels
enlarged spines, and optically erase them after learning,
and first demonstrated the causal relationship between
spine enlargement and memory (Hayashi, 2015).

In this year, we have explored dopamine actions onspine dynamics and pyschosis. Psychosis is adebilitating psychological condition with a long history.
Described in the medical writings of Hippocrates as
early as the 4th century B.C., the psychotic state ofhallucinations, delusions and disordered thought
represent an existential threat to an afflicted humanmind. Now, a team of researchers from theInternational Research Center for Neurointelligence(IRCN) and the Graduate School of Medicine at the
University of Tokyo, and the Graduate School ofInformatics at Kyoto University, proposes thatpsychosis involves defective neural signaling in a deepbrain area called the ventral striatum during a behavior
called discrimination learning (Ref. 1).
We studied the way mice predict future rewards in theirenvironment, a behavior known as reward learning,which is shared by us humans and other mammals, too.
Reward learning involves the release of a chemical
messenger dopamine to a receptor protein in the brain
called dopamine D1 receptor (D1R) to signal the
anticipation of a reward. Specifically, the teamsearched for a second dopamine signal that occurs only
when the anticipated reward fails to materialize —reward omission.
We suspected this signal for reward omission existed inneurons of the ventral striatum area of the brain that
contain a counterpart to D1R, dopamine D2 receptor(D2R). Coincidentally, D2R is the major brain receptor
for nearly every antipsychotic medication used to date.
The team showed that reward omission triggers a signal
in these neurons called the dopamine dip, a drop in
dopamine levels, which lasts less than a second.
These dips seem to contribute to the process of
discrimination learning, which includes how all
animals, including humans, judge previously learned
rewards and punishments. To explore the connection
between dips and discrimination learning, theresearchers
usedsophisticatedoptogenetic
technologies to artificially increase or decrease the dipsfor the first time and measured their effects on how themice estimated rewards. Optogenetics is a way toactivate artificial light-sensitive proteins with finely
controlled laser light to turn neuronal activity on or off.

571(2) Mechanical actions on presynaptic exocytosis(Ref. 8).
In the brain, synapses are often formed on small
protrusions (< 1 µm) from dendrites, called
dendritic spines. These spines touch small
swellings called presynaptic boutons, found onneighbouring neurons, which release glutamate
when they receive an action potential. In 2004, ourlab discovered the rapid enlargement of spines,
using a technique called repetitive two-photon
uncaging1. Back then, it was evident that enlarged
spines pressed onto the presynaptic terminals,
which are tightly connected to the spines via thesynaptic junction. Technical hurdles prevented
further exploration of this effect until recently.
Instead, we and other laboratories have focused on
how enlargement affected the spines themselves2.
Enlargement is confined to the stimulated spineand has a long-lasting component (> 2hr), whichis accompanied by increases in glutamate
sensitivities. This gives a cellular basis to theconceptual framework of memory and cell
assembly referred to as Hebb’s rule: Neurons thatfire together, wire together. Now, we address theremaining questions: Is the force of spineenlargement utilized for other purposes, and can
we measure this force acting in brain tissue?
Although two-photon glutamate uncaging has
enabled studies of single synapse physiology, we
needed to wait for some key technical advances
before using it to study presynaptic terminals.
These advances were: 1) optogenetic induction ofaction potential in presynaptic neurons; 2) afluorescent protein called iGluSnFR that can
detect glutamate release; 3) a technique callediSLIM, to image the assembly of SNARE proteinsthat enable the ultrafast exocytosis of glutamate
from presynaptic boutons when triggered by anaction potential.
We found that spine enlargement induced by
two-photon uncaging pushed the presynaptic
terminal, recessed the bouton, enhanced assemblyof SNARE complexes in the bouton andaugmented the glutamate release caused by
optogenetic induction of action potential. This
new phenomenon was named PREST (PREssure
Sensation and Transduction). Similar effects wereseen when the presynaptic terminal was recessedby pushing it with a sharp glass electrode, or
through increases in osmotic pressure. These
forces on the presynaptic terminal are roughly 0.5
atm, or 0.5 kg/cm2, comparable to the forces
produced by smooth muscle contraction. Thissuggests that these muscle-like forces in the brain
facilitate the assembly of SNAREs, and thereby
lead to exocytosis. Since the spine is the mostactin-rich structure in neurons, it is not surprisingthat a single spine is capable of producing an
estimated 10 nN of force. Unexpectedly, though,
PREST continued for more than 20 min after cells
regained their shape, implying that some traces of
the change remain inside the cells. Spineenlargement also has a prominent rapid andtransient compound (< 10 min), and it had been
puzzling that this is not strongly associated with
the increases in glutamate sensitivity caused by
the longer-lasting component1. Thus, PREST may
instead read out the rapid enlargement of a spine
for a particular function, possibly for a working
memory.
Synaptic transmission has previously been
considered either chemical or electrical. Ourfinding indicates that synapses can be mechanicalas well. Thus, the structural dynamics of synapses
play major roles in the formation of networks overa time scale less than 10 s. PREST is a novel
notion in the field of mechanobiology, and since
SNARE proteins are ubiquitous it may operate inmany cell types.
The force of spine enlargement is utilized in
two different ways: it acts to expand the spine
itself, and it also acts on the presynaptic terminal
for a rapid readout of the postsynaptic event by
PREST. Both mechanisms are still largely
mysterious, and this paper reveals only the tip of
the iceberg. For example, PREST also involves
cellular structures in other regions, including theactive zone, vesicle clusters, actin-based scaffolds
and microtubules.
Discovering the underlying mechanisms
behind the mechanical force and PREST — andfinding ways to manipulate them — are key tounderstand their functions in the brain, and theirroles in learning and memory. Many molecules

572

influencing our intelligence and mental disorders
are concentrated in spine synapses, and methods
to control the generation of mechanical force and
PREST will help to understand many other
mysteries of the brain.

References
1.

2.

3.

4.

5.

6.

7.

8.

Iino, Y., Sawada, T., Yamaguchi, Tajiri, M., K.,
Ishii, S., Kasai, H.* & Yagishita, S.* (2020)
Dopamine D2 receptors in discrimination learningand spine enlargement. Nature 579: 555-560.
Seaton, G., Hodges, G., de Haan, A., Grewal, A.,
Pandey, A., Kasai, K. & Fox, K. (2020) Dualcomponent structural plasticity mediated byalphaCaMKII-autophosphorylation on basal
dendrites of cortical layer 2/3 neurones. J.
Neurosci., 40:2228-2245.
Lee, S., Kume, H., Urakubo, H., Kasai, H., Ishii,
S. (2020) Multi-scale U-net for Two-Photon
Microscopy Image Denoising and Restoration in
Neural Networks. Neural Networks 125:92-103.
Ishii, S., Lee, Sehyung, Urakubo, H., Kume, H.,
Kasai, H. (2020) Generative and discriminativemodel-based approaches to microscopic image
restoration and segmentation. Microscopy 69, 7991.
Fujita, Y., Yagishita, S., Kasai, H., Ishii, S. (2020)
Computational Characteristics of the Striatal
Dopamine System Described by Reinforcement
Learning With Fast Generalization. Frontier in
Computational Neuroscience, 22 July, 2020. DOI:
10.3389/fncom.2020.00066
Urakubo, H., Yagishita, S., Kasai, H., & Ishii, S.
(2020) Signaling models for dopamine-dependent
temporal contiguity in striatal synaptic plasticity.
PLoS Computational Biology, July 23, 2020.
Hao Wang, Kouichi Mizuno, Noriko Takahashi,
Eri Kobayashi, Jun Shirakawa, Yasuo Terauchi,
Haruo Kasai, Katsuhide Okunishi, Tetsuro Izumi(2020) Melanophilin Accelerates Insulin Granule
Fusion Without Predocking to the Plasma
Membrane, Diabetes 69:2655-2666.
Ucar, H., Morimoto, Y., Watanabe, S., Noguchi,J., Iino, Y., Yagishita, S., Takahashi, N. & Kasai,
H. (2021). Mechanical actions of dendritic-spine

enlargement on presynaptic exocytosis. Nature
600: 686-689.
9. Kasai, H., Ziv, N. E., Okazaki, H., Yagishita, S. &Toyoizumi, T. (2021) Spine dynamics in the brain,mental disorders and artificial neural networks.
Nature Reviews Neuroscience 22: 407-422.
10. Shimizu, G., Yoshida, K., Kasai, H. & Toyoizumi,
T. (2021) Computational Roles of Intrinsic
Synaptic Dynamics, Current Opinions in
Neuroscience 70:34-42.
11. Urakubo, H., Yagishita, S., Kasai, H., Kubota, Y.
& Ishii, S. (2021) Molecular concentrations
required for dopamine dip-detection in D2 striatalprojection neurons. PLoS Computational Biology
17:e1009364.
12. Kasai, H. & Ucar, H. (2021) Forceful synapses
reveal mechanical interactions in the brain. Nature
online 24 November 2021. DOI:10.1038/d41586021-03516-0.

573

Laboratory of Biomedical
Equipment and Biomaterials
Professor
Taichi Ito, Ph.D.

Associate Professor
Kanako Harada, Ph.D.

Homepage

http://www.cdbim.m.u-tokyo.ac.jp/

Introduction and Organization
The Division tightly collaborates with Faculty ofEngineering. Prof. Ito charged at Department ofChemical System Engineering and Bioengineering.
Associate Professor Harada charged at Department of
Mechanical Engineering and Bioengineering.

Teaching activities
Prof. Ito and Associate Prof. Harada are sharing duties
for undergraduate and graduate students of both
Graduate School of Medicine and Graduate School ofEngineering. They give lectures on biomedical
engineering at Graduate School of Medicine. Prof. Itogives a lecture concerning biosystem engineering,
separation technology I, biotechnology II, Basic
Biology, and Overview of Chemical Bioengineering at
the Chemical System Engineering course and Bioengineering course at Graduate School of Engineering
School. Associate Prof. Harada teaches at the courses
titledBioengineering
ExerciseforSocialImplementation 1・2, Engineering Competency III –Summer Camp–, Engineering Competency I –PBL–，
Basic Biology，Overview of Mechano Bioengineering,and Clinical Biomechanics.

Research activities
Biomaterials are one of important keys in medicine
and medical engineering. In the field of tissue
engineering, scaffold materials are extremely

important. In the drug delivery field, drugs areencapsulated in various materials which achieve ideal
release kinetics. The functions of these biomaterials
and phenomena inside and outside biomaterials invivo are complicated both in terms of chemistry andbiology. Ito Laboratory is trying to design and develop
novel biomaterials for tissue engineering and drugdelivery by the combination of medicine and chemicalsystem engineering. Especially we focus on hydrogels
which can be utilized for islet regeneration and drugdelivery in peritoneum.
1) Development of Hydrogels for medical uses
- Development of novel in situ crosslinked hydrogels
for a medical use using hyaluronan, chitosan,
dextran, alginate, gelatin, carboxymethyl cellulose
and synthetic dendritic polymers.
2) Development of particles for medical uses
- Nano-sized semi-conductor and metal particles forimaging- Micro-sized particles composed of PLGA, PEG,
Albumin.
3) Challenge to establish novel treatments using new
medical hydrogels and particles.
- Peritoneal adhesion prevention- Hemostats- Drug delivery for peritoneal dissemination,
Mesothelioma, Liver cirrhosis- Hydrogel scaffolds for regeneration of islets andbones- Artificial Oxygen Carriers

574

In addition, Associate Professor Harada and his
students are developing surgical skill assessment
methods, surgical robots and robots assisting scientificexperiments.
1. Surgical Skill Assessment
Data sets collected during simulated surgery havebeen analyzed to quantify surgical skills. For example,
an image processing method to detect a surgical suture
has been developed to be used to quantify the
manipulation skills of expert surgeons.
2. Surgical robots
Surgical robotic systems for pediatric surgery,neurosurgery and eye surgery have been developed.
To study automation of robotic assistance, anautonomous collision avoidance method has beendeveloped to avoid collision between robotic tools andbetween a robotic tool and tissues. An autonomous
tool guidance method has been developed to assist thelooping task in a small body space.
3. Robots assisting scientific experiments
A robotic platform to assist scientific experiments,
such as the dissection of mouse, has been designed incollaboration with mathematicians, AI researchers,
robot researchers, and scientists.

(4)

(5)

(6)

(7)

(8)

References(1) Y. Oki, K. Harano, Y. Hara, Y. Sasajima, R. Sasaki,
T. Ito, M. Fujishiro, T. Ito "Cationic surface charge
effect on proliferation and protein production ofhuman dental pulp stem cells cultured ondiethylaminoethyl-modified
celluloseporousbeads" Biochemical Engineering Journal, 2021,
176, 108217(2) K. Yamaguchi, O. Hiraike, H. Iwaki, K. Matsumiya,
N. Nakamura, K. Sone, S.Ohta, Y. Osuga, T. Ito"Intraperitoneal administration of cisplatin-loaded
nanogel through a hybrid system containing alginicacid-based nanogel and in situ cross-linkablehydrogel for peritoneal dissemination of ovariancancer" Molecular Pharmaceutics, 2021, 18,4090−4098(3) X. Fu, S. Ohta, T. Kawakatsu, M. Kamihira, Y.
Sakai, T. Ito "Bioinspired perfluorocarbon-based(9)oxygen carriers with concave shape and deformableshell" Advanced Materials Technologies, 2021,
2100573
A.K..S. Chandel, A. Shimizu, K. Hasegawa, T. Ito"Advancement of biomaterial-based postoperativeadhesion barriers" Macromolecular Bioscience,
2021, 2000395
M. Okawa, M. Sakoda, S. Ohta, K. Hasegawa, Y.
Yatomi, and T. Ito "The balance between thehemostatic effect and immune response of
hyaluronan conjugated with different chain lengths
of inorganic polyphosphate", Biomacromolecules,
2020, 21(7), 2694-2704
A. Huaulmé, D. Sarikaya, K. Le Mut, F. Despinoy,
Y. Long, Q. Dou, CB. Chng, W. Lin, S. Kondo, L.
Bravo-Sánchez, P. Arbeláez, W. Reiter, M.
Mitsuishi, K. Harada, P. Jannin, “MIcro-surgicalanastomose workflow recognition challenge report”,
Comput. Methods Programs Biomed. 2021, 212:
106452.
SA. Heredia Perez, MM. Marinho, K. Harada, M.
Mitsuishi, “The effects of different levels of realismon the training of CNNs with only synthetic images
for the semantic segmentation of robotic
instruments in a head phantom”, Int J Comput
Assist Radiol Surg, 2020, 15(8):1257-1265.
MM. Marinho, H. Ishida, K. Harada, K. Deie, M.
Mitsuishi, “Virtual Fixture Assistance for Suturingin Robot-Aided Pediatric Endoscopic Surgery”,
IEEE Robot Autom Lett, 2020, 5.2: 524-531.
A. Nakazawa, K. Harada, M. Mitsuishi, P. Jannin,“Real-time surgical needle detection using
region-based convolutional neural networks”, Int J
Comput Assist Radiol Surg, 2020, 15:41-47.

575

Laboratory of Clinical
Biotechnology
Professor
Yuichi Tei/ Ung-il Chung, M.D.,Ph.D.

