ISSN 1883-9606

2021

Vol.143

ANNUAL REPORT OF
THE GRADUATE SCHOOL OF MEDICINEAND
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2020 ---- March 2021

ANNUAL REPORT OF THE GRADUATE SCHOOL OF
MEDICINE
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2020-March 2021

Introduction
This is volume 143(the edition of year 2021) 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, 2021

i

CONTENTS
Introduction
History
Organization Chart
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 ·········································································

11

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

12

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 ····································································································

36

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

37

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

39

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

43

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

44

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

48

ii

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

51

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

52

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

55

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

58

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

59

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

64

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

65

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

71

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

72

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

76

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

79

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

82

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

85

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

86

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

89

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

95

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

96

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

99

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

100

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

105

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

111

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

116

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

117

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

121

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

126

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

127

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

130

iii

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

133

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

134

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

138

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

142

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

148

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

149

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

154

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

160

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

163

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

166

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

169

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

172

Department of Clinical Laboratory Medicine (See Department of Clinical Laboratory [P.455] )Department of Transfusion Medicine ·········································································

173

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

176

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

177

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

180

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

182

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

184

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

186

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

187

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

193

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

198

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

199

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

204

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

205

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

210

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

215

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

218

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

222

iv

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

228

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

233

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

237

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

239

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

240

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

243

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

247

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

252

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

261

Department of Otorhinolaryngology and Head and Neck Surgery ········································

264

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

268

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

271

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

272

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

276

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

280

Department of Health Sociology(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.358] )Department of Mental Health ··················································································

281

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

285

Department of Social Gerontology(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.358] )Department of Biomedical Ethics & Department of Health Promotion Sciences ·······················

289

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

292

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

293

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

297

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

300

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

303

Department of Gerontological Home Care and Long-term Care Nursing/Palliative Care Nursing ···304

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

308

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

311

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

315

v

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

323

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

324

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

327

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

330

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

331

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

333

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

335

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

339

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

342

Department of Biostatistics(See Department of Biostatistics / Epidemiology and Preventive Health Sciences [P.285] )Department of Social and Preventive Epidemiology ························································

343

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

346

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

354

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

357

Department of Mental Health (See Department of Mental Health [P.281] )Department of Health Sociology and Health Education(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.358] )Departments of Health and Social Behavior & Health Education and Health Sociology ···············

358

Department of Biomedical Ethics & Department of Health Promotion Sciences(See Department of Biomedical Ethics & Department of Health Promotion Sciences [P.289] )3. Health Services Sciences ·························································································

362

Department of Health Policy(See Department of Public Health / Department of Health Policy [P.121] )Department of Healthcare Informatics (See Department of Biomedical Informatics [P.130] )Department of Clinical Information Engineering ····························································

363

Department of Forensic Medicine and Medical Law(See Department of Forensic Medicine [P.127] )Department of Global Environmental Health ································································

365

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

367

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

368

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

370

vi

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

373

Science for joint reconstruction (See Department of Orthopaedic Surgery [P.252] )Department of Bone & Cartilage Regenerative Medicine(See Central Clinical Facilities Division of Tissue Engineering [P.527] )Department of Osteoimmunology ··············································································

376

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

380

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

383

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

385

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

389

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

394

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

398

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

400

Department of Medical and pharmaceutical community Healthcare ·······································

402

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

406

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

407

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

411

Department of Ubiquitous Preventive Medicine ·····························································

416

Department of Clinical Trial Data Management ·····························································

418

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

421

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

422

Department of Imaging Nursing Science ·······································································

425

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

428

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

431

Department of Skincare Science ···············································································

433

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

436

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

438

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

441

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

445

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

448

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

451

University Hospital
Clinical Divisions ····································································································
Internal Medicine
Cardiovascular Medicine (See Department of Cardiovascular Medicine [P.134] )Respiratory Medicine (See Department of Respiratory Medicine [P.138] )

453

vii

Gastroenterology (See Department of Gastroenterology [P.142] )Nephrology and Endocrinology (See Department of Nephrology and Endocrinology [P.149] )Diabetes and Metabolic Diseases (See Department of Diabetes and Metabolic Diseases [P.154] )Hematology and Oncology (See Department of Hematology and Oncology [P.160] )Allergy and Rheumatology (See Department of Allergy and Rheumatology [P.163] )Infectious Diseases (See Department of Infectious Diseases (Internal Medicine) [P.166] )Neurology (See Department of Neurology [P.105] )Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research [P.199] )Psychosomatic Medicine(See Department of Stress Science and Psychosomatic Medicine [P.169] )Surgery
Stomach and Esophageal Surgery (See Department of Gastrointestinal Surgery [P.215] )Colon and Rectal Surgery (See Department of Surgical Oncology [P.228] )Hepatobiliary Pancreatic Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation
Division [P.218] )Vascular Surgery (See Department of Vascular Surgery [P.233] )Breast and Endocrine Surgery(See Department of Metabolic Care and Endocrine Surgery [P.237] )Artificial Organ and Transplantation Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation
Division [P.218] )Cardiovascular Surgery (See Department of Cardiac Surgery [P.210] )Thoracic Surgery (See Department of Thoracic Surgery [P.205] )Neurosurgery (See Department of Neurosurgery [P.111] )Anesthesiology and Pain Relief Center (See Department of Anesthesiology [P.272] )Urology and Andrology (See Department of Urology [P.222] )Gynecologic Surgery (See Obstetrics and Gynecology [P.176] )Sensory and Motor System Medicine
Dermatology (See Department of Dermatology [P.240] )Ophthalmology (See Department of Ophthalmology [P.261] )Orthopaedic Surgery and Spinal Surgery (See Department of Orthopaedic Surgery [P.252] )Otorhinolaryngology and Head and Neck Surgery(See Department of Otorhinolaryngology and Head & Neck Surgery [P.264] )Rehabilitation Medicine (See Department of Rehabilitation Medicine [P.268] )Plastic, Reconstructive and Aesthetic Surgery(See Department of Plastic and Reconstructive Surgery [P.243] )viii

Oral-Maxillofacial Surgery and Orhtodontics(See Department of Oral-Maxillofacial Surgery [P.247] )Pediatrics,Perinatal and Women’s Medicine
Pediatrics(See Department of Pediatrics, Department of Developmental Pediatrics [P.187] )Pediatrics Surgery (See Department of Pediatric Surgery [P.193] )Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of Gynecologic Oncology /Department of Perinatal Medicine [P.177/P.180/P.182] )Neuropsychiatry
Neuropsychiatry (See Department of Neuropsychiatry [P.100] )Radiology
Radiology (See Department of Radiology [P.65] )Acute Medicine
Acute Medicine (See Department of Acute Medicine [P.276] )Central Clinical Facilities ···························································································

454

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

455

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

460

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

463

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

465

Department of Transfusion Medicine and Immunohematology(See Department of Transfusion Medicine [P.173] )Rehabilitation Center ····························································································

470

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

473

Department of Intensive Care Unit (See Department of Acute Medicine [P.276] )Division of Diagnostic Pathology ··············································································

474

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

478

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

480

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

483

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

487

Department of Infection Control and Prevention(See Department of Infection Control and Prevention [P.55] )Department of Planning, Information, and Management(See Department of Biomedical Informatics [P.130] )University Hospital Medical Information Network (UMIN) Center ······································

491

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

494

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

496

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

500

ix

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

502

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

506

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

510

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

512

Department of Clinical Nutrition Therapy ····································································

513

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

518

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

520

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

527

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

532

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

538

Organization of Clinical Management
Immune-Mediated Diseases Therapy Center ··································································

540

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

542

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

544

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

546

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

547

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

549

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

553

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

555

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

560

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

565

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

567

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

570

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

573

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

574

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

575

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

577

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

584

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

586

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

589

x

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

591

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

593

The Tokyo Journal of Medical Sciences. Vol. 143, October 2021

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. 143, October 2021

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. 143, October 2021

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.

xiv

The Tokyo Journal of Medical Sciences. Vol. 143, October 2021

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

Collaborative Department

Cellular and Molecular Pharmacology
Systems Pharmacology
Brain Functional Dynamics
Pathology and Diagnostic Pathology

Pathology

Molecular Pathology
Surgical Pathology

Microbiology
Pathology, Immunology
and Microbiology
Immunology

Microbiology
Infection Control and Prevention
Immunology
Clinical Immunology
Infection Pathology

Collaborative Department

T umor 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. 143, October 2021

Preventive Medicine
Occupational, Environmental andPreventive Medicine

Public HealthRadiological HealthSocial Medicine

Forensic Medicine, and Medical
Informatics and Economics

Forensic Medicine
Medical Informatics
Cancer Control Policy and Research

Collaborative Department

Cancer Epidemiology
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
and Pathology
Collaborative Department

Clinical Laboratory Medicine
T ransfusion Medicine
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