Associate Professor
Hironori Hojo, Ph.D

Assistant Professor
Hiroyuki Okada, M.D., Ph.D

Homepagehttps://gel.tokyo/med/
http://www.cdbim.m.u-tokyo.ac.jp/

Introduction and Organization
The Laboratory of Clinical Biotechnology at theCenter for Disease Biology and Integrative Medicine(CDBIM) was launched in April 2003 under the
direction of Professor Kazunori Kataoka. As thisLaboratory is expected to serve as a bridge at The
University of Tokyo (UTokyo) for medical bioengineering, where medicine and engineering areclosely intertwined with each other, we are conducting
research on medical bioengineering through oncampus collaborations with the Graduate School ofEngineering, the Graduate School of Medicine, andThe University of Tokyo Hospital and its affiliateddivisions such as the Division of Tissue Engineeringand the Cooperative Unit of Medicine andEngineering Research. We also aim to recruit and train
professionals — including
physicians,
dentists,
pharmacists, veterinarians, life science researchers,
engineering researchers, and engineers — who are
equipped with a deep understanding of medical
bioengineering. To achieve this, we have utilized
undergraduate and graduate education programs suchas the Graduate Program for Leaders in Life
Innovation (GPLLI) of UTokyo.
Professor Kataoka, who directed the laboratory
until March 2016, worked on the development andclinical applications of nanotechnology-based drugdelivery systems and imaging.
Professor Yuichi Tei (Ung-il Chung) has served
as Director of the Laboratory of Clinical Biotechnology since November 2016. With a particularfocus on skeletal tissues (bones and cartilage), we are
currently studying molecular mechanisms underlying
cell fate specification as well as signaling factor-based
systems to manipulate cell differentiation andproliferation. We are also working on the developmentof novel biomaterials that will fulfill the characteristics required for in vivo use as scaffolds. By
integrating these studies, we aim to develop novel
systems for skeletal tissue engineering and regenerative medicine, in which cell differentiation andproliferation are regulated directly and locally in situ.
Professor Tei has a cross-appointment with the
Department of Bioengineering, Graduate School ofEngineering, and he also serves as Research Leader of
The University of Tokyo Center for Innovation (COI)
Self-Managing Healthy Society. In collaboration withthe program, we are also working on the establishmentof an Open Innovation Platform and the promotion ofindustry-academia collaborations for the social
implementation of research products.

576

Education
The development of advanced medical systems, suchas regenerative medicine and medical devices, is an
important and globally growing research field inwhich medical biology and engineering are integrated
and play important roles. Since the medicineengineering cooperation that has occurred to date has
been mainly research collaborations, the developmentof theoretical systems as well as education systems forthe integrated field have been delayed. This oftencauses a mismatch between clinical needs andtechnological seeds. The delay is likely due todifficulties in identifying basic principles that underlie
both of the quite different fields of medical biology
and engineering, when they are integrated.
Through multi-discipline and cross-sectional
research projects integrating medical biology andengineering, we aim to train biomedical professionals
who themselves integrate medicine and engineering;that is, engineers who understand medical needs andmedical researchers who understand technologicalseeds. We are offering students with varying
backgrounds opportunities to study a broad spectrumof biomedical engineering — from basic principles ofliving organisms to advanced medical systems — on
the basis of each student's expertise. We alsocollaborate with The University of Tokyo COI
Self-Managing Healthy Society, in order to utilize theOpen Innovation Platform in which all stakeholders
from industry, government, academia, and the private
sector join the program as equals from the start, as apractical education tool for developing the aforementioned biomedical professionals.

Research
We pursue two scientific interests with a particularfocus on skeletal tissues (bones and cartilage): (1) the
manipulation of progenitor cell differentiation andproliferation based on the understanding of molecularmechanisms underlying cell fate specification, and (2)the development of novel biomaterials fulfilling thecharacteristics required for in vivo use as scaffolds.
We aim to develop novel systems for skeletal tissue
engineering and regenerative medicine in which celldifferentiation and proliferation are directly regulated
in situ. The following four projects are ongoing.

1. Understanding of epigenome dynamics and gene
regulatory networks during cell fate specification
processes
Organogenesis depends on cell fate specification andthe subsequent differentiation and maturation of
specified cells. Gene transcription underlies a series ofprocesses; appropriate genes are transcribed withappropriate amounts and at the appropriate timing for
inducing cell activities and characteristics. In thiscontext, the epigenome works as a main switch forgene expression. Transcription factors, which bind to
the genome in a sequence-dependent manner, in turnincrease the amount of transcripts, in a manner that is
analogous to turning up the volume of a radio.
Against this background, we seek to understandthe mechanisms of cell fate specification, celldifferentiation, and cell maturation during skeletal
development with a particular focus on epigenome
dynamics and genomic targets of transcription factors.
We also plan to apply the knowledge gained to thedevelopment of regenerative therapies for skeletal
tissue defects. Here we rely on the following
approaches: (1) observations of intracellular events bydirect and comprehensive techniques, (2) the construction of hypotheses driven by these observations,and (3) verification of the hypotheses. Thus, theapproach starts with the collection of genome-scaledata on gene expression, epigenome, and transcription
factor binding sites by taking advantage ofnext-generation sequencers. The data are analyzed bybioinformatics approaches, leading to the constructionof a new biological hypothesis. Each hypothesis isverified by molecular-biological approaches andmouse genetics. With this research strategy, we areinvestigating the regulatory landscape on the genomethat determines the specification of bone- andcartilage-forming cells, osteoblasts and chondrocytes,
respectively, and their phenotypes. A series of studies
reveals transcriptional networks that mediate
pluripotency and the differentiation of pluripotent
stem cells (Stem Cells 31:2667, 2013), epigenome
dynamics and modes of action of master transcription
factors that specify osteoblasts and chondrocytes, andthe gene regulatory networks mediated by thosemaster transcription factors (Cell Reports 12:229,
2015; Developmental Cell 37:238, 2016; Development
143:3012, 2016; Trends in Genetics 32:774, 2016;

577

Regen Ther 6, 100-107, 2017; Int J Mol Sci. 20(24).
pii: E6324, 2019; Bone. 137:115458, 2020; Nat
Commun. 12(1):6271, 2021). A fuller understanding ofcell fate specification processes during skeletal
formation, we believe, will enable the development ofnovel therapeutic strategies, in which bone andcartilage repair and regeneration are induced by the
manipulation of the specification processes.
2. The development of tissue-development modelingsystems using pluripotent stem cells
It would be ideal to study the mechanisms of tissue
formation and maintenance in in vivo working cells.
However, the number of cells that can be obtained invivo is often not sufficient for molecular-levelmechanistic studies; this is a technical limitation in
studying skeletal development and regeneration.
Pluripotent stem cells (PSCs; i.e., embryonic stem
cells — ES cells and induced pluripotent stem
cells — iPS cells), which have the ability to self-renew
and differentiate into all of the lineages present in thebody, are a promising tool for study; reproducing
organogenesis and metabolism in vitro potentiallyovercomes the above limitation. Considering thesafety, cost, and biological conciseness, it would bebetter to induce tissues from PSCs under definedconditions by using small molecules while avoiding
differentiation into lineages of no interest.
We have therefore been developing protocols for
directing mouse and human PSCs toward osteoblasts
under defined conditions using only small molecules,
while recapitulating in vivo osteoblast development(Stem Cell Reports 2:751, 2014). With the protocol,
we addressed a molecular mechanism in osteoblast
development (Stem Cell Reports. 15(1):125-139,
2020). We are also attempting to apply the protocols
to the generation of PSC-derived bone-like tissues, inwhich distinct cell populations regulating boneformation and maintenance (osteoblasts, osteocytes,
and osteoclasts) function three-dimensionally on
culture dishes (Science Advances 3:e1602875, 2017).
Such culture systems in combination with human
PSCs could enable us to reproduce human bonedevelopment and metabolism in a physiologically
relevant manner. These systems will also allow us tovisualize bone metabolism in vitro with imaging
techniques, contributing to drug discoveries for thetreatment of various bone diseases such as
osteoporosis, and to our understanding of the diseases'
pathophysiology and of the molecular mechanisms
underlying skeletal formation and maintenance.
3. The identification of bioactive factors that inducebone/cartilage formation and their application tobone/cartilage repair
Skeletal formation is regulated by various signaling
pathways and transcription factors. The manipulationof key pathways and/or factors would enable us to not
only induce skeletal formation and regeneration, butalso suppress the progression of skeletal degeneration.
Thus, we are carrying out molecular-biological andmouse genetic studies to elucidate the roles ofosteogenic and chondrogenic signaling pathways aswell as the modes of their actions. Based on thesebasic findings, we are also working on theidentification and application of bioactive moleculesthat induce osteogenesis and chondrogenesis.
We have been focusing on: (1) hedgehog (Hh)signaling-mediated cell fate specification duringosteoblast development (Development 131:1309,
2004； Journal of Biological Chemistry 282:17860,
2012; Journal of Biological Chemistry 288:9924,
2013), and (2) transcriptional regulation mediating
osteoblast differentiation and maturation (Developmental Cell 14:689, 2008; PLOS ONE, 2014). Thesestudies further extend to the development of the small
molecule-based treatment of bone fractures, using the
Hh signaling-activator molecule SAG (Biochemical
and Biophysical Research Communications 479:772,
2016) and bone regenerative therapy with SAG-loaded
calcium phosphate artificial bones (Biomaterials
34:5530, 2013). By combining biological findings
with engineering techniques, we are working on boneregeneration by plasmid delivery using polymericnanomicelles as nucleic acid carriers (Molecular
Therapy 15:1655, 2007) and the suppressive treatmentof cartilage degeneration by mRNA delivery(Scientific Reports 6:18743, 2016).
We have also identified novel small moleculesthat induce bone and cartilage formation (Biochemical
and Biophysical Research Communications 357:854,
2007; Annals of Rheumatic Diseases 72:748, 2013),
through the screening of compound libraries withcell-based sensors enabling the high-throughput

578

detection of osteoblast and chondrocyte differentiation(Biochemical and Biophysical Research Communications 376:375, 2008; Journal of Bone and Mineral
Metabolism 28:627, 2010).
4. The development of tissue-inductive implant
devices integrating tissue-regeneration signals andhighly functional and biocompatible biomaterials
In the current aging society, the treatment of tissue
defects in locomotive organs is a crucial task toachieve the extension of healthy life expectancy.
There is an urgent need for low-invasive reconstruction therapies that recover lost or damaged tissues
with the same functional and aesthetic qualities as
those in healthy states. The transplantation of donor
tissues obtained from patients’ healthy sites has been
widely used for tissue reconstruction (autologoustransplantation). However, this strategy often causes
post-operative pain and the cosmetic disturbance ofdonor sites. Although reconstruction with biomaterials
avoids donor site problems, its tissue induction
capacity is generally inferior to that of autologoustransplantation.
As signaling networks mediating the formation
and regeneration of tissue and organs are being
elucidated by recent advances in stem cell biology,
some biomaterial-based systems are being developed
for delivering signaling factors to target tissues. We
are studying these approaches as mentioned above. In
addition, the emergence of three-dimensional (3D)
printers has rapidly improved the techniques available
for controlling the shapes of scaffold materials. By
controlling the 3D shape of biomaterials, we havebeen attempting to improve the performance of
biomaterials for tissue repair. We developed custommade calcium phosphate artificial bone (CT-bone) thatis manufactured using 3D printers and have appliedthem to clinical settings in cooperation with the
Department of Oral and Maxillofacial Surgery, The
University of Tokyo Hospital (Journal of Artificial
Organs 9:234, 2006; Journal of Artificial Organs
12:200, 2009; Regenerative Therapy 5:1, 2016). We
have also worked on the development and applicationof tetrapod-shaped calcium phosphate artificial bone
(Tetrabone), which is fabricated at 1-mm size by
injection molding, and a custom-made titanium meshcage fabricated by laser sintering (Acta Biomaterialia

8:2340, 2012; Biomaterials 35:3229, 2014).
However, either signaling factors or biomaterials
alone are not sufficient for the clinically sufficient
regeneration of tissues, and interface units integratingthem are necessary for fully utilizing their performance. A candidate for the integrating interface unit isa high-performance hydrogel unit, which maintains
the spatial arrangement of signaling factors and candeliver them to target cells at a selected timing bytemporally controlled degradation. However, conventional hydrogels do not provide the characteristics
required for an integrating interface unit.
In cooperation with Professor Takamasa Sakai atthe Department of Bioengineering, UTokyo, we aredeveloping a high-performance hydrogel unit that
fulfills the necessary characteristics, based on
knowledge and techniques that we have accumulated
regarding the design and fabrication of novelhydrogels (Macromolecules 41:5379, 2008; Science
343:873, 2014; Advanced Materials 27:7407, 2015;
Nature Biomedical Engineering 1:44, 2017; Phys Rev
Lett. 125(26):267801, 2020; RSC Advances 11, 23637,
2021). The high-performance hydrogel unit would
integrate signaling factors with shape-controlled
scaffold materials, leading to the development of
implant devices that work as scaffolds for tissue repair
and also as carriers of bioactive factors. Through aseries of these studies, we are aiming to create a"four-dimensional scaffold system" that achieves
efficient tissue regeneration by controlling cellproliferation and differentiation in temporal andspatial manners. The system will not only beapplicable to the regeneration of other tissues; it will
also contribute to the development of basic
technologies for the temporal-spatial control of in situ
tissue formation, which is versatile in the prevention,
diagnosis, and treatment of various diseases.

Publications
1.

Wang
JS,
KamathT,
Mazur
CM,
Mirzamohammadi F, Rotter D, Hojo H, Castro
CD, Tokavanich N, Patel R, Govea N, Enishi T,
Wu Y, da Silva Martins J, Bruce M, Brooks DJ,
Bouxsein ML, Tokarz D, Lin CP, Abdul A,
Macosko EZ, Fiscaletti M, Munns CF, Ryder P,
Kost-Alimova M, Byrne P, Cimini B, Fujiwara M,

579

2.

3.

4.

5.

6.

7.

Kronenberg HM, Wein MN. Control of osteocyte
dendrite formation by Sp7 and its target gene
osteocrin. Nat Commun. 12(1):6271, 2021
Yamada D, Nakamura M, Takao T, Takihira S,
Yoshida A, Kawai S, Miura A, Ming L,
Yoshitomi H, Gozu M, Okamoto K, Hojo H,
Kusaka N, Iwai R, Nakata E, Ozaki T, ToguchidaJ, Takarada T. Induction and expansion of human
PRRX1 + limb-bud-like mesenchymal cells frompluripotent stem cells. Nat Biomed Eng. 5(8):926-940, 2021
Kanazawa S, Okada H, Hojo H, Ohba S, Iwata J,
Komura M, Hikita A, Hoshi K. Mesenchymal
stromal cells in the bone marrow niche consist ofmulti-populations with distinct transcriptionaland epigenetic properties. Sci Rep. 11(1):15811,
2021
Fujiyabu T, Sakai T, Kudo R, Yoshikawa Y,
Katashima T, Chung UI, and Sakumichi N.
Temperature Dependence of Polymer Network
Diffusion. Physical Review Letters 127, 237801,
2021
Ishikawa S, Kamata H, Chung UI, Saka T.
On-demand retrieval of cells three-dimensionallyseeded in injectable thioester-based hydrogels.
RSC Advances 11, 23637, 2021
Yoshikawa Y, Sakumichi N, Chung UI, and Sakai
T. Negative Energy Elasticity in a Rubberlike Gel.
Physical Review X 11, 11045, 2021
Tang J, Katashima T, Li X, Mitsukami Y,
Yokoyama Y, Chung UI, Shibayama M, Sakai T.
Effect of Nonlinear Elasticity on the Swelling
Behaviors of Highly Swollen Polyelectrolyte
Gels. Gels 7, 25, 2021

580

Laboratory of Microenvironmental
and Metabolic Health Sciences
Professor
Makoto Murakami, Ph.D.

Associate Professor
Seiichiroh Ohsako, Ph.D., D.V.M.

Research Assistant
Hiroyasu Sato, Ph.D.

Project Assistant
Rina Takamiya, Ph.D.

Home Page

http://lmmhs.m.u-tokyo.ac.jp

Introduction

Research activities

Laboratory of Environmental Health Sciences of theCenter for Disease Biology and Integrative Medicine
moved the laboratory from the 3rd floor of the Medical
Faculty of Medicine Building 1 to the 8th floor of theClinical Research Center A on October 2016 andmodified the laboratory name to Laboratory ofMicroenvironmental and Metabolic Health Sciences on
April 2017, aiming at examining biochemistry andmicroenvironmental biology of lipids as well as
environmental toxicology. One professor, one associate
professor, one research assistant, one project assistant,
one project researcher, one visiting researcher, six
graduate students (four for the doctoral course and two
for the master course), four external researchers, andone research assistant conducted the researches
together during the year of 2022.
This laboratory belongs to the Department of Social
Medicine, cooperates to the Departments International
Health Sciences and Social Public Health, and isengaged in education and research on relationships.
The laboratory is also associated with the Department
of Cellular Signaling, the Molecular Cell Biology.

Laboratory of Microenvironmental and Metabolic
Health Sciences was constituted by two major research
projects; “lipid biology” by a group of Murakami(professor) and “environmental toxicology” by a groupof Ohsako (associate professor).
1. Lipid biology (Murakami’s group)
The main theme of this research project is to clarify
the role of lipids in health and diseases. Lipids supply
the largest source of energy in living organisms, aremain components of cell membranes, act as signal
molecules, and constitute a barrier covering the bodysurface (four major functions of lipids). Lipids areenvironmental nutritional factors ingested from foods,
as well as tissue microenvironmental regulators thatspatiotemporally coordinate various biologicalresponses after being metabolized to specific bioactive
lipids. By performing comprehensive lipid analysis(lipidomics) on gene-manipulated mice for lipidmetabolizing enzymes, particularly those in thephospholipase A2 (PLA2) family, we aim to elucidate
the molecular pathophysiology of diseases (e.g.
metabolic and immune diseases) that are problematic

581

in modern society. Based on this, we will promote theresearch of Quality of Lipids (QOL) for Quality of Life
(QOL) and aim at building a theoretical foundation for
diagnosis, prevention and treatment of diseases
involving alteration of lipid metabolism.
1) Metabolic diseases
We previously reported that PLA2G5 (sPLA2-V),
secreted from hypertrophic white adipocytes duringobesity, hydrolyzes phosphatidylcholine (PC) in LDL
to release oleic and linoleic acids, which attenuate M1
polarization of macrophages and thereby protect fromdiet-induced obesity, adipose tissue inflammation, andinsulin resistance (Sato et al, Cell Metab, 2014), andthat PLA2G2D (sPLA2-IID), secreted from M2-likemacrophages in white adipose tissue, releases 3polyunsaturated fatty acids (PUFAs) to promote coldinduced adipocyte browning and thermogenesis (Satoet al, Cell Rep, 2020). In addition, we have recently
found that PLA2G2E (sPLA2-IIE) is highly induced inbrown and beige adipocytes in response to cold and thatits genetic deletion leads to partial impairment of
adipocyte browning and thermogenesis.
Choline supplies methyl groups for regeneration ofmethionine and the universal methyl donor Sadenosylmethionine (SAM) in the liver. Althoughmembrane PC is the main cellular reservoir for choline,
the pathway for hepatic PC catabolism that generates
free endogenous choline remains unexplored. We
found that PNPLA7, a lysophospholipase that catalyzes
the hydrolysis of lysophosphatidylcholine (LPC) toglycerophosphocholine (GPC), is crucial for thispathway. Pnpla7-deficient mice show marked
decreases in hepatic GPC, choline, betaine and SAM,
accompanied by various signs of methionine
insufficiency including impaired triglyceride storage
and secretion, hypoglycemia, increased energy
expenditure, reduced fat mass with adipocyte browning,and decreased epigenetic histone and DNA methylation.
Accordingly, Pnpla7-/- mice are lean, display growth
retardation, and die prematurely. We further found thatmice lacking PNPLA8 (iPLA2), which acts as
PLA1/A2, recapitulate most of these phenotypes,
suggesting that PNPLA8 lies upstream of PNPLA7.
Thus, the methyl group flux from choline
endogenously generated through PC breakdown by the
PNPLA8-PNPLA7 axis is essential for liver functions
and systemic energy homeostasis (submitted). In

addition, skeletal muscle-specific Pnpla7-deficient
mice develop sarcopenia-like symptoms over 6 months.
2) Skin diseases
Lipids play crucial roles in skin homeostasis anddiseases. We previously reported that PLA2G2F(sPLA2-IIF), which is specifically expressed inepidermal keratinocytes, mobilizes lysoplasmalogen,a unique lysophospholipid that promotes epidermal
hyperplasic diseases such as psoriasis and skin cancer(Yamamoto et al, J Exp Med, 2015), and that PNPLA1,
a member of the intracellular iPLA2 family whose
mutations cause autosomal recessive congenitalichthyosis, acts as a transacylase to produce ω-Oacylceramide, an essential lipid component for skinbarrier function (Hirabayashi et al, Nat Commun,2017). PLA2G4E (cPLA2, which is expressed inepidermal keratinocytes, exhibits a unique Nacyltransferase activity that transfers a fatty acid fromthe sn-1 position of PC to the amino group ofphosphatidylethanolamine (PE) to give rise to N-acyl
PE (NAPE), a precursor of the non-canonicalbioactive lipid N-acylethanolamine (NAE). Pla2g4edeficient mice display exacerbation of psoriasis withmarked reduction of various NAE species, suggestingthat PLA2G4E plays a role in putting a brake on
psoriasis by generating the anti-inflammatory lipid
mediator NAE (Liang et al, FASEB J 2022). In
addition to the skin, PLA2G4E participates in NAE
generation in the skeletal muscle and stomach(Murakami et al, Biochem Pharm 2022).
PLA2G3 (sPLA2-III) is expressed in epidermal
keratinocytes and its global or skin-specific deletion
leads to perturbation of skin barrier function due tofragile cornified envelope and loosened epidermal
tight junction. Accordingly, following topical antigen
challenge, global or skin-specific Pla2g3-deficient
mice display more severe atopic dermatitis-like
symptoms with increased expression of type 2
cytokines, serum IgE levels, eosinophil infiltration,scratching behavior, and disturbed skin microbiota.
Global or skin-specific deletion of EP4 (PGE2
receptor) or FP (PGF2 receptor) largely if not solely
recapitulate these phenotypes, and treatment with FP
or EP4 agonists rescues skin abnormalities in Pla2g3deficient mice. Moreover, global or skin-specificPla2g3-deficient mice exhibit more severe asthma
following topical antigen challenge. These results

582

suggest that PLA2G3-driven PGE2-EP4/PGF2-FPsignaling in keratinocytes plays an important role inskin barrier formation and thereby skin homeostasis,
perturbation of which leads to exacerbation of atopic
march.
3) Allergic and other immunological diseases
We previously reported that PLA2G3, an sPLA2
isoform secreted from mast cells (MCs), promotes MCmaturation by driving the paracrine PGD2 circuit incooperation with microenvironmental fibroblasts(Taketomi et al, Nat Immunol 2013; Taketomi et al,
Cells 2021) and that PAF-AH2, a unique PLA2 thathydrolyzes oxidized phospholipids, ensures optimal
MC activation and thereby allergic responses throughproducing unique EPA/DHA metabolites (ω3 epoxides)(Shimanaka et al, Nat Med 2017). Furthermore, wehave recently found that PLA2G3 is also coupled withanother lipid mediator, lysophosphatidic acid (LPA),
which acts in concert with PGD2 to facilitate MC
maturation.
PLA2 subtypes that regulate T cell immunity are
unknown. By transcriptional and functional screeningof PLA2 enzymes expressed in T cells, we have foundthat PLA2G12A (sPLA2-XIIA) is induced in Th17 cells
and participates in Th17 differentiation. Global andCD4+ T cell-specific Pla2g12a-deficient mice havelower psoriatic inflammation with decreased Th17 andT cells in the skin and draining lymph nodes. We are
now analyzing a particular lipid mediator that acts
downstream of PLA2G12A in inducing Th17 immunity.
4) Gut microbiota
Despite the restricted intestinal expression of
PLA2G2A (sPLA2-IIA) in BALB/c mice, its genetic
deletion leads to amelioration of skin carcinogenesis.
Metagenome, transcriptome and metabolome analyses
have revealed that Pla2g2a deficiency alters the gut
microbiota, accompanied by notable changes in theintestinal expression of genes related to immunity andmetabolism as well as the levels of various blood
metabolites and fecal bacterial lipids, suggesting that
PLA2G2A contributes to shaping of the gut microbiota(Miki et al, JCI Insight, 2022). Pla2g2a-/- mice also
display an alteration in passive cutaneous anaphylaxis(Taketomi et al, Metabolites 2022). These results
highlight a new aspect of PLA2G2A as a modulator ofgut microbiota, perturbation of which affects distal skin
responses. Furthermore, mice lacking PLA2G10(sPLA2-X), which is predominantly expressed in thecolorectal epithelium, also have altered gut microbiota,
and their systemic effects are now being analyzed.
5) Cancer
Extracellular vesicles (EVs) including exosomes
act as intercellular communicators by transferring
protein and microRNA cargoes, yet the role of EV
lipids remains unclear. We have recently found that the
pro-tumorigenic action of lymphoma-derived EVs isaugmented via sPLA2-driven lipid metabolism.
Hydrolysis of EV phospholipids by PLA2G10 (sPLA2X), which is induced in a specific population ofmacrophages in Epstein-Barr virus (EBV)-induced
lymphoma, increases the production of fatty acids,
lysophospholipids and their metabolites. sPLA2-treatedEVs are smaller, self-aggregate, show better uptake,and increase cytokine expression and lipid mediatorsignaling in recipient tumor-associated macrophages.
Lymphoma growth in EBV-infected mice is suppressedby a sPLA2 inhibitor, while treating the mice withsPLA2-modified EVs can reverse this phenotype.
Overall, the sPLA2-driven EV modification promotes
tumor development (Kudo et al, Cell Metab 2022). It is
anticipated that modification of EVs by sPLA2s may
occur universally in various cancers as well as inallergic and metabolic diseases, a possibility that iscurrently under investigation.
6) Infectious diseases
PLA2G2D expressed in dendritic cells and M2
macrophages attenuates anti-viral Th1 immunity bysupplying 3 PUFAs and PGD2 (Miki et al, J Exp Med2013). In collaboration with a foreign group, we havereported that Pla2g2d deficiency protects mice frompneumonia caused by coronavirus infection (Roy Wonget al, Nature 2022). Therefore, PLA2G2D may be an
attractive drug target for treatment of COVID-19.
7) Neuronal and retinal diseases
Mutations in the PNPLA6 gene cause neuronal andretinal degeneration such as hereditary spastic
paraplegia (SPG39), Boucher-Neuhauser syndrome,
Oliver-McFariane syndrome, and Laurence-Moon
syndrome. PNPLA6 acts a phospholipase B (PLA1/A2+ lysophospholipase), hydrolyzing PC to give rise totwo fatty acids and GPC, in cells. Intriguingly, neuronspecific deletion of PNPLA6 and its closest homolog
PNPLA7 leads to neurodegenerative disorders similar
to hereditary spastic paraplegia and that tamoxifen-

583

inducible eye-specific deletion of PNPLA6 results inretinal degeneration. Retinal degeneration in thesemice can be prevented by eye drops of choline, a PC
degradation product. Clarifying the regulatory roles oflipid metabolism driven by PNPLA6/PNPLA7 willshed light on the molecular mechanism underlying the
PNPLA6-related neuronal and retinal disorders.
Furthermore, in collaboration with an externalgroup, a particular sPLA2 isoform that is induced after
cerebral infarction is found to be involved in protection
against neuronal damage by mobilizing a unique lipid
metabolite (submitted).
2. Environmental Toxicology (Ohsako’s group)
Ohsako found a new phenotype that was accidentally
discovered in the course of a project using the famous
Ahr-deficient mouse (AhrKO). AhrKO mice have long
been reported to have phenotypes such as liver fibrosis,
decreased fertility, and immune system dysfunction.
Ahr is a gene essential for detoxification and excretionof carcinogens such as benzo[a]pyrene, which is atypical xenobiotic substance. Ahr is activated bybinding to these ligands and induces down-stream
genes for drug-metabolizing enzyme. However, Ahr
has also been reported to regulate differentiation of thehelper T-cells such as Th17/Treg through binding to its
endogenous ligands. This suggests that Ahr is involvedin autoimmune diseases. Ohsako found that AhrKO
exhibited loose stools and melena at about 10 weeks ofage, followed by obvious rectal prolapse and continued
to survive. Compared to the wild type, AhrKO mice
showed enlargement of the spleen and mesentericlymph nodes, enlargement of the colon and marked
inflammatory cell infiltration of the lamina propria.
CD4+IL17+IFN-Th17 cells were significantly
increased in the spleen, mesenteric lymph nodes, andcolonic lamina propria, whereas there was nodifference in CD4+Foxp3+Treg cells. In contrast to thefinding above, previous reports have reported that Th17
differentiation is suppressed in spleen cells of Ahrdeficient mice. In addition, liver fibrosis did not cause
clear lesions. By using metagenomic analysis, it was
found that the content of the mouse colon in the SPF
facility of Tokyo University of Science represents
specific bacterial flora. Therefore, AhrKO was bred at
the SPF facility of Japan CLEA Co., Ltd. fromindividual restored by IVF. In these mice inflammatory

colitis was not observed. Additionally, it was found that
there is a clear difference between the flora of Japan
CLEA and those of Tokyo University of Science flora.
These results suggested that specific gut microbiota
that are supposed to produce Ahr endogenous ligands
are involved in the development of the inflammatory
bowel disease discovered in the AhrKO mice.

Teaching activities
The Laboratory of Microenvironmental andMetaboilic Health Sciences/ the Department of Cellular
Signaling has important missions to train postdoctoral
fellows to become promising scientist leaders in thefield of medical sciences and environmental toxicology
and to provide biochemistry, molecular biology,
toxicology and environmental health courses forgraduate and undergraduate students. The following
lectures have been provided to students.
Graduate education
Lectures, Seminars, and laboratory practices, as wellas guidance for the dissertation for the Master’s andDoctor’s degrees, have been provided.
Undergraduate education
Lectures on biochemistry and molecular biology,
with a focus on the diversity, structures and functionsof lipids, for medical students (M0). Fourundergraduate students (three M2 students and one M4
student) participate in the Murakami’s team throughout
the year.

Publications
1.

2.

Miki Y, Taketomi Y, Kidoguchi Y, Yamamoto K,
Muramatsu K, Nishito Y, Park J, Hosomi K,
Mizuguchi K, Kunisawa J, Soga T, Boilard E,
Gowda SGB, Ikeda K, Arita M, Murakami M.
Group IIA secreted phospholipase A2 controls
skin carcinogenesis and psoriasis by shaping the
gut microbiota. JCI Insight. 7, e152611, 2022.
Doré E, Joly-Beauparlant C, Morozumi S,
Mathieu A, Lévesque T, Allaeys I, Duchez AC,
Cloutier N, Leclercq M, Bodein A, Payré C,
Martin C, Petit-Paitel A, Gelb MH, RangachariM, Murakami M, Davidovic L, Flamand N, Arita
M, Lambeau G, Droit A, Boilard E. The

584

3.

4.

5.

6.

7.

8.

9.

interaction of secreted phospholipase A2-IIA withthe microbiota alters its lipidome and promotes
inflammation. JCI Insight. 7, e152638, 2022.
Kudo K, Miki Y, Carreras J, Nakayama S,
Nakamoto Y, Ito M, Nagashima E, Yamamoto K,
Higuchi H, Morita S, Inoue A, Aoki J, Ando K,
Nakamura N, Murakami M, Kotani A. Secreted
phospholipase A2 modifies extracellular vesicles
and accelerates B-cell lymphoma. Cell Metab. 34,
1-19, 2022.
Roy Wong LY, Zheng J, Wilhelmsen K, Li K,
Ortiz ME, Schnicker NJ, Pezzulo AA,
Szachowicz PJ, Klumpp K, Aswad F, Rebo J,
Narumiya S, Murakami M, Meyerholz DK,
Fortney K, McCray PB, Perlman S. Eicosanoid
signaling as a therapeutic target in middle-aged
mice with severe COVID-19. Nature. 605, 146151, 2022.
Shibata T, Kawana H, Nishino Y, Ito Y, Sato H,
Onishi H, Kano K, Inoue A, Taketomi Y,
Murakami M, Kofuji S, Nishina H, Miyazawa A,
Kono N, Aoki J. Abnormal male reproductionand embryonic development induced bydownregulation of a phospholipid fatty acidintroducing enzyme Lpgat1 in zebrafish. Sci Rep.
12, 7312, 2022.
Liang L, Takamiya R, Miki Y, Heike K, Taketomi
Y, Sugimoto N, Yamaguchi M, Shitara H. Nishito
Y, Kobayashi T, Hirabayashi T, Murakami M.
Group IVE cytosolic phospholipase A2 limits
psoriatic inflammation by mobilizing the antiinflammatory lipid N-acylethanolamine. FASEB
J. 36, e22301, 2022.
Taketomi Y, Miki Y, Murakami M. Old but new:Group IIA phospholipase A2 as a modulator ofgut microbiota. Metabolites. 12, 352, 2022.
(Review)
Taketomi Y, Murakami M. Regulatory roles ofphospholipase A2 enzymes and bioactive lipids inmast cell biology. Front. Immunol. 13, 923265,
2022. (Review)
Murakami M, Takamiya R, Miki Y, Sugimoto N,
Nagasaki Y, Suzuki-Yamamoto T, Taketomi Y.
Segregatedfunctionsoftwocytosolicphospholipase A2 isoforms (cPLA2α and cPLA2ε)in lipid mediator generation. Biochem. Pharmacol.
203, 115176, 2022. (Review)

10. Ekuban A, Zong C, Ekuban FA, Kimura Y,Takizawa R, Morikawa K, Kinoshita K, Ichihara
S, Ohsako S, Ichihara G. Role of macrophages incytotoxicity, reactive oxygen species production
and DNA damage in 1,2-dichloropropane-exposed
human cholangiocytes in vitro. Toxics. 9, 128,2021.
11. Ekuban FA, Zong C, Takikawa M, Morikawa K,
Sakurai T, Ichihara S, Itoh K, Yamamoto M,
Ohsako S, Ichihara G. Genetic ablation of Nrf2
exacerbates neurotoxic effects of acrylamide inmice. Toxicology. 456, 152785, 2021.