Geriatrics
Aging Research
Health Policy for Children and Families

Collaborative Department
Medical Science for Life and Aging
T horacic Surgery
Cardiovascular Surgery
Gastrointestinal Surgery
Hepatobiliary Pancreatic Surgery
Surgery

Urology
Artificial Organ and T ransplantation
Division
Surgical Oncology
Vascular Surgery
Breast and Endocrine Surgery

xv

The Tokyo Journal of Medical Sciences. Vol. 143, October 2021

xvi

Surgical Sciences

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

Orthopaedic Surgery
Ophthalmology
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

Medical Science (Master’s Program)

Epidemiology and Health Sciences

Developmental Medical Sciences
Human Ecology
Biomedical Chemistry
Biostatistics
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

The Tokyo Journal of Medical Sciences. Vol. 143, October 2021

Healthcare Informatics
Health Services Sciences

Clinical Information Engineering
Forensic Medicine and Medical Law
Global Environmental Health

Collaborative Department

Public Health Science

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
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 T raining Program
Museum of Health and Medicine

Institution

Office for Human Research Studies
Office for Life Science Research Equipment
SupprtLife 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 andT herapeutics
Computational Diagnostic Radiology andPreventive Medicine
Department of Molecular Neurology
Clinical T rial Data Management
Ubiquitous Preventive Medicine
Science for Joint Reconstruction
Department of T herapeutic Strategy for Heart
FailureDepartment of Molecular Structure and Dynamics
Department of Home Care Medicine
Department of Advanced T ranslational Researchand Medicine in Management of Pulmonary
Hypertension
Department of Advanced Cardiology
Department of medical research andmanagement for musculoskeletal pain
Department of Osteoimmunology
Department of medical and pharmaceuticalcommunity healthcare
Health Economy and Society Policy
Departmento of Biostatics and Bioinformatics

xvii

xviiiThe Tokyo Journal of Medical Sciences. Vol. 143, October 2021
Laboratory for Advanced Research on
Pathophysiology of Metabolic Diseases
Artificial Intelligence in Healthcare
Department of Lipidomics
Social Cooperation
ProgramAdvanced Nursing T echnology
T issue 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 Office

Department of Prevention of Diabetes and Lifestyle Related Disease

Faculty of
Medicine
Graduate School of
Medicine

Research Support Office

Department of Next-Generation
Pathology Information Networking

Educational Affairs

Chronic kidney disease pathophysiology

Graduate Student Affairs

Administrative officeAcquisition Office Medical Library
Cataloging Office Medical Library

Administrative Division
Information Service Medical LibraryCenter for Disease Biology
and Integrative medicine
Cell Biology and Anatomy
Biochemistry and Molecular Biology
Physiology
Pharmacology
Pathology

School of Medicine
Faculty of
Medicine

Facilities Office

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

Administrative Office

The Tokyo Journal of Medical Sciences. Vol. 143, October 2021

xix

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
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 T ransplantation Surgery
Cardiothoracic Surgery
T horacic 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

xx

The Tokyo Journal of Medical Sciences. Vol. 143, October 2021

Obstetrics and Gynecology

Central ClinicalFacilities

Neuropsychiatry

NeuropsychiatryRadiology

Radiology

Acute Medicine

Acute Medicine

Pharmaceutical Department

Office of General Administration

Nursing Department

Office of Procurement andFacility Management

Administration Office

Office of Management Planning

Department of Clinical Laboratory

Office of Research Support

Surgical Center

Office of Medical Management

Radiology Center

Office of Medical Accounting

Department of Blood T ransfusion
Perinatal Center
Rehabilitation Center
Department of Medial Engineering
Central Supply Service
Intensive Care Unit
Pathology
Department of Corneal T ransplantation
Department of Cell T herapy andT ransplantation Medicine
Department of Endoscopy and Endoscopic
Surgery
Department of Hemodialysis and Apheresis
Infection Control and Prevention Service
Department of Healthcare Information
Management
University Hospital Medical Information
Network Center
Organ T ransplantation Center
Labor Safety and Health Management Office
Staff Wellness Consulting RoomChild Psychiatry
T issue 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

The Tokyo Journal of Medical Sciences. Vol. 143, October 2021

xxi

Clinical Research Promotion Center
22nd Century Medical and Research Center
Department of T issue Engineering
Clinical Research
Division

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

Medical Specialists T raining Center
Medical Support Center
Office of Performance Monitoring

Department of Performance Monitoring and
Risk Management
Organization ofClinical Management

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

Department of Education and Staff
Development

General Education Center
Hospitality Center

Department of Hospital Planning andManagement
Department of Research Support
Inpatient Services
Administration
Organization ofClinicalManagement

Outpatient Services
Administration
Central Clinical Services
Administration

Department of Clinical Research Governance
Admission and Discharge Center
Cancer Board
Vascular Board
Perioperative Assessment Center
Epilepsy Center
Immune-Mediated Diseases T herapy Center
SSc Center
Osteoporosis Center
Center for Female Pelvic Medicine
and Reconstructive Surgery
Spine Center
Hip Fracture Board
Palliative Care Consulation T eam
Nutrition Support T eam

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. 143, October 2021

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

Nobuhito Saito(Dean, Faculty of Medicine)
Chairman, School of Health Sciences and Nursing

Noriko Yamamoto

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

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

Department of Radiology

Professor

Osamu Abe

Department of Biomedical Engineering

Professor

Kiyoshi Miyagawa

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

The Tokyo Journal of Medical Sciences. Vol. 143, October 2021

xxiii

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

Kazuhiko koike

Professor

Masaomi Nangaku

Professor

Toshimasa Yamauchi

Professor

Mineo Kurokawa

Professor

Keishi Fujio

Professor

Kyoji Moriya

Professor

Yutaka Yatomi

Professor

Hitoshi Okazaki

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 Obstetrics and Gynecology

Professor
Professor

Yutaka Osuga

Department of Pediatric Science

Professor

Motohiro Kato

Department of Pediatric Surgery

Professor

Jun Fujishiro

Department of Aging Science

Professor

Masahiro Akishita

Professor

Jun Nakajima

Professor

Minoru Ono

Professor

Yasuyuki Seto

Professor

Kiyoshi Hasegawa

Professor

Haruki Kume

Professor

Soichiro Ishihara

Professor

Shinichi Sato

Surgical Sciences
Department of Surgery

Department of Sensory and Motor System Medicine

xxiv

The Tokyo Journal of Medical Sciences. Vol. 143, October 2021

Department of Vital Care Medicine

Professor

Mutsumi Okazaki

Professor

Kazuto Hoshi

Professor

Sakae Tanaka

Professor

Makoto Aihara

Professor

Tatsuya Yamasoba

Professor

Nobuhiko Haga

Professor

Kanji Uchida

Professor

Naoto Morimura

Professor

Norito Kawakami

Professor

Yutaka Matsuyama

Professor

Hideki Hashimoto

Professor

Akira Akabayashi

Professor

Kiyoko Kamibeppu

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

Masashi Mizuguchi

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. 143, October 2021

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 Environmental and Metabolic Health Sciences

Professor

Makoto MurakamiLaboratory of Animal Resources

Professor

Atsu Aiba

Laboratory of Molecular Radiology

Professor

Kiyoshi Miyagawa

International Research Center for Medical Education

Professor

Masato Eto

Global Nursing Research Center

Professor

Hiromi Sanada

Medical LibraryProfessor

Hideo Yasunaga

International Academic Affairs

Professor

Shinichi Sato

Medical Scientist Training Program

Professor

Haruhiko Bito

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

Endowed Departments
Artificial Intelligence in Healthcare

Project Associate professor

Yoshimasa Kawazoe

Department of Bone & Cartilage Regenerative Medicine

Project Associate professor

Fumiko Yano

Cell & Tissue Engineering (Fujisoft)

Project Associate professor

Atsuhiko Hikita

Immunotherapeutics

Project Professor

Kazuhiro Kakimi

Department of Advanced Clinical Science andProject Associate professor

Mutsuo Harada

Project Professor

Naoto Hayashi

Ubiquitous Preventive Medicine

Project Associate professor

Yuichi Ikeda

Science for joint reconstruction

Project Associate professor

Toru Moro

Therapeutic Strategy for Heart Failure

Project Associate professor

Masaru Hatano

Department of Molecular Structure and Dynamics

Project Professor

Nobutaka Hirokawa

Department of Advanced Translational Research andProject Associate professor

Haruhiro Toko

Project Professor

Koh Matsudaira

Department of Osteoimmunology

Project Associate professor

Kazuo Okamoto

Department of medical and pharmaceutical community

Project Professor

Hirohisa Imai

Project Professor

Tomoyuki Takura

Therapeutics
Computational Diagnostic Radiology and Preventive
Medicine

Medicine in Management of Pulmonary Hypertension
Department of medical research and management formusculoskeletal pain

healthcare
Health Economy and Society Policy

xxvi

The Tokyo Journal of Medical Sciences. Vol. 143, October 2021

Department of Biostatistics and Bioinformatics

Project Professor

Daisuke Koide

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

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

Department of Healthcare Quality Assessment

Project Professor

Hiroaki Miyata

Department of Innovative Dementia Prevention

Project Associate professor

Tadafumi Hashimoto

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 Yoshimuraof Metabolic Diseases

Social Cooperation Program

Networking
Department of Prevention of Diabetes andLifestyle-Related Diseases

Immunological Diseases

SystemOrgan Disorders
University Hospital
Clinical Divisions
General Medicine

Head

Issei Komuro

Cardiovascular Medicine

Head

Issei Komuro

Respiratory Medicine

Head

Takahide Nagase

Gastroenterology

Head

Kazuhiko Koike

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

The Tokyo Journal of Medical Sciences. Vol. 143, October 2021

xxvii

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

Nobuhiko Haga

Plastic, Reconstructive and Aesthetic Surgery

Head

Mutsumi Okazaki

Oral-Maxillofacial Surgery and Orthodontics

Head

Kazuto Hoshi

Pediatrics

Head

Naoto Takahashi

Pediatric Surgery

Head

Jun Fujishiro

Obstetrics and Gynecology

Head

Yutaka Ohsuga

Neuropsychiatry

Head

Kiyoto Kasai

Radiology

Head

Osamu Abe

Acute Medicine

Head

Naoto Morimura

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

Nobuhiko Haga

Department of Medical Engineering

Head

Kento Doi

Central Clinical Facilites

xxviii

The Tokyo Journal of Medical Sciences. Vol. 143, October 2021

Central Supply Service

Head

Kazuhiko Fukatsu

Intensive Care Unit

Head

Naoto Morimura

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 Center

Head

Naoto Morimura

Department of Pain and Palliative Medicine

Head

Masahiko SumitaniChildren’s Medical Center

Head

Naoto Takahashi

Department of Disaster Medical Management

Head

Naoto MorimuraInternational 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

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.

Fujioka Y, Alam JM, Noshiro D, Mouri K, Ando
T, Okada Y, May AI, Knorr RL, Suzuki K,
Ohsumi Y, Noda NN. Phase separation organizes

3

2.

3.

4.

5.

6.

the site of autophagosome formation., Nature
578: 301-305, 2020
Nagao Y, Sakamoto M, Chinen T, Okada Y,
Takao D. Robust classification of cell cycle phaseand biological feature extraction by image-based
deep-learning. Mol Biol Cell 31: 1346-1354,
2020
Yamamoto N and Okada Y, ed. Single Molecule
Microscopy in Neurobiology, Springer 2020,
ISBN: 978-0716-0531-8
Kondratiev AY, Yaginuma H, Okada Y, Krylov
AS, and Sorokin DV. A method for automatic
tracking of cell nuclei with weakly-supervised
mitosis detection in 2D microscopy image
sequences. Proceedings of the 2020 5thInternational Conference on Biomedical Signal
and Image Processing. Association for
Computing Machinery, New York, NY, USA,67–73. 2020
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
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

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

Project Research Associate
Akihisa Tsutsumi, Ph. D

Homepage

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

Introduction and Organization

Teaching activities

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.

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

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, Koichiro Yamashita, Yuma Tani, andYuqing Liue (graduate students), Yuta Komori, andUeno Risa (MSTP students), Akiko Oosakaya,
Sakamaki Yoichi, and Toshie Furuya (technicalassistant), Kazuhiro Nakamura (Advanced Academic
Specialist), and Mikako Yanagiuchi and Setsuko Yuge
(assistant clerk).

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.

5

Cryo-electron microscopy and cryo-electron
tomography
One of our strength is in the high-resolution
cryo-electron microscopy (cryo-EM). This techniqueenables preserving biological samples by quickly
freezing them and observing the frozen samples
without staining. Using electron microscopy, we areable
toobtainnano-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.

3.

4.

5.

6.

7.

8.

References
1.

2.

M. Ueda, T. Aoki, T. Akiyama, T. Nakamuro, K.
Yamashita, H. Yanagisawa, O. Nureki, M.
Kikkawa, E. Nakamura, T. Aida, and Y. Itoh.
Alternating
Heterochiral
Supramolecular
Copolymerization. J Am Chem Soc, 2021.
R. Sekine, P. Ravat, H. Yanagisawa, C. Liu, M.
Kikkawa, K. Harano, and E. Nakamura. Nanoand Microspheres Containing Inorganic andBiological Nanoparticles: Self-Assembly andElectron Tomographic Analysis. J Am Chem Soc,

143(7):2822–2828, 2021.
H. Takeda, A. Tsutsumi, T. Nishizawa, C. Lindau,
J. V. Busto, L. S. Wenz, L. Ellenrieder, K. Imai, S.
P. Straub, W. Mossmann, J. Qiu, Y. Yamamori, K.
Tomii, J. Suzuki, T. Murata, S. Ogasawara, O.
Nureki, T. Becker, N. Pfanner, N. Wiedemann, M.
Kikkawa, and T. Endo. Mitochondrial sorting
and assembly machinery operates by beta-barrel
switching. Nature, 2021.
K. Matoba, T. Kotani, A. Tsutsumi, T. Tsuji, T.
Mori, D. Noshiro, Y. Sugita, N. Nomura, S. Iwata,
Y. Ohsumi, T. Fujimoto, H. Nakatogawa, M.
Kikkawa, and N. N. Noda. Atg9 is a lipid
scramblase that mediates autophagosomal
membrane expansion. Nat Struct Mol Biol, 2020.
H. Lu, T. Nakamuro, K. Yamashita, H.
Yanagisawa, O. Nureki, M. Kikkawa, H. Gao, J.
Tian, R. Shang, and E. Nakamura. B/N-Doped
p-Arylenevinylene Chromophores: Synthesis,
Properties,
andMicrocrystal
Electron
Crystallographic Study. J Am Chem Soc,
142(44):18990–18996, 2020.
S. Tojo, Z. Zhang, H. Matsui, M. Tahara, M.
Ikeguchi, M. Kochi, M. Kamada, H. Shigematsu,
A. Tsutsumi, N. Adachi, T. Shibata, M.
Yamamoto, M. Kikkawa, T. Senda, Y. Isobe, U.
Ohto, and T. Shimizu. Structural analysis reveals
TLR7 dynamics underlying antagonism. Nat
Commun, 11(1):5204, 2020.
Y. Zhang, M. Inoue, A. Tsutsumi, S. Watanabe, T.
Nishizawa, K. Nagata, M. Kikkawa, and K.
Inaba. Cryo-EM structures of SERCA2b reveal
the mechanism of regulation by the luminal
extension tail. Sci Adv, 6(33):eabb0147, 2020.
R. Nakamura, T. Numata, G. Kasuya, T.
Yokoyama, T. Nishizawa, T. Kusakizako, T. Kato,
T. Hagino, N. Dohmae, M. Inoue, K. Watanabe,
H. Ichijo, M. Kikkawa, M. Shirouzu, T. J.
Jentsch, R. Ishitani, Y. Okada, and O. Nureki.
Cryo-EM structure of the volume-regulated anion
channel LRRC8D isoform identifies features
important for substrate permeation. Commun Biol,3(1):240, 2020.

6

Department of Cytoarchitectonics
Lecturer
Yosuke Tanaka, M. D.

Research Associate
Tadayuki Ogawa, Ph. D.

Home page

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

Teaching activities
Our teaching responsibility is following.
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.

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,
cryoelectron microscopy at atomic resolution, andcryoultramicrotomy,
biochemistry,
immunocyto-chemistry, 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.

7

References
1.

2.

3.

Iwata S., Morikawa M., Takei, Y., and N.
Hirokawa. An activity-dependent local transport
regulation via degradation and synthesis of
KIF17 underlying cognitive flexibility. Science
Advances 2020 6: eabc8355
Yoshihara S., Jiang X., Morikawa M., 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 compaensating KIF3-based
CRMP2 transport. Cell Rep 35: 108971, April 13,
1-15, 2021
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. in press
2021

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 26 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.

6.

7.