585

Laboratory of Animal Resources
Professor
Atsu Aiba, Ph.D.

Associate Professor
Hidetoshi Kassai, Ph.D.

Assistant Professor
Harumi Nakao, Ph.D., Ryo Saito, Ph.D., Shoko Noda-Narita M.D., Ph.D.

Project Assistant Professor
Yusuke Sakai, Ph.D.

Homepage

http://lar.cdbim.m.u-tokyo.ac.jp/index.html

Introduction and Organization
Our laboratory was established as the Division ofAnimal Research affiliated with the Faculty of
Medicine in April 1971. The building for animal
experimentation was completed and the accommodation and experimentation of laboratory animals
started in 1973. In 2003, the laboratory was
reorganized as the Section of Animal Research of theCenter for Disease Biology and Integrative Medicine(CDBIM). In 2008, the Laboratory of Animal
Resources was established to strengthen research activities in addition to the Section of Animal Resources.
The members of our laboratory and section are 6
teaching staffs, 6 technical support staffs, anadministrative staff, 2 assistant laboratory animal
technicians, 2 assistant clerks and 2 temporary staffs(veterinarian, support staff). In addition, about 15
contracted employees are involved in animal breeding
and maintenance of the animal facility.
The laboratory animals in our facility include
macaque monkeys, dogs, swine, rabbits, rats, mice,and marmosets. The number of registered users of ourfacility was 637 at the end of academic year 2021.
We provide quality care for all animals in our facility
and assist animal experimentation carried out by the
researchers. The office of our section is in charge ofthe secretariat of the Institutional Animal Care and the

Use Committee (IACUC) of the Graduate School of
Medicine, the University of Tokyo. The committee(Chair, Prof. Atsu Aiba) reviews the plans of animal
experimentation and helps researchers carry out
animal experiments in accordance with law,regulations and University policies governing the useof animals.

Teaching activities
We are responsible for the education of laboratory
animal science to the 2nd-year students (M0) of theFaculty of Medicine. The lecture includes animal
welfare, refinement of animal experiments, animal
breeding, infectious diseases of laboratory animals
and zoonoses. We also give a lecture on mouse
molecular genetics and molecular embryology.
We are also involved in lectures by IACUC for the
researchers at the Graduate School of Medicine.

Research activities
Our laboratory focuses on understanding themolecular mechanisms which underlie the synaptic
plasticity, activity dependent formation of neuronal
circuitry, and neuropsychiatric disorders. We generateknockout mice and transgenic mice of signaltransduction molecules including the glutamate
receptors and mammalian target of rapamycin

586(mTOR). We also try to generate murine andmarmoset models for human genetic diseases.
1. Establishment of model marmosets for fragile X
syndrome
Common marmoset (Callithrix jacchus) is a
non-human primate and recently used for humanmodel, especially focusing on brain function. We haveestablished a novel protocol in which embryos arecollected from already mated females by oviductflushing and immediately transferred into the oviductof the very same donors following injections withgenome-editing components. Using this autologoustransfer protocol, we introduced guide RNAs for
FMR1 (fragile X mental retardation 1) gene encoding
fragile X mental retardation protein (FMRP) and Cas9
proteins into marmoset embryos. We obtained mutant
marmosets which carried mutations in coding regionof FMR1 gene. FMR1 mutant marmosets, which failto express the FMRP protein, exhibit epileptic-likeseizures and are lethal by 8 days of age.
Heterozygotes for FMR1 were successfully obtainedby crossing a mosaic male individual carrying
wild-type and mutant FMR1 alleles with wild-type
females. We are currently recording the movements
and vocalizations of the heterozygote underspontaneous behavior to determine whether thisanimal is a model for Fragile X Syndrome.
2. Elucidating the neural basis of comforting
behavior
Comforting behavior is affiliative social contact, forexample, a hug to alleviate pain or stress experienced
by another individual. In rodents, grooming behavior
toward a distressed mate is observed as a comfort-likebehavior. The division also attempted to detect
comforting behavior in inbred mice and constructed
an experimental system to see comforting behavior
prominently and efficiently.
Although ASD patients are thought to have atendency to have difficulty sharing feelings andemotions with others (lower levels of empathy), there
is little biological evidence to support a causal
relationship between such mental illness and lack of
empathy. To elucidate the mechanism by which
psychiatric disorders cause lack of empathy at theneural circuit and organism levels, we decided toinvestigate whether the lack of empathic behavior isobserved in genetically engineered mouse models of
psychiatric disorders that we developed previously,
such as 22q11.2 deletion syndrome mouse models.
Our study will reveal how having a genetic
predisposition to mental illness affects comforting
behavior, one of the empathic behaviors.
3. Functional analysis of the blood-brain barrier inbrain metastasis
The blood-brain barrier (BBB) plays an essential
role in brain metastasis of cancer. Although theanalysis of molecules required for brain metastasis
on the cancer cell side has been well performed,
molecular analysis of vascular endothelial cells andpericytes (mural cells), which constitute the BBB,
has not been elucidated well. Therefore, we aim toreveal the molecular mechanisms involved in
vascular permeability and cancer brain metastasis byreconstituting the BBB in vitro using vascularendothelial cells, pericytes, and astrocytes and by
genetically manipulating vascular endothelial cells
in individual mice.
In vitro BBB model indicated the necessity of
pericytes and astrocytes in brain metastasis. We
established the brain metastatic cell line of marine
lung cancer by repeating transplantation andisolation of brain metastasis in mice. The brain
metastatic cells showed highly metastatic feature in
our in vitro BBB model, although it could not
successfully migrate without pericytes andastrocytes. The mice with endothelial cell-specificknockout of focal adhesion kinase (FAK) also
indicated the different metastatic mechanism ofbrain metastasis compared to the trunk metastasis.
The brain metastasis is not suppressed by endothelial
cell-specific knockout of FAK, although it has beenreported that endothelial cell-specific knockout miceof FAK show the inhibition of metastasis in thetrunk.
Now we plan to elucidate the specific mechanism
needed for brain metastasis by analyzing theinteraction of cancer cells with BBB, especially forthe surrounding pericytes and astrocytes.

587

References
1.

2.

3.

4.

5.

6.

Arioka Y, Shishido E, Kushima I, Suzuki T, Saito
R, Aiba A, Mori D, and Ozaki N. Chromosome
22q11.2 deletion causes PERK-dependent
vulnerability in dopaminergic neurons. EBio
Medicine, 63, 103138, 2021.
Saito R, Miyoshi C, Koebis M, Kushima I, Nakao
K, Mori D, Ozaki N, Funato H, Yanagisawa M,
and Aiba A. Two novel mouse models mimicking
minor deletions in 22q11.2 deletion syndrome
revealed the contribution of each deleted region
to psychiatric disorders. Mol Brain, 14(1), 68,
2021.
Kawarada L, Fukaya M, Saito R, Kassai H,
Sakagami H, and Aiba A. Telencephalon-specific
Alkbh1 conditional knockout mice display
hippocampal atrophy and impaired learning.
FEBS Lett, 595(12), 1671-1680, 2021.
Yamasaki M, Aiba A, Kano M, and Watanabe M.
mGluR1 signaling in cerebellar Purkinje cells:
Subcellular organization and involvement in
cerebellar function and disease. Neuropharmacology, 194, 108629, 2021.
Hasegawa K, Takenaka N, Tanida K, Chan MP,
Sakata M, Aiba A, and Satoh T. Atrophy of White
Adipose Tissue Accompanied with Decreased
Insulin-Stimulated Glucose Uptake in Mice
Lacking the Small GTPase Rac1 Specifically in
Adipocytes. Int J Mol Sci, 22(19), 10753, 2021.
Abe Y, Nakao H, Goto M, Tamano M, Koebis M,
Nakao K, and Aiba A. Efficient marmoset
genome engineering by autologous embryotransfer and CRISPR/Cas9 technology. Sci Rep,
11(1), 20234, 2021.

588

Laboratory of Molecular Radiology
Professor
Kiyoshi Miyagawa, M.D., Ph.D.

Associate Professor
Noriko Hosoya, M.D., Ph.D.

LecturerAtsushi Enomoto, Ph.D.

Research Associate
Takaaki Yasuhara, Ph.D., Claudia Juliane Krause, Ph.D.

Homepage

http://www.cdbim.m.u-tokyo.ac.jp/

Introduction and Organization
When the Center for Disease Biology and Integrative
Medicine was established in 2003, the Department ofRadiation Oncology established in 1967 and theRadiation Research Institute established in 1992 werejoined to form the Section of Radiation Biology as apart of Divisions of Research Resources and Support.
In 2008, the Laboratory of Molecular Radiology was
also established to strengthen research activities inthis section. The scientists and staffs belong to boththe section and the laboratory.
The aim of this laboratory is to facilitatetranslational research from frontier life science toapplied radiology by introducing molecular biology
into conventional radiology.
To maintain the facility of radiation research,
responsible staffs at two facilities are elected from oursection. This year, the hospital radioisotope researchfacility was continued to be closed to prepare theopening of the new facility in the newly-constructed
Clinical Research Building.

Education
We are responsible for the education of basic radiation
medicine for the 3rd year medical students. The
students are expected to start with understanding of
the physics and the chemistry for radiation and thenunderstand the basic biology of radiation. Furthermore,they learn how to handle radioactive materials by the
2-day practical course.
In addition to these courses, the 4th year medical
students are expected to learn how to use clinicalradiation technology safely in hospitals. The
background for this addition is that clinical problems
arising from the lack of knowledge of radiation effects
have been increasing. Furthermore, the education ofradiation emergency medicine is included in thiscourse. Even though radiation casualty is rare, allclinicians should know how to treat patients exposed
to radiation. The importance of this education has
been widely recognized since the accident at the
Fukushima nuclear power plant.
We also take part in the education of radiation
health science for the 3rd year students specialized in
integrated health sciences. Radiation protection isemphasized in this course.
For graduate students, the education of molecularbiology of the DNA damage response to radiation and
DNA repair is more intensively integrated.
In addition, education courses for users of radioactive materials frequently take place.

Research
We focus on the mechanism underlying the cellular589

response to DNA double-strand breaks (DSBs).
Among various types of DNA damage, DSBs are themost deleterious if not repaired properly. To protect
the genome, at least four signaling cascades are
known to function as the repair machineries against
DSBs.
While
nonhomologous
endjoining,
microhomology-mediated end joining, and singlestrand annealing are error-prone repair pathways,
homologous recombination (HR) is an error-freepathway in principle using newly replicated DNA as atemplate for the repair. There is accumulating
evidence that defective HR plays a role in tumor
development. For example, BRCA1 and BRCA2,
tumor suppressors in hereditary breast and ovariancancers, are known to mediate the damage response to
DSBs and promote HR.
Rad51, a key player at early stages of HR, catalyzes
the invasion of a single-strand DNA end into an intact
homologous duplex. BRCA2 plays a mediator role atthis stage by directly binding to Rad51 and promoting
the formation of the filament consisting of thesingle-strand DNA and Rad51.
SYCP3 is a component in the synaptonemal
complex which is formed between homologous
chromosomes to ensure their connection in meiosis.
Expression of SYCP3 was observed in adrenal, liver,stomach, and kidney tumors, confirming that SYCP3
is a cancer testis antigen. Treatment of SYCP3nonexpressing cells with a methylation inhibitor
induced its expression, indicating that methylation
alteration in cancer is responsible for its ectopic
expression.
Since biological significance of cancer testis
antigens in somatic cells is largely unknown, weinvestigated the effects of SYCP3 expression on
cellular functions in somatic cells. This study revealed
that SCYP3-expressing cells are hypersensitive toradiation and cisplatin and are characterized byincreased aneuploidy. As these phenotypes are
consistent with those of defective HR, we screened themolecule that co-localizes with SYCP3 by immunefluorescence. Consequently, we identified that thetumor suppressor BRCA2 co-localizes with SYCP3.
We also confirmed that these proteins form a complex.
Furthermore, we found that binding of SYCP3 to
BRCA2 inhibits the HR repair activity mediated bybinding of BRCA2 to Rad51.

Since cells with BRCA1 or BRCA2 mutations are
hypersensitive to PARP inhibitors, their clinical trials
are internationally ongoing. However, the problem isthat the application of the trial is limited due to low
incidence of their mutations. Our findings implicatethat SYCP3-expressing cancers, even if they do notharbour BRCA mutations, are sensitive to PARP
inhibitors, providing novel insight into cancer therapy
based on the synthetic lethal approach in which both
two pathways essential for cell viability are disrupted
by an intrinsic genetic alteration and a specificpathway inhibitor.
SYCE2, a component constituting the synaptonemal
complex, is also expressed at varying levels in somatic
cells. SYCE2 insulates heterochromatin protein 1
from trimethylated histone H3 lysine 9 to promote
ATM-dependent DNA double-strand break repair. Thisfinding suggests that SYCE2 plays a role in the link
between the nuclear microenvironment and the DNA
damage response in somatic cells.
In addition to Rad51, 5 Rad51 paralogs, Rad54,
Rad54B, and Rad52 are also involved in early stagesof HR. While Rad51 paralogs and Rad54 were shownto assist the Rad51-dependent cascade, theinvolvement of Rad54B in HR is not closely
associated with Rad51and Rad54. This fact led us tohypothesize that Rad54B has a role distinct from otherHR factors. We found that levels of Rad54B are
inversely correlated with protein levels of p53 both
after DNA damage and Rad54B knockout cells.
Protein interaction analysis revealed that Rad54B
promotes proteasome-dependent degradation of p53
by directly binding to MDM2/MDMX, an E3
ubiquitin ligase complex targeting p53. Furthermore,
we found that overexpression of Rad54B facilitates
genomic instability by negatively regulating cell-cycle
checkpoints medicated by p53. Consistent with thisbiological function, high levels of Rad54B wereshown to correlate with poor prognosis in colorectal
cancers. In addition, increases in its expression are
also observed in other types of cancers.
Although the role of Rad52 in yeast homologous
recombination is established, its role in mammals
remains unclear. Its functional analysis in normal
human epithelial cells revealed that Rad52 is involvedin the processing of R-loop, the structure formed by
RNA and DNA at the site of a DNA double-strand

590

break. This finding suggests that Rad52 plays a role intranscription-associated homologous recombination,
providing novel insight into DNA repair at transcribedregions.
Thus, our studies on the mechanisms underlying
HR contribute to the establishment of important
strategies against cancer. Radiation and many DNAdamaging chemotherapeutic agents induce DNA DSBs,
which can be normally repaired by the intrinsic repair
pathways. The induced breaks therefore do not always
lead to apoptosis. If we will understand the details of
the repair pathways, the molecules in this pathway
will be the therapeutic targets. From the clinical pointof view, we are continuing the research exploring theprinciple in this field.

Publications
1.

2.

3.

4.