Iwasaki, K., Obashi, K., S. Okabe, S.
Vasodilator-stimulated phosphoprotein (VASP) is
recruited into dendritic spines via G-actindependent mechanism and contributes to spine
enlargement and stabilization. European Journalof Neuroscience 2020 51(3):806-821. doi: 10.
1111/ejn.14634.
International Brain Initiative: An innovative
framework for coordinated global brain research
efforts. International Brain Initiative (J. Bjaalie
and S. Okabe corresponding authors) Neuron
2020 105(2):212-216. doi: 10.1016/j.neuron.2020.
01.002.
Tanaka S, Masuda Y, Harada A, Okabe, S.
Impaired actin dynamics and suppression of
Shank2-mediated spine enlargement in cortactin
knockout mice. Microscopy (Oxf). 2020 69(1):44-52. doi: 10.1093/jmicro/dfaa001.
Iguchi, R., Tanaka, S., Okabe. S. Neonatal social
isolation increases the proportion of theimmature spines in the layer 2/3 pyramidal
neurons of the somatosensory
cortex.
Neuroscience Research 2020 154:27-34. doi:
10.1016/j.neures.2019.05.004.
Okabe, S. Recent advances in computational
methods for measurement of dendritic spines
imaged by light microscopy Microscopy (Oxf).
2020 69(4):196-213. doi: 10.1093/jmicro/dfaa
016..
Parajuli, L. K., Urakubo, H., Takahashi-Nakazato,
A., Ogelman, R., Iwasaki, H.,Oh W., H., Koike,
M., Kwon, H. B., Ishii, S., Fukazawa, Y., Okabe,
S. Geometry and the organizational principle ofspine synapses along a dendrite. eNeuro 2020
7(6):ENEURO.0248-20.2020. doi: 10.1523/
ENEURO.0248-20.2020.
Okabe, S. Regulation of actin dynamics indendritic spines: nanostructure, molecularmobility, and signaling mechanisms. Molecular

and Cellular Neuroscience 2020 109:103564.
doi: 10.1016/j.mcn.2020.103564.
8. 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.
9. Obashi, K, Taraska, J. W., Okabe, S. The role ofmolecular diffusion within dendritic spines insynaptic function. Journal of General Physiology
2021 Apr 5;153(4) e202012814. doi: 10.1085/jgp.
202012814.
10. 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.
11. 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.
12. 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
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,

10and MENTAL20) Health Initiative: A Global
Consortium Addressing the Human andEconomic Burden of Brain, Spine, and Mental
Disorders Through Neurotech Innovations andPolicies Journal of Alzheimer's Disease 2021 Sep
3. doi: 10.3233/JAD-215190.

Molecular Cell Biology
2. Biochemistry and Molecular Biology

12

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

Lecturer
Hayashi Yamamoto, Ph.D.

Research Associate
Yuji Sakai, Ph.D.

Project Associate Professor
Chieko Saito, Ph.D.

Project Lecturer
Ikuko Koyama-Honda, Ph.D.

Project Research Associate
Junichi Sakamaki, Ph.D., Takeshi Sugawara, Ph.D., Seiichi Koike, Ph.D. (~Apr 2020),
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

13

Biochemistry at Kyushu Imperial University. In 1943,
he took up a professorship at this Department. His
research was on oxidation and reduction, andnutrition.
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.
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, whichallow us to perform genetic analysis of autophagy
in mammals. We are currently addressing some of
the central questions remaining the autophagy
field and trying to elucidate the mechanisms of (1)regulation of autophagy, (2) initiation of
autophagosome formation, (3) elongation of the
autophagic membrane, (4) closure, fusion, anddegradation of the autophagosome (5) recognitionof selective substrates. In 2020, we reported thefollowing novel findings.
The formation of autophagosomes is aphenomenon that involves a unique, dynamicchange in membrane morphology. Flattened
disc-like vesicles bend into cup-shape structuresand finally form spherical autophagosomes.
Although many autophagy-related factors are
involved in the formation of autophagosomes, thephysical mechanisms behind the morphologicalchanges have not been fully elucidated. We
developed a mathematical model of thedevelopment of autophagosomes by the curvature
generators, and analyzed the morphologicalchanges during autophagosome formation. We
showed that the spontaneous change in the
distribution of curvature generators on themembrane determines the morphology of the14autophagic membrane. This mathematical model
was able to quantitatively explain the
autophagosome formation observed in live cells.
These results suggest that a mathematical model
based on simple physical mechanisms is effective
in analyzing the seemingly complex membrane
dynamics of autophagy (Sakai et al. iScience2020).
We also reported, in collaboration with Dr.
Otomo and colleagues at the Scripps ResearchInstitute in USA, that mammalian ATG9 has
scramblase activity and that the size of
autophagosomes is significantly reduced in cells
expressing functionally impaired ATG9 mutants
that were created based on structural analysis(Maeda et al. Nat Struct Mol Biol 2020).
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 2020, we revealed a new physiologicalrole for autophagy other than degradation. The
lungs of mammals and the swimbladder of fish are
air-containing organs that are essential forbreathing and generating buoyancy in water,
respectively. In order to inflate these organs withair, it is important to reduce the surface tension of
the water that covers the epithelial cells of thealveoli and the swimbladder. This is done by alipid-rich substance called a surfactant, which
spreads on the surface of the water at the air-waterinterface. These surfactants are produced andstored in the lysosome-related organelle, lamellar
body. In this study, we have shown that autophagy
is required for the generation of the surfactants inlungs and swimbladders by analysis using miceand zebrafish. In the epithelial cells of lungs andswimbladders, autophagosomes fuse withimmature lamellar bodies occurs, and suppressionof autophagy results in insufficient maturation oflamellar bodies. Such mice become lethal
immediately after birth due to respiratory distress,and zebrafish are unable to maintain a floating
posture in the water. Autophagy may contribute tolamellar body maturation by supplying lipid
components(membranousorganelles
andautophagosome inner membrane) to lamellar
bodies and/or expanding the surface area oflamellar body membranes (Morishita et al. Cell
Rep 2020).
3. Methods for monitoring autophagic activity
Measuring autophagic activity is critical to dissect
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 havegenerated a new mouse model ubiquitously
expressing this autophagy flux reporter.

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.

Morishita, H., Kanda, Y., Kaizuka, T., Chino, H.,
Nakao, K., Miki, Y., Taketomi, Y., Guan J.L.,
Murakami, M., Aiba, A., *Mizushima, N.
Autophagyisrequiredformaturationofsurfactant-containing lamellar bodies in the lungand swim bladder. Cell Rep. 33:108477 (2020).
2.

Maeda, S., Yamamoto, H., Kinch, L.N., Garza,
C.M., Takahashi, S., Otomo, C., Grishin, N.V.,
Forli, S., Mizushima, N., and *Otomo, T.
Structure, lipid scrambling activity and role inautophagosome formation of ATG9A. Nat. Struct.
Mol. Biol. 27:1194-1201 (2020).

3.

*Sakai, Y., Koyama-Honda, I., Tachikawa, M.,

15

Knorr,

R.L.,

membrane*Mizushima,morphologicalN.

Modelingchangeduringautophagosome formation. iScience 23:101466(2020).
4.

*Mizushima, N., Levine, B. Autophagy in humandiseases. N. Engl. J. Med 383:1564-1576 (2020).

5.

*Mizushima, N., *Murphy, L.O. Autophagy
Assays for Biological Discovery and Therapeutic
Development. Trends Biochem. Sci. 45:10801093 (2020).

6.

*Simon, A.K., *Mizushima, N. Beth Levine
1960-2020. Nat. Cell Biol. 22:909-910 (2020).

7.

Chino, H., *Mizushima, N. ER-phagy: Quality
control and turnover of endoplasmic reticulum.
Trends Cell Biol. 30:384-398 (2020).

8.

Yim, W.W., *Mizushima, N. Lysosome biology
in autophagy. Cell Discov. 6:6 (2020).

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,since August 2018. The laboratory is composed of one
professor and one assistant professor as well as
members of the Laboratory of Microenvironmental
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 3polyunsaturated 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 sPLA2-IIE is highly
induced in brown and beige adipocytes in response tocold and that its genetic deletion leads to partial
impairment of adipocyte browning and thermogenesis.
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
browning, and decreased epigenetic histone and DNA

17

methylation. Accordingly, Pnpla7-/- mice are lean,display growth retardation, and die prematurely. We
further found that mice 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).
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). Furthermore, by phenotypic screening (withperturbation of skin barrier function as a readout)using a series of PLA2 knockout strains, as well as bygene expression profiling of PLA2-related genes inmouse and human skins, we have identified several
PLA2s that appear to be linked to the regulation ofskin homeostasis and diseases.
Among these PLA2s, PLA2G4E (cPLA2,which is expressed in epidermal keratinocytes,
exhibits a unique N-acyltransferase activity thattransfers a fatty acid from the sn-1 position of PC tothe amino group of phosphatidylethanolamine (PE)to give rise to N-acyl PE (NAPE), a precursor of the
non-canonical bioactive lipid N-acylethanolamine(NAE). Pla2g4e-deficient mice display exacerbationof psoriasis 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.
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, Pla2g3-/- mice display more severe atopic

dermatitis-like symptoms with increased expressionof type 2 cytokines and chemokines (IL-4, IL-13,
IL-33, TSLP, and CCL17), serum IgE levels,
eosinophil infiltration, and scratching behavior.
Global or skin-specific deletion of EP4 (PGE2
receptor) or FP (PGF2 receptor) largely if not solely
recapitulate these phenotypes, suggesting that the
PLA2G3-driven PGE2-EP4/PGF2-FP signaling in
keratinocytes plays an important role in skin barrier
formation and thereby skin homeostasis, perturbationof which leads to exacerbation of atopic dermatitis.
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) and that
PAF-AH2, a unique PLA2 that hydrolyzes oxidized
phospholipids, ensures optimal MC activation andthereby allergic responses through producing unique
EPA/DHA metabolites (ω3 epoxides) (Shimanaka et al,
Nat Med 2017). We have recently confirmed the roleof PLA2G3 in MCs by demonstrating that micelacking PLA2G3 specifically in MCs, like thoselacking the enzyme in all tissues, have immature MCs
and display reduced local and systemic anaphylactic
responses. In addition, MC-specific Pla2g3-null micedisplay an aggravated contact hypersensitivity (CHS),
which is phenocopied by MC-specific deletion ofhematopoietic PGD2 synthase. Thus, MC-secreted
PLA2G3 promotes MC maturation via PGD2, thereby
facilitating acute anaphylactic reaction and limiting
delayed CHS response (Taketomi et al, Cells 2021).
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), an orphan sPLA2, is
induced in Th17 cells and participates in Th17
differentiation. Global or CD4+ T cell-specificPla2g12a-deficient mice have lower psoriaticinflammation with decreased Th17 and T cells inthe skin and lymph nodes. We are now analyzing aparticular lipid mediator that acts downstream of

18

PLA2G12A in inducing Th17 immunity.
4) Cancer
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. These results highlight a new aspect of
PLA2G2A as a modulator of gut microbiota,
perturbation of which affects distal skin responses(Miki et al, JCI Insight, in press).
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 macrophages of
Epstein-Barr virus (EBV) lymphoma, increases the
production of fatty acids, lysophospholipids and their
metabolites. sPLA2-treated EVs are smaller,
self-aggregate, show better uptake, and increasecytokine expression and lipid mediator signaling inrecipient tumor-associated macrophages. Lymphoma
growth in EBV-infected mice is suppressed by asPLA2 inhibitor, while treating the mice withsPLA2-modified EVs can reverse this phenotype.
Overall, the sPLA2-driven EV modification promotes
tumor development (submitted).
5) Infectious diseases
PLA2G2D expressed in dendritic cells and M2
macrophages attenuates anti-viral Th1 immunity bysupplying 3 PUFAs and PGD2. In collaboration witha foreign group, we have reported that Pla2g2d
deficiency protects mice from pneumonia caused bycoronavirus infection (Vijay et al, J Exp Med 2015;
Zheng et al, J Clin Invest 2021; Roy Wong et al,bioRxiv 2021). Therefore, PLA2G2D may be an
attractive drug target for treatment of COVID-19.
6) Neuronal 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. However, it is unclear how PNPLA6
mutations lead to these disorders. We have confirmedthat 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. Clarifying theregulatory roles of lipid metabolism driven by
PNPLA6/PNPLA7 will shed light on the molecularmechanism underlying the PNPLA6-related neuronaland retinal disorders.

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).

Publications
1.

2.

Inazumi T, Yamada K, Shirata N, Sato H,
Taketomi Y, Morita K, Hohjoh H, Tsuchiya S,
Oniki K, Watanabe T, Sasaki Y, Oike Y, Ogata Y,
Saruwatari J, Murakami M, Sugimoto Y.
Prostaglandin E2-EP4 axis promotes lipolysis
and fibrosis in adipose tissue leading to ectopic
fat deposition and insulin resistance. Cell Rep. 33,
108265, 2020.
Morishita H, Kanda Y, Kaizuka T, Chino H,
Nakao K, Miki Y, Taketomi Y, Guan. JL,

19

3.

4.

5.

6.

Murakami M, Aiba A, Mizushima N. Autophagy
is required for maturation of surfactantcontaining lamellar bodies in the lung and swim
bladder. Cell Rep. 33, 108477, 2020.
Murakami M, Sato H, Taketomi Y. Updating
phospholipase A2 biology. Biomolecules 10,
E1457, 2020. (Review)
Kitaura J, Murakami M. Positive and negativeroles of lipids in mast cells and allergic responses.
Curr. Opin. Immunol. 72, 186-195., 2021.
(Review)
Zheng J, Meyerholz D, Wong LR, Gelb M,
Murakami M, Perlman S. Coronavirus-specificantibody production in middle-aged micerequires phospholipase A2G2D. J Clin Invest.
131, e147201, 2021.
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. bioRxiv.
2021.04.20.440676.

7. Taketomi Y, Endo Y, Higashi T, Murase R, Ono T,
Taya C, Kobayashi T, Murakami M. Mast
cell-specific deletion of group III secreted
phospholipase A2 impairs mast cell maturationand functions. Cells. 10, 1691, 2021.

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, 1 postdoctoral fellow, 6 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. Fukushima Y, Nishiyama K, Kataoka H, Fruttiger
M, Fukuhara S, Nishida K, Mochizuki N,
Kurihara H, Nishikawa SI, Uemura A. Rho J
integrates attractive and repulsive cues in
directional migration of endothelial cells. EMBO
J. 29:e102930, 2020.
2. Saito R, Koebis M, Nagai T, Shimizu K, Liao J,
Wulaer B, Sugaya Y, Nagahama K, Uesaka N,
Kushima I, Mori D, Maruyama K, Nakao K,
Kurihara H, Yamada K, Kano M, Fukada Y, Ozaki
N, Aiba A. Comprehensive analysis of a novel
mouse model of the 22q11.2 deletion syndrome: amodel with the most common 3.0-Mb deletion at
the human 22q11.2 locus. Transl. Psychiatry.
10(1):35, 2020.
3. Higashijima Y, Nagai N, Yamamoto M, Kitazawa
T, Kawamura YK, Taguchi A, Nakada N,
Nangaku M, Furukawa T, Aburatani H, Kurihara
H, Wada Y, Kanki Y. Lysine demethylase 7aregulates murine anterior-posterior development

22

4.

5.

6.

7.

8.

by modulating the transcription of Hox genecluster. Commun. Biol. 3(1):725, 2020.
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 protein
hyperacetylation. 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,
Miyagawa-Tomita S, Kurihara H. Semaphorin3EPlexinD1 signaling is required for coronary arteryand lymphatic vessel development, with clinicalimplications in myocardial recovery. iScience
24(4):102305, 2021.
Maruyama K, Naemura K, Yoshihara K, ImanakaYoshida K, Kurihara H, Miyagawa-Tomita S.
Surgical protocol for permanent ligation of the left
anterior descending coronary artery in mice togenerate a model of myocardial infarction. STAR
Protoc. 2(3):100775, 2021.
Higashiyama H, Koyabu D, Hirasawa T,
Werneburg I, Kuratani S, Kurihara H. Mammalianface as an evolutionary novelty. Proc. Natl. Acad
Sci. U.S.A. (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 three 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 across theplasmamembrane,which
regulatevariousphysiological processes. Because of their broad
regulatory functions, GPCRs are implicated innumerous chronic diseases, such as diabetes, obesity,
nervous system disorders, migraine, asthma, allergies,
cardiovascular disorders, cancer, and others.
Consequently, they also represent the biggest group of
drug targets and are the subject of approximately 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

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

receptor activation by both native and synthetic
ligands. In the past two years, our results comprise
more than 30 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 last year
we were 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

25

automation frameworks for cryo-EM and cryo-ET.
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.

References
1. Zhao P, Liang Y-L, Belousoff MJ, Deganutti G,
Fletcher MM, Willard FS, Bell MG, Christe ME,
Sloop KW, Inoue A, Truong TT, Clydesdale L,
Furness SGB, Christopoulos A, Wang M-W,
Miller LJ, Reynolds CA, Danev R, Sexton PM,
Wootten D. Activation of the GLP-1 receptor by anon-peptidic agonist. Nature. 2020 Jan;577(7790):
432–6.
2. Liang Y-L, Belousoff MJ, Zhao P, Koole C,
Fletcher MM, Truong TT, Julita V, Christopoulos
G, Xu HE, Zhang Y, Khoshouei M, Christopoulos
A, Danev R, Sexton PM, Wootten D. Toward a
Structural Understanding of Class B GPCR
Peptide Binding and Activation. Mol Cell. 2020
Feb 6;77(3):656-668.e5.
3. Liang Y-L, Belousoff MJ, Fletcher MM, Zhang X,
Khoshouei M, Deganutti G, Koole C, Furness
SGB, Miller LJ, Hay DL, Christopoulos A,
Reynolds CA, Danev R, Wootten D, Sexton PM.
Structure and Dynamics of Adrenomedullin
Receptors AM1 and AM2 Reveal Key
Mechanisms in the Control of Receptor
Phenotype by Receptor Activity-Modifying
Proteins. ACS Pharmacol Transl Sci. 2020 Apr 10;
3(2):263–84.
4. Boopathi R, Danev R, Khoshouei M, Kale S,
Nahata S, Ramos L, Angelov D, Dimitrov S,
Hamiche A, Petosa C, Bednar J. Phase-platecryo-EM structure of the Widom 601 CENP-A
nucleosome core particle reveals differential
flexibility of the DNA ends. Nucleic Acids Res.
2020 Jun 4;48(10):5735–48.