Hosoya N, Miyagawa K. Synaptonemal complex
proteins modulate the level of genome integrityin cancers. Cancer Sci, 112:989-996, 2021.
Hosoya N, Miyagawa K. Implications of thegermline variants of DNA damage response
genes detected by cancer precision medicine forradiological risk communication and cancer
therapy decisions. J Radiat Res, 62 (Suppl. 1):
i44–i52, 2021.
Ochi Y, Yoshida K, Huang YJ, Kuo MC, Nannya
Y, Sasaki K, Mitani K, Hosoya N, Hiramoto N,
Ishikawa T, Branford S, Shanmuganathan N,
Ohyashiki K, Takahashi N, Takaku T, Tsuchiya S,
Kanemura N, Nakamura N, Ueda Y, Yoshihara S,
Bera R, Shiozawa Y, Zhao L, Takeda J, Watatani
Y, Okuda R, Makishima H, Shiraishi Y, Chiba K,
Tanaka H, Sanada M, Takaori-Kondo A, Miyano
S, Ogawa S, Shih LY. Clonal evolution andclinical implications of genetic abnormalities inblastic transformation of chronic myeloid
leukaemia. Nat Commun, 12:2833, 2021.
Kobayashi H, Makise N, Shinozaki-Ushiku A,
Ishibashi Y, Ikegami M, Kohsaka S, Ushiku T,
Oda K, Miyagawa K, Aburatani H, Mano H,
Tanaka S. Scapular angiomatoid fibrous
histiocytoma with EWSR1-CREB1 fusion in an
adult patient. Case Rep Orthop, 30:9434222,
2021.

5.

Fukasawa T, Yoshizaki A, Ebata S, YoshizakiOgawa A, Asano Y, Enomoto A, Miyagawa K,
Kazoe Y, Mawatari K, Kitamori T, Sato S.
Single-cell-level protein analysis revealing theroles of autoantigen-reactive B lymphocytes in
autoimmune disease and the murine model. Elife,
10:e67209, 2021.

591

Laboratory of Biomedical
Informatics
Associate Professor
Takeshi Imai, Ph.D.

Homepage

http://www.cdbim.m.u-tokyo.ac.jp/

Introduction and Organization
When the Center for Disease Biology and Integrative
Medicine was established in 2003, Section of
Biomedical Informatics was launched as one of thedepartments in Division of Research Resources &Support. In 2017, Laboratory of Biomedical
Informatics was established as a part of Division of
Research in the Center. Because of the parallel
establishments, the both of organizations are made upof the same faculties.
The objective of Laboratory of Biomedical
Informatics which is placed in the interdisciplinary
field between medicine, engineering and informatics is
to offer feedback to clinical medicine and contributions
toward the healthcare and our society through studies
such as analyses of medical information, gaining
medical findings in secondary use of medical
information, and developing and applying diagnosis
support systems. Besides the studies, our laboratory
takes a roll of graduate education for the doctor’s
program in the Department of Biomedical Informatics
at the Division of Social Medicine, the master’s
program in the Medical Science Graduate Program, andthe School of Public Health, the Graduate School of
Medicine.
Section of Biomedical Informatics, Division of
Research Resources & Support has an operation of the
Office for Information Services, Graduate School of
Medicine to maintain MERCS (Medical Research
infrastructure with Computer System). The operations
include: (1) handling the incidents of CERT andmaintaining network infrastructure, (2) offering
software service of medical research supports, (3)operating mailing service for Faculty of Medicine, (4)operating DNS service and allocating global IP
addresses for UT-Net connections, (5) operating websites and servers of Faculty of Medicine and the
Graduate School of Medicine, (6) offering learning
devices at the medical library, and so on.

Teaching activities
In 2020, we took charge of lectures: “Description
and Processing of Medical Knowledge” in the 2-year
master course in the Medical Science Graduate
Program, “Natural Language Processing and Computer
Processing of Medical knowledge” in School of Public
Health course, and “ICT and AI applications in
Medicine” in the Lecture of Overview of Biomedical
Engineering.
We accept students in the 2-year master course in the
Medical Science Graduate Program, and 4-year
Medical Sciences doctoral course, cooperating withteaching staffs in other laboratories in the field of
medical informatics. Three students in the doctor’s
program, one student in the master’s program, and two
visiting researchers are enrolled in our laboratory in
FY2020. Additionally, six undergraduate students tookpractice education in our laboratory through M3
Elective Clerkship program. We also accepted fivegraduate students from Toyama University as shortterm intern.

Research activities
Our primary research domains are: (1) methods toknowledge representation and processing knowledge in592

healthcare, (2) analysis of electronic medical records
and gaining medical knowledge with natural language
processing and machine learning, (3) developing
diagnosis support system, (4) standardization in thefield of healthcare informatics, and so on.
In these domains, major research topics are listed
below:(1) DevelopmentofMedicalKnowledge
Infrastructure.
A large amount of medical information has
been accumulated with the prevalence ofcomputerization in medicine. Correspondingly,
the needs of secondary use of the accumulated
information for diagnosis support system andgaining medical knowledge have been
increasing. Ontology, knowledge database,which is assembled mass of information
describing the relationship of terms and concepts
marshaled in a structured manner, is required forthe study besides the techniques of machinelearning and knowledge deduction. We havedeveloped the clinical ontologies in particularfields such as anatomy, diseases, and abnormal
status, as a funded research by the Ministry of
Health, Labor and Welfare, Japan. For example,
the ontology for diseases has been developedwith approximately 6,000 diseases, that they aredescribed as causal chains of abnormal states.
We have also participated in “Research anddevelopment of intellectual information systeminfrastructure in medicine” project, sponsoredby AMED since 2015. As further developing theontology, we have worked on the study thatclinical information of a targeted patient is
automatically mapped on chronic disease
ontology in order to perceive changes of diseasestates.
(2) Development of Diagnosis Support System for
General Physicians.
It is difficult in community medicine topromote cooperation between medical experts
and the core medical institutions. The experts ofregional communities are required to havecomprehensive diagnosis skills and technicalknowledge in the domain they specialize in.
However, given the difficulty of such a situationthat physicians take all the responsibilities,

depending on only their knowledge andexperiences, the need of diagnosis support
system is pointed out. In this study, we havedeveloped support system, that gives physiciansin outlying regions access to refer to information
matching experiences and knowledge matured
general physicians have, to solve the issues. This
project has been launched sponsored by AMED
since January 2017. The current developed
system is made up of approximately 20,000 casereports in internal medicine. The reports aretransformed into knowledge database, describedas chains of clinical states, so that the system cansuggest a list of candidate diseases
corresponding to a query, with certainty scoresand reasons. The system (“J-Casemap”) was
released and socially implemented as a service
for members of the Japanese Society of Internal
Medicine in August 2020. We also have worked
on a study to automatically extract knowledge
from raw texts in case reports using natural
language processing for the continuous updatingof the system.
(3) Analysis of Electrocardiogram (ECG) by Deep
Learning.
Automatic analyzers of ECG data used inmost hospitals are rule-based models that
outputs ECG data in waveforms with clinicalannotations. However, it still has difficulties onclassification on abnormal findings. In fact, it ispointed out that it has a low sensitivity or
potential for a false-positive diagnosis.
Therefore, it needs an enhancement in its
classification performance. We have developed
another classification model using deep learning,
intended for standard 12-leads ECG data. The
current clinical annotations used for training ourmodel is the ones given by the automatic
analyzers; however we plan to apply diagnosis
confirmed by echocardiogram as annotation data
in future, so that our proposed model can be
specialized in more specific abnormal findings
and achieve comparable performance todiagnosis by experts.
In addition to the researches, we have worked onother studies such as automatic selection of the593

underlying cause of death from death certificates using
machine learning, and developing prescription support
system in medical care for hypertension patients basedon the clinical guidelines. Furthermore, we also havepromoted a project aimed at the application of ICD-11
released in June 2018 for domestic use in Japan.

References
1.

2.

3.

4.

5.

6.

7.

8.

Iwai S, Mitani T, Hayakawa J, Shinohara E, Imai
T, Kawazoe Y, Ohe K. Development of GraphBased Algorithm for Differentiating Pathophysiological Conditions. Applied Medical
Informatics. 2020;42(2):107-117.
Mitani T, Doi S, Yokota S, Imai T, Ohe K. Highly
accurate and explainable detection of specimen
mix-up using a machine learning model. Clin
Chem Lab Med. 2020 Feb 25;58(3):375-383.
Imai T, Myojin T, Oigawa H, Kagawa R, Imamura
T. Research on the actual situation and problemsof determining the primary cause of death, and theapplicability and challenges of machine learningfor improving accuracy and efficiency. Journal of
Health and Welfare Statistics. 2020;67(3):17-24.
(In Japanese).
Imai T. Application of Artificial Intelligence
Technology in the Field of Medical Natural
Language Processing. Journal of the JapaneseSociety for Artificial Intelligence. 2020;35(4):474-479. (In Japanese).
Imai T. ICD-11 as a clinical terminology andissues for the application in Japan. Japan Journalof Medical Informatics. 2020; 40(suppl.): 324-327.
(In Japanese).
Ogawa T, Imai T, Takizawa M, Komatsu M,
Imamura T. Consideration of Japanese translations
for the domestic application of ICD-11 in Japan.
Japan Journal of Medical Informatics. 2020;
40(suppl.): 328-331. (In Japanese).
Ogishima S, Imai T, Yoshida T, Ohara O,
Tsutsumi M, Furuta K, Nakagome H, Nishimura K.
Standardization of clinical sequence data. Japan
Journal of Medical Informatics. 2020; 40(suppl.):371-373. (In Japanese).
Myojin T, Oigawa H, Kagawa R, Imamura T, Imai
T. Extraction of issues in determining theunderlying cause of death in Japan to improve the9.

accuracy and efficiency of cause-of-death
statistics. Japan Journal of Medical Informatics.
2020; 40(suppl.): 674-676. (In Japanese).
Oigawa H, Myojin T, Kagawa R, Imamura T, Imai
T. Feasibility of Domestic Use of Iris in the
Determination Process of the Underlying Cause of
Death. Japan Journal of Medical Informatics.
2020; 40(suppl.): 677-682. (In Japanese).

The International Research Center
for Medical Education (IRCME)

595

Department of Medical Education
Studies
Professor
Masato Eto, M.D., Ph.D.

Lecturer
Masashi Izumiya, M.D., Ph.D.

History and organization
International Research Center for Medical
Education, established in 2000, had functioned as acenter for the whole university and kept relations with
Graduate School of Medicine in various ways. IRCME
became an affiliated center for education and researchunder the control of Graduate School of Medicine sinceApril 2013. IRCME previously consisted of two
departments of International Cooperative Study in
Medical Education, and Planning & Cooperation forInternational Cooperative Projects and Information on
Medical Education. Names of two new departments are
Department of Medical Education Studies andDepartment of International Cooperation for Medical
Education.
The mission of Department of Medical Education
Studies includes promotion of medical education not
only in Faculty of Medicine of the University of Tokyo
but also of the whole country. Specific contents are as
follows:(1) Research in medical education and dissemination
within and outside of the University
Medical and health professions education needs tocontinue revisions to meet health care needs of thecountry or the region. However, since every country or
region has different culture or social system,
experiences to apply updated evidence to the realsettings to revise the system.
(2) Support to undergraduate and postgraduate education in the University
Through the support to education in Faculty of

Medicine and the University Hospital, we show theeffective ness of such teaching practice and apply it toother medical schools in Japan for future reform.

Activities
This department promotes research related to
medical education field. As the studies of medical
education develop very rapidly all over the world, thedepartment expands research to construct theories andemphasizes activities of educational practice or
improvement.
In the University, this department provides
information and members as to the education of Facultyof Medicine in such as academic affair committee,
medical education reform working group, and clinicalclerkship. Moreover, the department offers educational
activities such as PBL (problem-based learning) andclinical skill practical training. The department
operates OSCE (objective structured clinicalexamination). The department also runs and manages“Tsutsuji no kai” under the consortium with Tokyo
Medical Dental University to develop simulated
patients indispensable for education of medical
interview.
This department promotes practical activities for the
pre-graduate education of medical students andresearch in fields related to medical education. In thefield of pre-graduate education, the department aims tonurture and produce human resources who can lead
medicine and medical care in Japan, as well as toprovide educational content of international standard.

596

In addition, against the backdrop of the rapid
development of digital technology in recent years, thedepartment will conduct research to provide effective
and efficient medical education utilizing these newtechnologies.
The faculty members of this division are active
members of the Academic Affairs Committee, working
groups on educational reform, clinical clerkships, andother committees related to education at the Faculty of
Medicine. The department also conducts PBL tutorials,
clinical introductory training, and interprofessional
education (IPE) in collaboration with otherdepartments and universities. The department is also incharge of the administration of the OSCE (objective
structured clinical examination). In addition, thedepartment operates and manages the Tsutsuji no kai, aconsortium with Tokyo Medical and Dental University,
to train simulated patients, which is essential for
medical interviewing education.
The department is also in charge of conducting
institutional research (IR) and class/curriculum surveys
for continuous evaluation and improvement of medical
education, as well as the administrative office of theMedical Education Improvement Committee.

597

Department of International
Cooperation for Medical
Education
Assistant Professor
Hirotaka Onishi, M.D., M.H.P.E., Ph.D.

Homepage https://www.icme.m.u-tokyo.ac.jp/
Introduction and Organization

Education

International Research Center for Medical Education(IRCME), established in 2000, had functioned as acenter for the whole university and kept relations with
Graduate School of Medicine in various ways.
IRCME became an affiliated center for education andresearch under the Graduate School of Medicine
umbrella since April 2013. IRCME currently consistsof the Department of Medical Education and theDepartment of International Cooperation for Medical
Education (ICME). Since April 2018, the Department
of International Cooperation in Medical Education,
which had been operated in an integrated manner with
the Department of Medical Education, has been
operated independently. It is one of the departments of
the IRCME, and encompasses international
cooperation in areas related to medical education, as
well as practice and research in areas that connect
policies and actual clinical practice, such as global
health, community medicine, and general practice.

The Department of ICME offers classes as cooperative
department for School of International Health (SIH)and School of Public Health (SPH). In SIH special
lectures of international cooperation for medical
education are offered twice a year (spring and autumn).
In SPH the class in spring is human resource
development in health and medical practice and theclass in autumn is learner assessment.
Since 2019, several graduate students are studying
in ICME, and weekly seminars are provided every
Wednesday.

International Cooperation
Since March 2020, a faculty member has participatedas an expert in the "Information Gathering andConfirmation Survey on Higher Education and
Vocational Education in Indonesia" conducted by
JICA. However, the pandemic of COVID-19 greatly
affected the progress of the survey. The dispatch of thefaculty remains suspended.

Research(1) International Cooperation in the Field of HealthProfessions Education: We explore how education andpolicies in the health and medical fields should bebased through participation in international
cooperation projects in countries mainly in Asia. We
try to become the core center for the research in thisarea by conducting practical efforts as an expert on the
project under Japan International Cooperation Agency,
by accumulating experiences in the area such as
evaluation
method,policyrecommendation,
coordination of stakeholders, and by disseminating
the research results.
(2) Study on Learner Assessment: When certifying thecompletion of the program, it is very important toinvestigate how the learner's assessment is conductedand how the decision is made. Various changes are598

seen in the concept of assessment itself. As forresearch, development of work-based assessment
methods, verification of reliability and validity,
improvement of methods for setting pass / failjudgment criteria are examples.
(3) Research related to ACP (advance care planning):
We are continuing research on how and where theelderly want to end their own life and the relationshipbetween their family's thoughts.
(4) Practice and research in the field linking healthpolicy and clinical practice: We currently work for
how to train the professionals contributing tocommunity-based integrated care system.

References
1.

Osamu Nomura, Hirotaka Onishi, Yoon Soo Park,
Nobuaki Michihata, Tohru Kobayashi, Kazunari
Kaneko, Tetsushi Yoshikawa, Akira Ishiguro &Japan Pediatric Society Steering Committee ofBoard Examination (2021). Predictors of
performance on the pediatric board certification
examination. BMC medical education, 21(1), 1-7.

599

Global Nursing Research Center
Director, Professor
Hiromi Sanada, R.N., P.H.N., W.O.C.N., Ph.D.