5. Chang R, Zhang X, Qiao A, Dai A, Belousoff MJ,
Tan Q, Shao L, Zhong L, Lin G, Liang Y-L, Ma L,
Han S, Yang D, Danev R, Wang M-W, Wootten D,
Wu B, Sexton PM. Cryo-electron microscopy
structure of the glucagon receptor with adual-agonist peptide. J Biol Chem. 2020 Jul 10;295(28):9313–25.
6. Danev R, Iijima H, Matsuzaki M, Motoki S. Fastand accurate defocus modulation for improved
tunability of cryo-EM experiments. IUCrJ. 2020
May 1;7(3):566–74.
7. Buijsse B, Trompenaars P, Altin V, Danev R,
Glaeser RM. Spectral DQE of the Volta phase
plate. Ultramicroscopy. 2020 Nov 1;218:113079.
8. Dong M, Deganutti G, Piper SJ, Liang Y-L,
Khoshouei M, Belousoff MJ, Harikumar KG,
Reynolds CA, Glukhova A, Furness SGB,
Christopoulos A, Danev R, Wootten D, Sexton
PM, Miller LJ. Structure and dynamics of theactive Gs-coupled human secretin receptor. Nat
Commun. 2020 Aug 18;11(1):4137.
9. Zhang X, Belousoff MJ, Zhao P, Kooistra AJ,
Truong TT, Ang SY, Underwood CR, Egebjerg T,Šenel P, Stewart GD, Liang Y-L, Glukhova A,
Venugopal H, Christopoulos A, Furness SGB,
Miller LJ, Reedtz-Runge S, Langmead CJ,
Gloriam DE, Danev R, Sexton PM, Wootten D.
Differential GLP-1R Binding and Activation by
Peptide and Non-peptide Agonists. Mol Cell.
2020 Nov 5;80(3):485-500.e7.

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 FreeQuarter decided to get into the Ph-D. course after thecompletion of the 2-year clinical training and started
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) Sensory inputs sparsely activate neurons in thesensory cortex, which is postulated to be an efficient
information coding. However, how sparsely active
neurons represent information and how the
information is optimally decoded from the sparse
representation have not been determined.
In the primary visual cortex (V1), simple cells
each have a receptive field (RF) structure that ismodeled by a two-dimensional (2D) Gabor function.
Theoretically, a single natural scene is represented bya relatively small number of neurons using Gabor-like28

RFs, whereas information about multiple scenes is
distributed among the neuronal population. Indeed, V1
neurons sparsely respond to natural scenes. Population
activity with higher sparseness exhibits greater
discriminability between natural scenes.
What types of information from natural scenes
are represented in the sparsely active neurons in thebrain? The visual contents of natural scenes arereconstructed from single-unit activity within thelateral geniculate nucleus collected from several
experiments and functional magnetic resonanceimaging data from the visual cortices. However,whether the visual contents of natural images could be
represented by simultaneously recorded, sparsely
active neurons has not been addressed experimentally.
It also remains to be revealed which decoding strategy
is the most optimal for sparse representation. Whether
only the small number of strongly active neurons
represent information, or whether the remaining
neurons contribute additional information remains to
be determined. Furthermore, do the sparsely active
neurons reliably represent the natural image contents,
regardless of trial-to-trial response variability?
Although a computational model has suggested thatsparse and overcomplete representation is optimal fornatural image representation with unreliable neurons,
this model has not been examined experimentally.
We also address how visual information is
distributed in a neuronal population. Some neurons
are “unresponsive” to simple visual stimuli, such as
moving gratings (e.g., the response rate of the mouse
V1 is 26–68%). However, this may be partly because
visual stimuli are not complex enough to completely
cover the RF properties of all neurons. The proportionof neurons involved in the information processing is amatter of debate.
Here, we examined how sparsely active neurons
represent natural image contents and how the
information was optimally decoded from this sparse
representation. Using two-photon calcium (Ca2+)
imaging, we recorded visual responses to natural
images from the V1 of anesthetized and passively
viewing awake mice. A small percentage of neurons
responded to each image, which was sparser than thatpredicted by a linear encoding model. On the other
hand, most neurons were involved in processing of
natural images. The visual contents of a natural image

were linearly decodable from a small number ofhighly responsive neurons, and the additional use of
the remaining neurons even degraded thereconstruction performance. The responsive neurons
reliably represent the image, regardless of trial-to-trial
response variability, which was supported by multiple
neurons with partially overlapping representation.
These results revealed a new representation of anatural image by a small number of neurons in which
information is reliably represented, while thecorresponding neuronal patterns change across trials
and implies that collecting only the activity of highly
responsive neurons is an optimal decoding strategy forsparse representation. (Hayashi et al., 2018).

References(1) Kenta Hagihara, AyakoWendyIshikawa, Yumiko
Yoshimura, YoshiakiTagawa, Kenichi Ohki
Author Notes Long-Range Interhemispheric
Projection Neurons Show Biased Response
Properties and Fine-Scale Local Subnetworks in
Mouse Visual Cortex Cerebral Cortex, Volume
31, Issue 2, February 2021, Pages 1307–1315,(2) Yoshida T, Ohki K. Natural images are reliably
represented by sparse andvariable populations ofneurons in visual cortex Nature Communications..2020.Feb13;11.872

29

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

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

Homepage

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

Introduction and Organization
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, 2 postdoctoral
researchers, 6 graduate students.

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.

Research activities
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.
(1) Structural dynamics and stability of corticocorticaland thalamocortical axon terminals during motor
learning
Synapses consist of presynaptic and postsynaptic sites,
and are indispensable prerequisites for communication
between neurons. Anatomically, synapses can be
newly formed, eliminated, or undergo a change in size.
Motor learning induces synaptic plasticity in M1. In

30

vivo two-photon imaging in rodents revealed that
dendritic spines in M1 dynamically change during
motor learning, and that the stabilization of a subset of
L1 spines of layer 5 (L5) pyramidal neurons, which
are newly formed in the early stage of learning, isrelevant to improvement in motor performance.
However, the structural plasticity of axonal boutons in
M1 during motor learning is poorly understood. L1
dendritic spines in M1 receive not only axons fromM1 neurons, but also axons from neurons in thesecondary motor cortex (M2) and motor thalamus,
with M2 and the motor thalamus being necessary for
motor skill learning. Therefore, we hypothesized that
the M2–M1 and thalamocortical pathways havedistinct roles in motor learning, and that their axonal
boutons would show distinct structural plasticity.
First, we anatomically confirmed that L1 in M1
receives axonal projections from M2 and the thalamus.
Next, we injected adeno-associated virus (AAV)
encoding either the tdTomato gene or GFP into M2 or
the motor thalamus. After 2–3 weeks, we used
two-photon microscopy to image the fluorescently
labeled axons and their en passant boutons in L1 of
M1 in anesthetized mice. The bouton size was larger
in thalamic boutons than in M2 boutons. This result is
consistent with previous studies showing thatthalamocorticalsynapsesarelargerthan
corticocortical synapses. Over a 7-day training period,a group of mice were trained to perform an
accelerating rotarod task with the rotation speed being
increased from 3 to 100 RPM over 3 min. We pursued
the axonal boutons in the same imaging fields underanesthesia on days 0, 2, 4, and 7 in both the trained
mice and untrained control mice. We found that the
total numbers of M2 and thalamic boutons weresimilar between the trained and control mice acrossthe imaging days. In the trained mice, the relative sizeof thalamic boutons on day 2 in comparison with theirsize on day 0 was slightly larger than in the control
mice. The sizes of thalamic boutons on day 7 and M2
boutons on days 2–7 were similar between the trained
and control mice.
Next, we examined the stability and dynamics of M2
axonal boutons during learning. The survival rate of
M2 boutons that existed on day 0 in both trained andcontrol mice (pre-existing boutons) showed a gradualdecrease over time. The day 7 survival rates ofpre-existing M2 boutons in trained and control mice
were approximately 85%. In both trained and control
mice, the day 0 sizes of those pre-existing M2 boutons
that were still present on day 7 were larger than thosethat were eliminated before day 7. Thus, large boutons
were more stable than small boutons.
When the formation, elimination, and turnover rates
were averaged over days 0–2, 2–4, and 4–7, theformation rates of M2 boutons were higher in trained
mice than in control mice. When the formation andelimination rates for each interval between imaging
days were compared between the control and trained
mice, only the formation rate during days 2–4 wassignificantly higher in trained mice than in control
mice. These results suggest that formation of M2
boutons generally increased during the training days.
The survival rates of boutons that were newly formed
over days 0–2 or 2–4 were similar between trained
and control mice.
In contrast to M2 axonal boutons, the day 7 survival
rate of pre-existing thalamic boutons was higher intrained mice than in control mice, exceeding 0.9.
Consistent with the M2 dynamics, the day 0 sizes of
those pre-existing thalamic boutons that were stillpresent on day 7 were larger than those that were
eliminated before day 7. By contrast, the day 7
survival rate of small pre-existing thalamic boutons
was higher in trained mice than in control mice. These
results suggest that some of the pre-existing thalamicboutons stabilized during motor learning. In contrast
to M2 axonal boutons, the training-period-averaged
elimination rate of thalamic boutons was significantly
lower in trained mice than in control mice, as was theelimination rate over days 4–7. These results suggestthat the elimination of thalamic boutons generally
decreased over the training days. Our results suggestthat the late stabilization of thalamic boutons in M1
contributes to motor skill learning.
(2) Reorganization of cortical activity during learningof a forelimb motor task in the marmoset
It is indispensable to unravel information processing
mechanism under physical movement for developmentof functional recovery after intracranial injury,
auxiliomotor robot and so on. Previous studies ofmotor learning on the non-human primate have mainly
employed macaque monkeys. However, it is very

31

difficult to record several areas simultaneously or
track the same subsets of neurons over the long termwith calcium imaging that is well used in rodent
studies.
Instead, we use common marmoset (Callithrix
jacchus), a New-World monkey, to visualize theneuronal activity by introducing a fluorescent proteinin the cerebral cortex to elucidate the reorganization
during motor learning. Although the brain ofmarmoset is approximately 10-fold smaller than thatof macaque, it is known that its basic cytoarchitecture
is common with those of other primates including thehuman. Furthermore, its lissencephalic form issuitable for calcium imaging with fluorescent proteins.
In the behavior task, we train marmosets to control
a pole with the left forelimb to move a cursor to atarget on the monitor to acquire a reward. First, theanimals learned a pole-pull task. Then, we injected
AAV coding GCaMP into M1, the premotor area (PM),and the surrounding areas. After GCaMP expression
became substantially high, we introduced a pole-pushtask to the motor task. Performing the task for 30-90
minutes per day, the animals learned the novel
movement, the movement of the forelimb pushing thepole, in 20-40 days. To clarify whether the movementdirection selectivity of neuronal activity changes
during movement learning or not, we conducted
one-photon imaging for simultaneous multiarea
recording and two-photon imaging for tracking layer
2/3 neurons in M1 and PM throughout the motor
learning period. We are now analyzing the neuronal
encoding and decoding of physical movements withneuronal activity recorded with calcium imaging andphysical movements extracted with CCD camera anddeep learning algorithm. Additionally, we examine
whether inhibition of the neuronal activity in
task-related M1 and PM with microinjection ofmuscimol.
As mentioned above, employing not only classicalphysiological method but novel genetic engineering
techniques and mathematical and statistical methods
as well onto marmosets, we have deepened ourunderstanding of the neural mechanisms of motor
learning as never before. We expect that our study willcontribute to both basic and clinical medicine because
the results may be applied to the human.

(3) Independent representations of reward-predicting
cues and reward history in frontal cortical neurons
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.
In the rodent cerebral cortex, M2 plays critical roles invalue estimation, action selection, working memory,and motor planning. The type of action required toobtainarewardvariesacrossdifferent
decision-making studies, and the representation ofeach M2 neuron is frequently assigned to one type oftask-related information, that which is dominantly
represented.
To clarify action-type-independent decision-makingrelated information in M2, it is necessary to measure
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). We found that in all dorsal
cortical areas, licking- related activity dominated,while information regarding the reward-predicting cue
emerged over the dorsal cortex and information
regarding the recent reward history emerged in the32frontal cortex. Individual dmFrC neurons strongly but
separately represented these types of task-related
information. Our results suggest that dmFrC canintegrate different types of task-related information to
select the appropriate action in the decision-making
process.
(From a paper submitted to Biorxiv in 2020)(4) Non-action Learning: Saving action-associatedcost serves as a covert reward“To do or not to do” is a fundamental decision that has
to be made in daily life. Behaviors related to multiple“to do” choice tasks have long been explained byreinforcement learning, and “to do or not to do” tasks
such as the go/no-go task have also been recently
discussed within the framework of reinforcement
learning. In this learning framework, alternative
actions and/or the non-action to take are determinedby evaluating explicitly given (overt) reward andpunishment. However, we assume that there are reallife cases in which an action/non-action is repeated,even though there is no obvious reward or punishment,
because implicitly given outcomes such as saving
physical energy and regret (we refer to this as “covert
reward”) can affect the decision-making. If this is thecase, can learning of the non-action be explained byan increase in the value of the non-action according tosuch a covert reward? If not, is the non-action chosenbecause of the reduction in the action value?
To address these issues, we developed a new
behavioral paradigm in which head-fixed mice choose
to either pull a lever with their right forelimb. In thecurrent task, mice chose to pull a lever or notaccording to two tone cues assigned with different
water reward probabilities (70% and 30% in condition
1, and 30% and 10% in condition 2). As the micelearned, the probability that they would choose to pull
the lever decreased (<25%) in trials with a 30%
reward probability cue (30% cue) in condition 1, andin trials with a 10% cue in condition 2, but increased(>80%) in trials with a 70% cue in condition 1 and a
30% cue in condition 2, even though a non-pull was
followed by neither an overt reward nor avoidance ofovert punishment in any trial.
This behavioral tendency was not well explained by a
combination of commonly used Q-learning models,
which take only the action choice with an overt

reward outcome into account. Instead, we found thatthe non-action preference of the mice was best
explained by Q-learning models, which regarded the
non-action as the other choice, and updated non-action
values with a covert reward. We propose that “doing
nothing” can be actively chosen as an alternative to“doing something,” and that a covert reward could
serve as a reinforcer of “doing nothing.”

References
1. Tanimoto S., Kondo M., Morita K., Yoshida E.,
and Matsuzaki M.Non-action learning: Saving
action-associated cost serves as a covert reward.
Frontiers in Behavioral Neuroscience 14, 141,2020.
2. Hasegawa R., Ebina T., Tanaka Y.R., Kobayashi
K., and Matsuzaki M.Structural dynamics andstability of corticocortical and thalamocorticalaxon terminals during motor learning. PLoS One
15, e0234930, 2020.
3. Matsuzaki M. and Ebina T.Common marmoset asa model primate for study of the motor control
system. Current Opinion in Neurobiology 64,
103-110, 2020.
4. Kato D., Wake H., Lee P.R., Tachibana Y., Ono R.,
Sugio S., Tsuji Y., Tanaka Y.H., Tanaka Y.R.,
Masamizu Y., Hira R., Moorehouse A.J.,
Tamamaki N., Ikenaka K., Matsukawa N., Fields
R.D., Nabekura J., and Matsuzaki M. Motorlearning requires myelination to reduce
asynchrony and spontaneity in neural activity.
Glia 68, 193-210, 2020.

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
1996, 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, 9 graduate students,
2 research student and 6 technicians. We teachneurophysiology for medical undergraduates and forstudents in the Master and Ph.D. courses. Our researchaims at elucidating cellular and molecular mechanisms
underlying regulation of synaptic transmission andpostnatal 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 human gastricnemius 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 dissociatedculture, 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) andinvestigate molecular mechanisms of synaptic trans-

34

mission 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.
(2) Retrograde synaptic modulation mediated byendogenous cannabinoids:
We reported in 2001 that endogenous cannabinoids
are released from postsynaptic neurons in an activitydependent manner, act retrogradely onto presynaptic
cannabinoid receptors and suppress transmitter release.
Since then, we have been investigating themechanisms of this retrograde modulation. We arealso interested in elucidating the physiologicalsignificance of this phenomenon including learningand memory, addiction, and anxiety.
(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.