Vice Director, Professor
Noriko Yamamoto-Mitani, R.N, Ph.D.

Project Associate Professor
Takashi Naruse, R.N., P.H.N., Ph.D.
Project Senior Lecturer
Kojiro Morita, M.P.H., R.N., P.H.N., Ph.D.

Project Assistant Professor
Hiromi Tobe, R.N., P.H.N., Ph.D., Toshiaki Takahashi, R.N., Ph.D.
Shio Higashimura, R.N., Ph.D., Sameh Eltaybani, Ph.D.

Project Researcher
Ayano Nakai, Ph.D. , Chia Chien Li, Ph.D.

Homepage

http://gnrc.m.u-tokyo.ac.jp/en/

Introduction and Organization
With a falling birthrate and a super-aging society,Japan is in need of a paradigm shift toward a medical
and nursing care that supports the aging, as well as
those dealing with chronic health conditions, to lead
lives with maximum independence and well-being. In
order to provide a healthy life expectancy for its
people, it will be necessary for Japan to face its
forthcoming challenges and bring about the realizationof a ‘care’ society that lightens the difficulty of theliving and brings a self-reliant way of life to theJapanese nation. Nursing, which plays a central role inproviding care, must develop into a new field as ascience for the realization of this ‘care’ society.
Currently, however, the dominant paradigm employedin various nursing fields embraces a structure that
supports the training of clinical nurses, not thedevelopment of a science aimed at producing a'medical and nursing care that supports.’ Thus, GNRC
seeks to promote research into an innovative,

transdisciplinary nursing science that systematizes thistype of care. In particular, our focus is to create atransdisciplinary research and educational environment that fosters young leaders in nursing research
who will promote care innovation and develop nursing
systems for implementation.
In order to achieve this, we must work toward
integrating nursing with fields it has yet to fully
collaborate with, such as bio-engineering, molecularbiology, human engineering, philosophy, educational
psychology, information science, and policy science.
Moreover, as the field of nursing science continues todevelop, further attention must be paid to both thedevelopment of the necessary human resources thatwill be required to promote this transdisciplinary
research, as well as the networks necessary to create
collaborative relationships among industry, government, and academia. In short, our aim is to create along-term research system that allows young
researchers to conduct transdisciplinary work that
ranges from fundamental research to studies with

600

commercial application.
Thus, the Global Nursing Research Center has been
established as an affiliated research center, which isthe first of its kind in nursing science. The GNRC willcontinue to execute the following three goals:
1) Establish an innovative nursing research field basedon transdisciplinary integration;2) Carry out cutting-edge research and present it to theworld with young researchers pursuing the sciences;
3) Build up a foundation of these new fields throughrepeated research trials that will strengthen the newresearch and education systems.

Establishing an Innovative Nursing Research
Field
1. Division of Care Innovation
The Division of Care Innovation promotes various
research activities, such as robotics nursing, biologicalnursing, visualized nursing, clinical nursing technology and reverse translational research, with the aimof ‘developing and producing patient care productsthat lighten unfavorable conditions of daily life due tothe health impairment of each person.’
2. Division of Nursing Systems
The Division of Nursing Systems promotes suchresearch activities as health-quality outcome researchand care quality management, in order to provide‘nursing practice solutions that reflect important
cultural and social concerns, constructing Japan-origin
nursing theories that support high quality practices,and making policy proposals.’
3. Achievements
In 2021, one international joint research project and
one industry-government-academia research project
were undertaken. In addition, 72 original English
articles were published.

Head of Wound Research Group, Monash University.
2. Post-doctoral Program
Post-doctoral (PD) researchers engage in focusedresearch projects, the findings of which will be madeknown to the public. In addition, PD researchers musttake five essential seminars that cover comprehensive
research knowledge, skills, and global awareness forthe training of youth for leadership.
These five required seminars are, as follows: (1) How
to Write a Research Paper in English, (2) Leadershipin Nursing Research, (3) Qualitative Research
Methods, (4) Health Quality Outcome Research, and(5) Introductory Seminar to Nursing Science andEngineering.
Further, there are an additional five optional seminars:(1) Skin Assessment, (2) Ultrasonography, (3)Qualitative Sketch Techniques, (4) Biological Nursing,and (5) 3D Measurement and Modeling Hands-on
Seminar for Nursing Science and Engineering.
In 2021, two PD researchers participated in thisprogram, and completed the program.
3. Other Universities’ Young Researchers
In 2021, our PD seminars and lectures were opened toyoung researchers from other universities, and by theend of the year, a total of 1541 participants attended.

Building Future Research
1. Global Nursing Research Center FundThe Global Nursing Research Center Fund wascontinued for the purpose of fostering young
researchers.

Accomplishments
1.

Executing Innovative Research
1. International Invited Faculty
In 2021, we had one Project Professor: Prof. Ardith
Doorenbos: Professor in Biobehavioral Nursing
Science, University of Illinois, Chicago, and invited
two researchers: Prof. Seonae Yeo: Professor of
School of Nursing, University of North Carolina at
Chapel Hill, and Prof. Carolina D. Weller: Professor,

2.

Astrada A, Nakagami G, Minematsu T, Goto T,
Kitamura A, Mugita Y, et al. Concurrent validityof biofilm detection by wound blotting on
chronic wounds. J Wound Care. 2021;30(Sup4):
S4-13.
Kataoka Y, Kunimitsu M, Nakagami G,
Koudounas S, Weller DC, Sanada H.
Effectiveness of ultrasonic debridement on
reduction of bacteria and biofilm in patients withchronic wounds: A scoping review. Int Wound J.
2021;18(2):176-86.

601

3.

Koyanagi H, Kitamura A, Nakagami G,
Kashiwabara K, Sanada H, Sugama J. Local
wound management factors related to biofilm
reduction in the pressure ulcer: a prospective
observational study. Jpn J Nursing Sci. 2021;
18(2):e12394.2020.
4. Hasegawa Y, Yoshida M, Sato A, Fujimoto Y,
Minematsu T, Sugama J, et al. A change intemporal muscle thickness is correlated with pastenergy adequacy in bedridden older adults: A
prospective cohort study. BMC Geriatrics. 2021;
21(1):182.
5. Matsumoto M, Nakagami G, Kitamura A, Kurita
M, Suga H, Miyake T, et al. Ultrasoundassessment of deep tissue on the wound bed andperiwound skin: a classification system using
ultrasound images. J Tissue Viability. 2021;30(1):28-35.
6. Matsumoto M, Fujioka M, Okada T, Naka Y,
Amemiya A, Matsushima E, et al. Evaluation of
bowel preparation before colonoscopy byultrasonographic monitoring of colonic fecal
retention: A case series. Med Ultrason. 2021;
23(2):147-52.
7. Abe-Doi M, Murayama R, Komiyama C, Sanada
H. Changes in the subcutaneous tissue ofcatheterization site from the precatheterization
state to the onset of anticancer drug-induced
induration: a case report. Clin Case Rep. 2021;
9(1): 57.
8. Murayama R, Abe-Doi M, Kogure T, Takahashi T,
Kanno C, Ishigaki M, et al. The influence of
peripheral intravenous catheterization on thesleep quality of ophthalmic inpatients: An
observational study. J Nurs Sci Eng. 2021;8:13442.
9. Oe M, Tsuruoka K, Ohashi Y, Takehara K,
Noguchi H, Mori T, et al. Prevention of diabetic
foot ulcers using a self-monitoring device
smartphone and mobile thermography: Casestudy. J Wound Care. 2021;30(2):116-9.
10. Morisaki-Nakamura M, Suzuki S, Kobayashi A,
Kita S, Sato I, Iwasaki M, et al. Development andvalidation of a Japanese version of the
TRANSITION-Q. Pediatr. Int. 2021;63(3):270-8.
11. Eltaybani S, Igarashi A, Yamamoto-Mitani N.
Palliative and end-of-life care education in

12.

13.

14.

15.

16.

17.

18.

19.

prelicensure nursing curricula: A nationwide
survey in an Arab country. Nurse Educ Today.
2021;96:104644.
Sakka M, Kita S, Sato I, Soejima T, Eguchi H,
Tokita M, et al. Reliability and validity of theJapanese version of the Caregiving Interface
Work Scale in employed Japanese family
caregivers. Geriat Gerontol Int. 2021;21(2):254-61.
Sari DW, Minematsu T, Yoshida M,
Noguchi-Watanabe M, Tomida S, Kitamura A, etal. Validity of skin blot examination for albuminand nerve growth factor β to detect itching of theskin in Indonesian older adults. J Tissue Viability.
2021;30(1):42-50.
Eltaybani S, Yamamoto-Mitani N, Ninomiya A,
Igarashi A. The association between nurses’
burnout and objective care quality indicators: across-sectional survey in long-term care wards.
BMC Nurs. 2021;20(1):34.
Kida R, Togari T, Yumoto Y, Ogata Y. The
association between workplace social capital andauthentic leadership, structural empowerment,
and forms of communication as antecedentfactors in hospital nurses: a cross-sectional
multilevel approach. J Nurs Manag. 2021;29(3):508-17.
Inoue M, Kunie K, Takemura Y, Ichikawa N,
Kida R. The influence of learning circumstancesand on-the-job opportunities for professional
growth on perceived person-environment fit
among hospital nurses: a longitudinal study. J
Nurs Manag. Forthcoming.
Saiki M, Kunie K, Takemura Y. Nursing
assistants’ desired roles, perceptions of nurses’
expectations, and effect on team participation:
A cross-sectional study. J Nurs Manag.
Forthcoming.
Piao X, Tsugawa S, Takemura Y, Ichikawa N,
Kida R, Kunie K, et al. Disability Weights
Measurement for 17 Diseases in Japan: A Survey
Based on Medical Professionals. Econ Anal
Policy. 2021;70:238-48.
Takahashi Y, Kunie K, Takemura Y. The lasting
impacts of work-attendance decisions of healthcare employees under uncertainty: Japanesehospital nurses’ experiences outside the

602

20.

21.

22.

23.

24.

25.

26.

27.

evacuation zone after the nuclear accident. The
Journal of Organization and Discouse.
Forthcoming.
Abe-Doi M, Murayama R, Kawamoto A,
Komiyama C, Doorenbos A, Sanada H. Damage
to subcutaneous tissue at the catheterization site
during chemotherapy: A prospective observational study using ultrasonography. Jpn J Nurs Sci.
2021;18:e12436.
Abe-Doi M, Murayama R, Komiyama C, Tateishi
R, Sanada H. Effectiveness of ultrasonography
for peripheral catheter insertion and catheter
failure prevention in visible and palpable veins.
J Vasc Access. 2021, DOI: 10.1177/
11297298211022078
Tanaka S, Kunie K, Takemura Y, Ichikawa N,
Kida R. Exploring nurses’ clinical reasons forbed transfers in acute care wards: An
observational study. J Nurs Manag. (accepted 26
Apr. 2021) doi: 10.1111/jonm.13352
Kawaguchi S, Takemura Y, Takehara K, Kunie K,
Ichikawa N, Komagata K, et al. Relationshipbetween teams’ Leader–Member Exchange
characteristics and psychological outcomes fornurses and nurse managers: A cross-sectional
study in Japan. SAGE Open Nursi 2021; 7: 1-11.
Tanaka S, Kunie K, Takemura Y, Ichikawa N,
Kida R. The patterns and reasons for changing
bed placement in multi-bed rooms in acute caresettings. J So Nurs Pract. (accepted 24 Jun. 2021)
Ishii K, Takemura Y, Ichikawa N, Kunie K,
Kida R. The relationship between nursing
groups’ organizational socialization and nurses’
perception of organizational learning subprocesses: A cross-sectional study in hospitalwards. Team Perform Manag. (accepted 15 Jul.
2021) doi: 10.1108/TPM-01-2021-0002
Hikita N, Batsaikhan E, Sasaki S, Haruna M,
Yura A, Oidovsuren O. Factors Related toLacking Knowledge on the Recommended Daily
Salt Intake among Medical Professionals in
Mongolia: A Cross-Sectional Study. Int J Environ
Res Public Health. 2021;18(8):3850.
Tahara-Sasagawa E, Ota Y, Matsuzaki M,
Shimpuku Y, Oishi T. Visualization of midwifery
education in 109 countries on a world map:
Secondary analysis of the data from the

28.

29.

30.

31.

32.

33.

34.

35.

International Confederation of Midwives (ICM).
J Jpn Acad Midwif. 2021;35(1):48-56.
Murakami M, Yonezawa K, Shimizu S, Haruna
M, Sasagawa E, Usui Y. Newborn-oriented andenvironmental factors for newborns’ skin barrier
functions. Jpn J Nurs Sci. 2021. (Accepted)
Koudounas S, Minematsu T, Mugita Y, Tomida S,
Nakai A, Nakagami G et al. Inhibiting effect ofsynthetic urine on the growth and mobility of
Pseudomonas aeruginosa, Escherichia coli,
Proteus mirabilis and Klebsiella pneumoniae
shifts to a promoting effect during culture. J Nurs
Sci Engineer. 2021; 8: 220-9.
Hsu W, Minematsu T, Nakagami G, Koudounas S,
Tomida S, Nakai A et al. Identification of
microRNAs responsive to shear loading in rat
skin. Int Wound J. Online ahead of print. 2021.
Kunimitsu M, Nakagami G, Kitamura A,
Minematsu T, Mugita Y, Ogai K et al.
Dissemination of microbiota between wounds
and the beds of patients with pressure injuries: A
cross-sectional study. Wound Pract Res. 2021;
29(2): 70-6.
Astrada A, Nakagami G, Minematsu T, Goto T,
Kitamura A,Mugita Y et al. Concurrent validityof biofilm detection by wound blotting on
chronic wounds. J Wound Care. 2021; 30 (Sup4):
S4-13.
Tsukatani T, Minematsu T, Dai M, Tamai N,
Nakagami G, Sugama J et al. Polymorphism
analysis of candidate risk genes for pressure
injuries in older Japanese patients: A crosssectional study at a long-term care hospital.
Wound Repair Regen. 2021; 29(5): 741-51.
Sawada U, Shimazu A, Kawakami N, Miyamoto
Y, Speigel L, Leiter MP. The Effects of the
Civility, Respect, and Engagement in the
Workplace (CREW) Program on Social Climate
and Work Engagement in a Psychiatric Ward inJapan: A Pilot Study. Nursing Reports. 2021;
11(2):320-330.
Iida M, Watanabe K, Imamura K, Sakuraya A,
Asaoka H, Sato N, Nozawa K, Kawakami N.
Development and validation of the Japaneseversion of the team job crafting scale for nurses.
Research in Nursing & Health. 2021; 44(2):329-43.

603

36. Asaoka H, Sasaki N, Imamura K, Kuroda R,
Tsuno K, Kawakami N. Changes in COVID‐19
measures in the workplace: 8‐month follow‐up ina cohort study of full‐time employees in Japan.
Journal of Occupational Health. 2021; 63(1):e12273.
37. Sasaki N, Asaoka H, Kuroda R, Tsuno K,
Imamura K, Kawakami N. Sustained poor mental
health among healthcare workers in COVID‐19
pandemic: A longitudinal analysis of thefour‐wave panel survey over 8 months in Japan.
Journal of occupational health. 2021; 63(1):e12227.
38. Eltaybani S, Ahmed FR. Family satisfaction in
Egyptian adult intensive care units: A mixedmethod study. Intensive Crit Care Nurs. 2021
Oct;66:103060.
39. Sumikawa Y, Honda C, Yoshioka-Maeda K,
Yamamoto-Mitani N. Characteristics of COVID19-related free telephone consultations by publichealth nurses in Japan: A retrospective study.
Healthcare. 2021 Aug 9;9(8):1022.
40. Matsumoto H, Maeda A, Igarashi A, Weller C,
Yamamoto-Mitani N. Dementia education andtraining for the general public: a scoping review.
Gerontology & Geriatrics Education.
41. Honda C, Naruse T, Yamana H, YamamotoMitani N. Infant Injury Prevention Education
for Pregnant Women Attending Antenatal Class:
A Quasi-Experimental Study. Int. J. Environ. Res.
Public Health 2021, 18(17), 9393
42. Matsumoto M, Tamai N, Miura Y, Okawa Y,
Yoshida M, Igawa Y, et al. Evaluation of apoint-of-care ultrasound education program fornurse educators. J Contin Educ Nurs. 2021;52(8):375-81.
43. Matsumoto M, Karube M, Nakagami G,
Kitamura A, Tamai N, Miura Y, et al.
Development of an automatic ultrasound image
classification system for pressure injury based on
deep learning. Appl Sci. 2021;11(17):7817.
44. Kunimitsu M, Nakagami G, Kitamura A,
Minematsu T, Mugita Y, Ogai K et al.
Dissemination of microbiota between wounds
and the beds of patients with pressure injuries: A
cross-sectional study. Wound Pract Res. 2021;
29(2): 70-6.

45. Astrada A, Nakagami G, Minematsu T, Goto T,
Kitamura A,Mugita Y et al. Concurrent validityof biofilm detection by wound blotting on
chronic wounds. J Wound Care. 2021; 30 (Sup4):
S4-13.
46. Qin Q, Oe M, Ohashi Y, Shimojima Y, Imafuku
M, Dai M, Nakagami G, Yamauchi T, Yeo S,
Sanada H. Factors associated with the local
increase of skin temperature, ‘hotspot,’ of callus
in diabetic foot: A cross-sectional study. Journalof Diabetes Science and Technology. 2021:
19322968211011181.
47. Mugita Y, Minematsu T, Nakagami G, Sanada H.
Promoting effect of acylated homoserine lactone
on the healing of tissue damage in incontinenceassociated dermatitis model rats. Journal of
Wound Care. 2021.
48. Kunimitsu M, Kataoka Y, Nakagami G, CWeller
DC, Sanada H. Factors related to the compositionand diversity of wound microbiota investigatedusing culture-independent molecular methods: ascoping review. Drug Discoveries & Therapeutics.
2021;15(2):78-86.
49. Mugita Y, Koudounas S, Nakagami G, Weller C,
Sanada H. Assessing Absorbent Products’
Effectiveness for the Prevention and Management of Incontinence-associated Dermatitis
Caused by Urinary, Faecal or Double Adult
Incontinence: A Systematic Review. Journal of
Tissue Viability. 2021.
50. Haba D, Nakagami G, Minematsu T, Sanada H.
Low-frequency vibration promotes AMPKmediated glucose uptake in 3T3-L1 adipocytes.
Heliyon. 2021.
51. Yoshinaga N, Nakagami G, Fukahori H,
Shimpuku Y, Sanada H, Sugama J. Initial Impactof the COVID-19 Pandemic on Time JapaneseNursing Faculty Devote to Research: CrossSectional Survey. Japan Journal of Nursing
Science. 2021.
52. Honda C, Naruse T, Yamamoto-Mitani N.
Pregnant Women’s Intentions to Implement
Safety Practices for Preventing Infant Injury: A
Cross-Sectional Study. International journal ofenvironmental research and public health. 2021;
18(1):24.

604

53. Sumikawa Y, Yamamoto-Mitani N. Transitionalcare during COVID-19 pandemic in Japan: calls
for new strategies to integrate traditional
approaches with information and communication
technologies. BioScience Trends. Published
online 2021.
54. Matsumoto H, Kawagoe M, Hotta S. Older
Adults Used Fewer Home Care Services during
the COVID-19 Pandemic: Findings from a
Secondary Analysis of an Urgent Survey in Japan.
Ann Geriatr Med Res. 2021;25(4):286-293.
55. Igarashi A, Matsumoto H, Takaoka M, Kugai H,
Suzuki M, Murata S, Miyahara M, YamamotoMitani N. Building Relationships Between
Community Care Professionals and Convenience
Stores in Japan: Community-Based Participatory
Research. Progress in Community HealthPartnerships: Research, Education, and Action(inPress).
56. Matsumoto H, Maeda A, Igarashi A, Weller C,
Yamamoto-Mitani N. Dementia education andtraining for the general public: a scoping review.
Gerontol Geriatr Educ. 2021. Doi: 10.1080/
02701960.2021.1999938. Epub ahead of print.
57. Eltaybani S, Abdelhalim GE, Abdelgawad ME.
Nursing students' and educators' experience withe-learning during a pandemic: An online survey.
Nurs Forum. 2021;56(4):878-888. doi: 10.1111/
nuf.12634.
58. Yonezawa K, Haruna M, Ohya Y. Impact of skinconditions of infants on their mothers’ quality oflife. J Neonatal Nurs. 2021. Doi.org/10.1016/j.jnn.
2021.10.012
59. Sugawara C, Yamana H, Sasagawa E, Yonezawa
K, Hikita N, Morita K, Matsui H, Yasunaga H,
Haruna M. Factors Associated with SurgicalTreatment in Postpartum Women with Mastitis or
Breast Abscess: A Retrospective Cohort Study.
Breastfeed Med. 2021. doi.org/10.1016/j.jnn.
2021.10.012
60. Shiraishi M, Matsuzaki M, Tsunematsu R,
Watanabe S, Kobayashi R & Haruna M. Effects
of Individual Dietary Intervention on Nutrient
Intake in Postpartum Japanese Women: A
Randomized Controlled Trial. Nutrients. 2021;
13(9): 3272.

61. Tamai N, Minematsu T, Sanada H. Changes in
scalp epidermal thickness using in vivo
reflectance confocal microscopy in breast cancer
patients undergoing chemotherapy: a case series.
J Nurs Sci Eng. 2021;8:143-150.
62. Koudounas S, Mugita Y, Minematsu T, Nakagami
G, Weller C, Sanada H. Does the presence ofbacterial urinary infection contribute to thedevelopmentofincontinence-associateddermatitis? A scoping review. Journal of Tissue
Viability. 2021;30(2):256-261.
63. Miura Y, Tamai N, Kitamura A, Yoshida M,
Takahashi T, Mugita Y, et al. Diagnostic accuracyof ultrasound examination in detecting aspirationand pharyngeal residue in patients withdysphagia: A systematic review and metaanalysis. Japan Journal of Nursing Science.
2021;18:e12396.
64. Sari WD, Minematsu T, Yoshida M, NoguchiWatanabe M, Tomida S, Kitamura A, et al.
Validity of skin blot examination for albumin andnerve growth factor β to detect itching of the skinin Indonesian older adults. Journal of Tissue
Viability. 2021;30(1):42-50.
65. Takahashi T, Shintani Y, Murayama R,
Noguchi H, Abe-Doi M, Koudounas S, et al.
Ultrasonographic measurement of blood flow ofperipheral vein in the upper limb of healthy
participants: a pilot study.Journal of the JapaneseSociety of Wound, Ostomy, and ContinenceManagement. 2021;25(3).
66. Minematsu T, Dai M, Tamai N, Nakagami G,
Urai T, Nakai A, et al. Risk scoring tool forforearm skin tears in Japanese older adults: A
prospective cohort study. Journal of Tissue
Viability. 2021;30(2):155-160.
67. Shimizu S, Yonezawa K, Haruna M, Sasagawa E,
Hikita N, Sanada H, et al. Relationship between
the skin barrier function of 2-week old infants
after bathing and facial skin problems during thefirst 6 weeks of life: A prospective observational
cohort study. The Japan Journal of Nursing
Science. 2021:e12408.
68. Nakagami G, Yokota S, Kitamura A, Takahashi T,
Morita K, Noguchi H, et al. Supervised machinelearning-based prediction for in-hospital pressure
injury development using electronic health

605

69.

70.

71.

72.

records: A retrospective observational cohort
study in a university hospital in Japan.
International Journal of Nursing Studies. 2021:
119:103932.
Takahashi T, Murayama R, Abe-Doi M, Miyahara
M, Kanno C, Nakagami G, et al. Catheter failurein the administration of hyperosmotic drugs
through a peripheral vein and vascular selection:
A retrospective cohort study. Drug Discoveries &Therapeutics. 2021;15(5):236-240.
Maeda T, Tamai N, Minematsu T, Noguchi H,
Yabunaka K, Nakagami G, et al. The relationshipbetween pressure injuries and dynamic buttock
pressure distributions during performance inwheelchair basketball athletes. Wound Practiceand Research. 2021.
Kitamura A, Nakagami G, Minematsu T,
Kunimitsu M, Sanada H. Establishment of an
infected wound model by bacterial inoculation on
wound surface in rats. J Nurs Sci Eng. 2021;9:
1-8.
Takizawa C, Kitamura A, Nakagami G,
Matsumoto M, Hayashi C, Kawasaki A, et al.
The relationship between the temperature
distribution detected by thermography andsuspected deep tissue injuries. Jpn J PU. 2021.

606

Center for Diversity in Medical
Education and Research
Director/Professor
Kiyoto Kasai, M.D., Ph.D.

Vice Director/Associate Professor
Yoshihiro Satomura, M.D., Ph.D.

Homepagehttps://cdmer.jp

Introduction and Organization
The University of Tokyo Center for Diversity in
Medical Education and Research was established in
April 2021. The main purpose of the center is topromote education and research on diversity andinclusion in medicine. As part of this, the center aims
to provide training programs for medical students withdisabilities.
The center is working on the education, support,
research and organizational change/ co-production
divisions in close collaboration with the Graduate
School of Medicine and Faculty of Medicine andDisability Services Office in the University of Tokyo.
The center aims to improve the quality of patientcentered medical services by the inclusion of medical
professionals with disabilities in the team medical care.

Education
Through education on diversity and inclusion in
medicine, we will develop medical personnel including
physicians and medical researchers who understand thesignificance of patient-public involvement (PPI) in
medical research and development, and who have a coproduction mindset in medical research and practice.
For this purpose, we will be giving lecture to medical
students in some of the existing educational programs.
For a more integrated and systematic education on
diversity and inclusion in medicine, we are preparing
to establish the “ Human Resource Development
Program for Diversity and Inclusion in Medicine”. In

this program, participating students will take theinitiative in deepening their learning based on thephilosophy of co-production and will not only be
exposed to academic theory, but also participate in thepractical field.

Research
There are many research issues that need to beclarified in order to promote diversity and inclusion in
medicine. The actual situation regarding the presence
rate of personnel with disabilities, and reasonableaccommodation in medical education and practicesettings needs to be clarified. Research on stigma heldby health care providers, considered one of the mostsignificant barriers to participation of medical
personnel with disabilities, and the development ofanti-stigma educational intervention methods are alsoneeded. We will also need to explore the conditions fororganizations in which personnel with disabilities canplay an active role safely.

Publications
1.

Kanehara A, Koike H, Fujieda Y, Yajima S,
Kabumoto A, Kumakura Y, Morita K, Miyamoto
Y, Nochi M, Kasai K: Culture-dependent anduniversal constructs and promoting factors for theprocess of personal recovery in users of mental
health services: Qualitative findings from Japan.
BMC Psychiatry, 2022 Feb 10;22(1):105. doi:
10.1186/s12888-022-03750-4.

607

2.

3.

Morishima R, Kumakura K, Usami S, Kanehara A,
Tanaka M, Okochi N, Nakajima N, Hamada J,
Ogawa T, Ando S, Tamune H, Nakahara M, Jinde
S, Kano Y, Tanaka K, Hirata Y, Oka A, Kasai K:
Medical, welfare, and educational challenges andpsychological distress in parents caring for anindividual with 22q11.2 deletion syndrome: A
cross-sectional survey in Japan. American Journalof Medical Genetics Part A. 2022 Jan;188(1):3745. doi: 10.1002/ajmg.a.62485. Epub 2021 Sep 3.
PMID: 34480405.
Kaji N, Ando S, Nishida A, Yamasaki S,
Kuwabara H, Kanehara A, Satomura Y, Jinde S,
Kano Y, Hiraiwa-Hasegawa M, Igarashi T, Kasai
K: Children with special health care needs andmothers' anxiety/depression: findings from theTokyo Teen Cohort study. Psychiatry Clin Neurosci.
2021 Dec; 75(12):394-400. doi: 10.1111/pcn.13301.
doi: 10.1111/pcn.13301. PMID: 34549856.

608

Office ofInternational Academic Affairs
HeadShinichi Sato

Assistant Professors
Keiko Nanishi
David Kipler
Florence Ene

Homepage: http://koryu.m.u-tokyo.ac.jp
Status and functions
The Office of International Academic Affairs(OIAA) is under the direct authority of the Dean of
the Faculty of Medicine. Its three most importantroles, as defined by the Committee on International
Academic Affairs, are facilitating 1) international
academic exchange, 2) international academic andresearch agreements, and 3) education and research
activities.

Activities
This report details the activities of the OIAA during
the 2021-22 academic year (1 April 2021 through 31
March 2022).
1. International Academic Exchange
1.1 Student guidance on education and research
The OIAA assists international students in applying
for various scholarships, and the OIAA on-campus
screening committee evaluates applicants forscholarships that require university recommendations.
To promote friendship among international students,
the OIAA organizes a get-together every spring at
Capo Pellicano, a restaurant in the Faculty of
Medicine
Experimental
Research
Building.
Unfortunately, the 2021-22 event was cancelled
because of the COVID-19 pandemic.

The OIAA oversees undergraduate clinical training(elective clerkships) for international students at the
University of Tokyo Hospital; however, border
restrictions in Japan forced many cancellation ofelective clerkships scheduled, resulting in only two
students being hosted in 2021-22.
1.2 Guidance on short-term and long-term overseas
study programs for medical students and researchersat the University of Tokyo
The OIAA provides guidance and information on
study abroad during the school year, prepares lettersof recommendation and other documents, andsupports communication with study-abroad partner
institutions. Of particular importance is assisting
fourth-year medical students with their elective
clerkships abroad.
As of March 2020, the University of Tokyo Facultyof Medicine has agreements for exchange programs—
which provide one to two months of clinicaltraining—with the University of Pennsylvania, Johns
Hopkins University, University of Michigan,
University of Hawaii, Seoul National University,
National Taiwan University, National University ofSingapore, Karolinska Institute and Ludwig
Maximilian University of Munich. The OIAA
nominates qualified students for each university andassists in their preparation for study abroad.

609

Although students were nominated for electives
scheduled for April through July 2021, the pandemic
caused the host institutions to cancel these electives;
only two students—those nominated for National
Taiwan University—could complete their elective.
1.3 Support for overseas training of graduates
The OIAA assists graduates in preparing documents
for applications to graduate schools and otherinstitutions abroad and in obtaining medical licensurein other countries. During 2021-22, the OIAA assisted
in preparing Medical Student Performance Evaluations for two applicants.
2. International Academic and Research
Agreements
During the 2021-22 academic year, theinterdepartmental agreement with the University of
Munich was renewed. We continued interaction withstrategic partnership universities such as the
University of Chicago and National Taiwan
University, including jointly hosting workshops
online, which was possible during the COVID-19
pandemic.
3. Education and Research Activities
Dr. Florence Ene supervised and taught the Medical
English I/II courses.
David Kipler trained graduate and undergraduate
students in writing research articles and making oralpresentations in English.
Dr. Keiko Nanishi served as a lecturer in the Schoolof International Health, where she supervised
graduate students and conducted research oninternational health.

Publications
1.

2.

Nanishi K, Green J, Hongo H. Development of
the breastfeeding support scale to measure
breastfeeding support from lay and professional
persons, and its predictive validity in Japan.
PeerJ. 2021 Jul 27;9:e11779.
Shibanuma A, Ansah EK, Kikuchi K, Yeji F,
Okawa S, Tawiah C, Nanishi K, Addei S,
Williams J, Asante KP, Oduro A, Owusu-Agyei S,
Gyapong M, Asare GQ, Yasuoka J, Hodgson A,

3.

4.

5.

Jimba M; Ghana EMBRACE Implementation
Research Project Team. Evaluation of a packageof continuum of care interventions for improved
maternal, newborn, and child health outcomesand service coverage in Ghana: A clusterrandomized trial. PLoS Med. 2021 Jun 25;18(6):e1003663.
Kikuchi K, Gyapong M, Shibanuma A, Asah E,
Okawa S, Addei S, Nanishi K, Tawiah C,
Yasuoka J, Yeji F, Oduro A, Owusu-Agyei S,
Quansah-Asare G, Hodgson A, Jimba M; Ghana
EMBRACE Implementation Research Team.
EMBRACE intervention to improve thecontinuum of care in maternal and newborn
health in Ghana: The RE-AIM framework-based
evaluation. J Glob Health. 2021 Mar 27;11:04017.
Binns CW, Lee MK, Maycock B, Torheim LE,
Nanishi K, Duong DTT. Climate Change, Food
Supply, and Dietary Guidelines. Annu Rev Public
Health. 2021 Apr 1;42:233-255.
Nanishi K, Hongo H, Tada K. Does giving infant
formula to prevent cow's milk allergy hinder
breast-feeding? J Allergy Clin Immunol. 2021
Mar;147(3):1118.

610

MD Scientist Training Program
Professor and Director
Kenzo Hirose, M.D., Ph.D.

Assistant Professor
Yuki Sugaya, M.D., Ph.D.
Takeshi Sawada, M.D., Ph.D.

Project Assistant Professor
Yoshitaka Kurikawa, M.D., Ph.D.

Homepage

http://www.ut-mdres.umin.jp/ (in Japanese)

Introduction and Organization
The MD Scientist Training Program (MDSTP) was
founded in 2008 to achieve the goal of systematicallyproviding an intensive basic medical research training
framework to the next generation of MD scientists
during their MD training at the School of Medicine,
The University of Tokyo. Capitalizing on the advances
made by launching a reliable and sustainable program
through the leadership of its first directors, Prof.
Shigeo Okabe (2008-2010), Prof. Masahide Kikkawa(2011-2014), and Prof. Haruhiko Bito (2015-2020),
the Program currently consists of its director Prof.
Kenzo Hirose and 3 staff members, Yuki Sugaya(assistant professor), Takeshi Sawada (assistantprofessor) and Yoshitaka Kurikawa (project assistantprofessor), and over 100 students who are seeking
extracurricular basic medical research training throughthe Program’s framework. With the help of two
assistants for clerical work, it provides a variety of
support programs to assist the research activities of
medical students. From 2011 on, the MDSTP at the
University of Tokyo has cooperated with its sister
programs at Kyoto University, Osaka University andNagoya University.
The number of the enrolled students during the launchyear (2008) of the MDSTP was 6. Since then, theProgram has expanded and now enrolls about 100

students (during Year 3 to 6 of the Medical School). A
sizable number of students write research honors
theses during their final year, which they defend to
become certificated as MDSTP graduates. The numberof research publications in scientific journal or awards
at international scientific meetings, which resulted
from these theses, is growing.

Achieving basic medical researchtraining in parallel with medical
education
The Program offers a platform of activities aimed atproviding an early exposure to basic medical researchand to basic skills required for achieving leadership inacademic medicine.
During the first 2 years after the entrance to the
University of Tokyo, we initially organize a lecture
series entitled ‘Introduction to Medical Biology’. In
this lecture series, top researchers of various fields at
the University of Tokyo provide exciting but
intelligible talks to students with little medical
knowledge. This helps students to get introduced
various research subjects in various fields of medical
research and strongly motivate them to find bythemselves a laboratory suitable to their aspirations.
Furthermore, we offer an opportunity to read the
textbook ‘Molecular Biology of the Cell’ in English,

611

in a small group setting, to get an exposure toscientific English, and to be formally introduced tobasic molecular and cellular biology, the foundation ofcurrent medical research.

Therefore, 8 fellows studied cutting-edge medical carein domestic hospitals instead. One fellow gained
invaluable experience as a student clinical clerk in auniversity hospital in Taiwan.

From Year 3 on, as the students choose the labs andprincipal investigators with whom to do science with,
the Program organizes journal clubs for basic medical
research and courses of medical researchcommunications are held every 2 weeks. In the journalclub, students are trained to critically read recent
scientific papers published in top journals, often in thepresence of the first authors, if they are available. In
medical research communications courses, thestudents discuss scientific topics and research issues
with a native English speaker with a strong researchbackground.

2) Organizing an MD scientist training program
retreat
A MDSTP retreat was held on February 2 and 13,2022 at Tetsumon Memorial Hole to present ongoing
research progress in a closed meeting among peers.
More than 50 participants, mostly medical school
students, but also some medical interns, graduate
students and Program-affiliated professors attended it.
Lively discussions among peers were exciting
throughout the meeting and the feedback from allparticipants was outstanding and unequivocal inemphasizing the critical importance for a research
progress retreat to promote their future research
projects. One important aspect of the retreat was toprovide students, interns, and professors to discuss
opportunities in various career paths available in thebasic medical research field.

Students who have shown their research abilities arehighly recommended to write their honors researchtheses by the end of the summer of Year 6. After
successfully defending their theses, they are certified
as qualified MDSTP trainee and, as such, they become
eligible for an exemption of a part of an entrance
examination for the Graduate School of Medicine. The
Dean’s Prize is awarded to the best thesis.

Enhancing awareness andproviding opportunities forexcellence in basic medical
research
1) Providing assistance for research and clinicalexperience in foreign laboratories and hospitals
We encourage students to plan and seek for basic
medical research experience in other countries during
their MD training. Based on research proposals
submitted to the Program, travel supports are provided
on a competitive basis. However, in 2021, thepandemic of COVID-19 prevented students fromdoing research abroad. Instead, 9 students participatedin international and domestic online conferences topresent their research. We also support exposure toclinical training in foreign hospitals with the Osamu
Otsubo Tetsumon Fellowship. Unfortunately, due tothe COVID-19 pandemic in the destination country,
most of the students were not able to travel abroad.

3) Cooperating with other medical universities acrossJapan
With the availability of governmental support from2011 to 2020, the MDSTP at the University of Tokyo
has been in close touch with sister organizations at
Kyoto University, Osaka University and Nagoya
University. With a view to enhancing collaborative
efforts in improving the basic medical researchtraining at the 4 medical schools, joint retreats were
held to promote communication and networking
among the medical students with research minds. The
previous retreat was held in Nagoya in 2019, at theoccasion of the Japan Medical Congress. More than90 people including medical school students andteachers from all over Japan participated in this retreat
and enthusiastically discussed about their research andfuture career as researchers. From 2021, a newpartnership of the four universities, the MD Scientist
Training Initiative, has been launched with the aim ofworking more closely together than ever before,
including lab tours and research exchanges.
The MSDTP also currently cooperates with 11 otheruniversities in eastern Japan to organize annual

612

research students’ retreats. In 2021, the annual
summer retreat was held online under the auspices of
Yokohama City University. More than 90 people
participated in the retreat and presented their ongoing
research progress and plans.

Activities (2021)
The number of registered students: 150 (3rd and 4th
grade: 73, 5th and 6th: 77)
Lectures for students in Years 1 and 2
Introduction to Medical Biology: 13 lectures
Group reading of Molecular Biology of the Cell: 13
lectures
Seminar for students (in Year 3 or above)
Journal Club for basic medical research: 5 lectures
Medical Research Communications: 62 lectures
Presentation of research progress: 2 (the retreat of MD
scientist training program in the University of Tokyoand the annual research students’ retreats with
universities in eastern Japan)
The number of students receiving travel supports forresearch: 9 (including support for international anddomestic online conference)
The number of students receiving Osamu Otsubo
Tetsumon Fellowship: 9
The number of Year 6 students who passed theirhonors thesis defense: 2 (the Dean’s Prize and theSatoshi Arima memorial fellowship were awarded to 2
and 1 student, respectively)613

Museum of Health and Medicine
Director
Kazuhiko Ohe

Associate
Atsushi Kitade

Homepage

http://mhm.m.u-tokyo.ac.jp/

History and overview
The origins of the School of Medicine and the
University of Tokyo Hospital can be traced back to theestablishment of the Kanda Otamaga-Ike Vaccination
Center in 1858. In 2008, it celebrated its 150th
anniversary. The Museum of Health and Medicine wasplanned as part of commemorative projects tocelebrate the 150th anniversary of the founding of the
School and the Hospital, and was opened on January
20, 2011. One of the themes for the commemorative
projects marking the 150th anniversary was the“development of communication between healthscience and care and society,” and the Museum of
Health and Medicine forms one of the pillars of this.
In establishing the Museum of Health andMedicine, we renovated the School of Medicine’s
Central Building (Medical Library), which hadoriginally been instituted as part of thecommemorative projects celebrating the 100th
anniversary of the founding of the School and the
Hospital. The Museum has about 400m2 areas,
including about 70m2 of a permanent gallery and230m2 of special exhibition rooms.
The aims of the Museum are to: (1) provide healthand medical information to the public, (2) educate
students studying medicine, health care services andrelated areas, (3) research the history of medicine andhealth care through archives, instruments andtechnology, and (4) preserve and investigate valuable
medical archives and instruments, etc.
In addition to the permanent gallery exhibiting
accomplishments related to the School and the
Hospital and its contributions made to modern andcontemporary development in Japan, a feature of theexhibitions is that a large space has also been set aside
for special exhibitions to promote understanding
among the public regarding the latest advances inmedical science and health care. Planning andsupervision of the permanent exhibition and special
exhibition is done with the cooperation of the various
research units within the School and the Hospital,
other departments within the University, industry, andmuseums. Special exhibitions will be changed several
times a year.
The first permanent exhibition since the openingof the Museum was a display of medical texts andinstruments from the early Meiji era, an Ishihara’s
Color Blind Test Chart and a gastroscope developed at
the University. The first special exhibition was related
to the beginnings of the School and the Hospital,
Entitled “the Challenge to Infectious Diseases”. It
introduced the history of vaccinations against
smallpox, research into infectious diseases conductedin the University and by its graduates since the Meiji
era (1868-1912), and the latest knowledge about
infectious diseases. The second was “the Secret of
Vessel System”, which introduced the circulatory
system. The third “diagnosis of cancer”, the fourth“Our brain”, the fifth “Locomotive syndrome”, thesixth “Diabetes Mellitus”, the seventh "Pediatrics",
the eighth "Forensic Medicine”, the ninth “the Colon”
followed, the tenth “Virus”, the eleventh “Kidney”
and the special exhibition “Mental Diseases”.
In April 2019, we reopened our museum in theSouth Clinical Research Building of The University ofTokyo Hospital.

614

Since the opening of the Museum, more than143,701 people had visited by the end of FY2019.
Since Mar. 2020, our museum has been temporarilyclosed due to COVID-19 pandemic

Overview of operations
The opening hours are 10:00-17:00. The Museum
is closed every Wednesday and during the New Yearholidays (however, it will open if Wednesday is a
public holiday). Admission is free.

615

Office for Human Research Studies(OHRS)
Director of OHRS ( Professor / Vice Dean)
Masaomi Nangaku, M.D., Ph.D.

Vice Director of OHRS ( Professor )Akira Akabayashi, M.D., Ph.D.

Vice Director of OHRS ( Associate Professor )Yuzaburo Uetake, M.D., Ph.D.

Homepage: http://www.m.u-tokyo.ac.jp/ethics/ethcom/gakugai2/index.html
http://www.u-tokyo-ohrs.jp/
Top page of online application system: https://u-tokyo.bvits.com/esct/
Introduction and Organization
The Office for Human Research Studies (OHRS) wasestablished in October 2009 for the advancement ofresearch ethics standards. OHRS aims to protect therights, health, and dignity of research participants.
Based on this principle, OHRS is providing research
ethics support services to researchers at Graduate
School of Medicine and Faculty of Medicine, theUniversity of Tokyo and the University of Tokyo
Hospital to enable them to better perform their studies
in an ethical manner. Our primary task is the management of the Ethics Committee secretariat. Additionally,
OHRS plans and manages research ethics seminars,
provides ethics education to researchers throughconsultation and develops human resources for future
research ethics specialists.

Activities
・Management of Ethics Committee
・Prior review of research activity documents (except
for clinical trial, GCP), at Graduate School of
Medicine and Faculty of Medicine, the University ofTokyo and the University of Tokyo Hospital.
Correspond in response to various research ethics
inquiries.

・Coordination of various matters with Ethics
Committee members, and other similar bodies anduniversities.
・New clinical documentary examinations inconnection with,-Medical treatments to implemented for the firsttime at the University of Tokyo Hospital,-Examination of the clinical use of the unapproved
medicines and medical devices,・ Preparation and maintenance of the organ transplantation manuals for the liver, kidney and hearttransplants.
◇ Specific items reviewed and examined by each
Ethics Committee in fiscal year 2021
・Research Ethics Committee (except for clinical
trial, GCP):
350 new applications, 1137 minor alterations ofapproved studies
・Clinical Research Review Board:174
・New clinical documentary examinations: 99

616

Research activities
At present, OHRS is a business section. For more
information about the research, see the contents of
Department of Biomedical ethics, which is acooperative department.

Though OHRS adopts various inclusive applications,the number of studies applied to and reviewed by ethics
committees over the last several years is on the increase.
The management duties of the Ethics Committee
secretariats are complicated and diversified, making it
difficult to be able provide adequate services toappropriately respond to such increasing needs.
OHRS operates an online application system andcontributes to the convenience of applicants and toenable them to efficiently plan their researchobligations.

Teaching and training activities
OHRS plans and manages research ethics seminars
with Department of Clinical Research Governance inthe University of Tokyo Hospital.
We provide a broad outline overview regarding ethics
education aimed generally for all researchers andstudents who are engaged in clinical studies throughsuch seminars. The ethics seminars were held monthly
in fiscal year 2021 with 3255 people attended.
OHRS makes efforts to educate researchers through its
research ethics support services. Additionally, the skill
development and support of the secretariat staff is oneof our important tasks.
OHRS also aims to advance research ethics standards
by cooperating and consulting with Ethics Consultant
specified by each laboratory.

617

The Office for Clinical Practice andMedical Education
Professor
Masato Eto, M.D., Ph.D.

Research Associate
Shoko Horita, M.D., Ph.D.

Homepagehttps://igaku-kyoiku.m.u-tokyo.ac.jp/training.html

Introduction and Organization
The Office for Clinical Practice and Medical Education
was established in April 2015, to support and promote
medical education, especially clinical practice at grade
5 and 6. The office used to be the Clinical ClerkshipSupport Center, which was established to meet thechange from bedside learning to clinical clerkship in
February 2013. Our aim is to run the clinical clerkship(CC) smoothly, as well as to improve the curriculumand evaluation methods in cooperation with teachersand students. In addition, we try to support each student
in cooperation with tutors, the instruction department
and the office for student assistance in the faculty of
medicine. The Information and Communication
Technology (ICT) system has launched in January 2018,
which greatly improved the efficiency of clerical works.
The office now consists of a general manager(professor), a research associate, and three staffs.

Activities
Before the CC begins in January for 4th grade medical
students, we have a meeting to explain the details to thestudents, and then make a schedule of the CC based on
the questionnaire. Just before the CC starts, we hold aceremony to name students that passed OSCE and CBTexaminations as “student doctors”, which the dean andthe chair of the academic affairs committee of the
medical faculty of The University of Tokyo, and the
director and the chief nursing officer of The Universityof Tokyo Hospital attend.

After the CC starts, we support students,
teachers and the external cooperative institutions to run
the clerkship smoothly, by making necessary contacts
with them. In addition, we handle with problems andconsiderations occurred during the practice if needed.
Particularly, we manage and support students who needhelps, with the instruction department, tutors, and theoffice for student assistance in the faculty of medicine.
The new ICT system permits the evaluations of thestudents in the CC to be revealed real-time, hence thestudents are able to look their scores, at the earliest on
the final day of each practice.
Twice a year, we hold a meeting with teachers
who are in charge of the CC. In this meeting, we
provide teachers the feedbacks about the practice fromstudents, and exchange the information and opinions
among the teachers, thus improving the CC. On theother hand, we have opportunities with students(working group on medical education), to discuss theCC and try to respond to comments from them.

Educations
Together with the IRCME department of medical
education studies, we take charge of “medical practice:the introduction” for 4th grade students and “tutorial
PBL” for 2th grade students, teaching medical
interview, physical examination and medical
professionalism. We also take charge of tutorials andindividual consultations related to the CC.

618

Research activities“Research of the coherence between the students’ daily
life and psychological conditions, and the outcome at
the graduation” is being conducted. The results werereleased in the domestic and international conferencesof medical education in 2018 and 2019, and published
for an international paper in 2021. Presently thisresearch is being conducted in multiple institutional
investigation. Moreover, “Research of the effect of
online medical interview trainings” is being conducted.