(3)

(4)

(5)

(6)

(7)

References(1) 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.
(2) Yamashiro K, Hori K, Lai ESK, Aoki R,
Shimaoka K, Arimura N, Egusa SF, Sakamoto A,
Abe M, Sakimura K, Watanabe T, Uesaka N,
Kano M, Hoshino M. AUTS2 governs cerebellar

(8)

(9)

development, purkinje cell maturation, motor
function and social communication. iScience.
2020 Nov 18;23(12):101820. doi: 10.1016/j.isci.
2020.101820. eCollection 2020 Dec 18.
Hoang H, Sato MA, Shinomoto S, Tsutsumi S,
Hashizume M, Ishikawa T, Kano M, Ikegaya Y,
Kitamura K, Kawato M, Toyama K. Improved
hyperacuity estimation of spike timing from
calcium imaging. Sci Rep. 2020 Oct 20;10(1):17844. doi: 10.1038/s41598-020-74672-y.
Sacai H, Sakoori K, Konno K, Nagahama K,
Suzuki H, Watanabe T, Watanabe M, Uesaka N,
Kano M. Autism spectrum disorder-like behavior
caused by reduced excitatory synaptictransmission in pyramidal neurons of mouse
prefrontal cortex. Nat Commun. 2020 Oct 12;
11(1):5140. doi: 10.1038/s41467-020-18861-3.
Kuboyama K, Inoue T, Hashimotodani Y, Itoh T,
Suzuki T, Tetsuzawa A, Ohtsuka Y, Kinoshita R,
Takara R, Miyazawa T, Gusain P, Kano M,
Yamada MK. Traceable stimulus-dependent rapid
molecular changes in dendritic spines in the brain.
Sci Rep. 2020 Sep 17;10(1):15266. doi: 10.1038/
s41598-020-72248-4.
Nagahama K, Sakoori K, Watanabe T, Kishi Y,
Kawaji K, Koebis M, Nakao K, Gotoh Y, Aiba A,
Uesaka N, Kano M. Setd1a insufficiency in mice
attenuates excitatory synaptic function andrecapitulates schizophrenia-related behavioral
abnormalities. Cell Rep. 2020 Sep 15;32(11):108126. doi: 10.1016/j.celrep.2020.108126.
Nagai H, Yokoi T, Kano M, Tabata T. A test
potential booster for fast-scan cyclic voltammetry
with an electrophysiological amplifier. Anal
Biochem. 2020 Dec 1;610:113934. doi: 10.1016/j.
ab.2020.113934. Epub 2020 Sep 3.
Nagumo Y, Ueta Y, Nakayama H, Osaki H,
Takeuchi Y, Uesaka N, Kano M, Miyata M. Tonic
GABAergic inhibition is essential for nerve
injury-induced afferent remodeling in thesomatosensory thalamus and ectopic sensations.
Cell Rep. 2020 Jun 23;31(12):107797. doi: 10.
1016/j.celrep.2020.107797.
Suzuki T, Suzuki T, Raveau M, Miyake N, Sudo
G, Tsurusaki Y, Watanabe T, Sugaya Y,
Tatsukawa T, Mazaki E, Shimohata A, Kushima I,
Aleksic B, Shiino T, Toyota T, Iwayama Y,

35

Nakaoka K, Ohmori I, Sasaki A, Watanabe K,
Hirose S, Kaneko S, Inoue Y, Yoshikawa T, Ozaki
N, Kano M, Shimoji T, Matsumoto N, Yamakawa
K. A recurrent PJA1 variant in trigonocephaly
and neurodevelopmental disorders. Ann Clin
Transl Neurol. 2020 Jul;7(7):1117-1131. doi: 10.
1002/acn3.51093. Epub 2020 Jun 12.
(10) Kumar D, Koyanagi I, Carrier-Ruiz A, Vergara P,
Srinivasan S, Sugaya Y, Kasuya M, Yu TS, Vogt
KE, Muratani M, Ohnishi T, Singh S, Teixeira
CM, Chérasse Y, Naoi T, Wang SH, Nondhalee P,
Osman BAH, Kaneko N, Sawamoto K, Kernie
SG, Sakurai T, McHugh TJ, Kano M, Yanagisawa
M, Sakaguchi M. Sparse activity of hippocampal
adult-born neurons during REM sleep isnecessary for memory consolidation. Neuron.
2020 Aug 5;107(3):552-565.e10. doi: 10.1016/j.
neuron.2020.05.008. Epub 2020 Jun 4.
(11) Farkas E, Varga E, Kovács B, Szilvásy-Szabó A,
Cote-Vélez A, Péterfi Z, Matziari M, Tóth M,
Zelena D, Mezriczky Z, Kádár A, Kővári D,
Watanabe M, Kano M, Mackie K, Rózsa B,
Ruska Y, Tóth B, Máté Z, Erdélyi F, Szabó G,
Gereben B, Lechan RM, Charli JL, Joseph-Bravo
P, Fekete C. A glial-neuronal circuit in the
median eminence regulates thyrotropin-releasing
hormone-release via the endocannabinoid system.
iScience. 2020 Mar 27;23(3):100921. doi: 10.
1016/j.isci.2020.100921. Epub 2020 Feb 17.
(12) Saito R, Koebis M, Nagai T, Shimizu K, Liao J,
Wulaer B, Sugaya Y, Nagahama K, Uesaka N,
Kushima I, Mori D, Maruyama K, Nakao K,
Kurihara H, Yamada K, Kano M, Fukada Y,
Ozaki N, Aiba A. Comprehensive analysis of anovel mouse model of the 22q11.2 deletion
syndrome: a model with the most common
3.0-Mb deletion at the human 22q11.2 locus.
Transl Psychiatry. 2020 Feb 5;10(1):35. doi: 10.
1038/s41398-020-0723-z.
(13) Sakairi H, Kamikubo Y, Abe M, Ikeda K, Ichiki
A, Tabata T, Kano M, Sakurai T. G proteincoupled glutamate and GABA receptors form
complexes and mutually modulate their signals.
ACS Chem Neurosci. 2020 Feb 19;11(4):567-578.
doi: 10.1021/acschemneuro.9b00599. Epub 2020
Feb 5.

Functional Biology
2. Pharmacology

37

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

Lecturer
Shigeyuki Namiki, Ph. D., Daisuke Asanuma, 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
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 to38

activate 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 technique 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. 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)
2. 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)
3. Aritake T, Hino H, Namiki S, Asanuma D, Hirose
K, and Murata N. Single-Molecule Localization
by Voxel-Wise Regression Using Convolutional
Neural Network. Results in Optics, 1, 100019(2020)
4. Sakamoto H, Namiki S, and Hirose K. Nanoscale
molecular imaging of presynaptic active zone
proteins in cultured hippocampal neurons.
Neuromethods, 154, 245-259 (2020)
5. Okubo, Y. Astrocytic Ca2+ signaling mediated by
the endoplasmic reticulum in health and disease. J.

Pharmacol. Sci., 144, 83-88 (2020)

39

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

Associate Professor
Etsuo A, Susaki, 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.

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40

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 and an
unprecedented
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41fact 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).
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 (Ode
and
Ueda,
Front.
Psychol.
2021).
Phosphorylation/dephosphorylation-mediated protein
regulation represents a promising target in sleep–wakeregulation because it can occur on variable dynamics
and time scale from minutes to hours, and allows forthe integration of genetic factors (regulation by aminoacid
sequence)
andenvironmental
factors(posttranslational modification of intracellularsignaling pathways). Do molecular mechanisms at thesingle amino acid residue level, such as specificprotein phosphorylation, control the organism-level
phenotype including human sleep-wake cycle? Wewill ask this question leveraging mouse genetics as aspringboard
tovalidate
genotype–phenotype
relationships. We also 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.

3.

4.

5.

6.

7.

Mano T., Murata K., Kon K., Shimizu C., Ono H.,
Shi S., Yamada R.G., Miyamichi K., Susaki E.A.,
Touhara K., Ueda H.R. CUBIC-Cloud provides
an integrative computational framework toward
community-driven whole-mouse-brain mapping.
Cell Rep. Methods 1, 100038 (2021)
Takahashi K., Tanabe R., Ehata S., Kubota S.I.,
Morishita Y., Ueda H.R., Miyazono K.
Visualization of the cancer cell cycle by tissueclearing technology using the Fucci reporter
system. Cancer Sci. 112, 3796-3809 (2021)
Yamamoto Y., Chino H., Tsukamoto S., Ode K.L.,
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)
Hasegawa S., Inoue T., Nakamura Y., Fukaya D.,
Uni R., Wu C.H., Fujii R., Peerapanyasut W.,
Taguchi A., Kohro T., Yamada S., Katagiri M.,
Ko T., Nomura S., Nakanishi Ozeki A., Susaki
E.A., Ueda H.R., 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. 32, 1599-1615 (2021)
Kubota S.I., Takahashi K., Mano T., MatsumotoK., Katsumata T., Shi S., Tainaka K., Ueda H.R.,
Ehata S., Miyazono K. Whole-organ analysis of
TGF-β-mediated remodelling of the tumour
microenvironment by tissue clearing. Commun.
Biol. 4, 294 (2021)
Kok S.Y., Oshima H., Takahashi K., NakayamaM., Murakami K., Ueda H.R., Miyazono K.,
Oshima M. Malignant subclone drives metastasisof genetically and phenotypically heterogenous
cell clusters through fibrotic niche generation.
Nat. Commun. 12, 863 (2021)
Yamaguchi H.Q., Ode K.L., Ueda H.R. A designprinciple for posttranslational chaotic oscillators.

42

iScience 1, 101946 (2021)
8. Takahashi K, Kubota S.I., Ehata S., Ueda H.R.,
Miyazono K. Protocol for Imaging and Analysisof Mouse Tumor Models with CUBIC Tissue
Clearing. STAR Protoc. 1, 100191 (2020)
9. Ode K.L., Ueda H.R. Phosphorylation
Hypothesis of Sleep. Front. Psychol. 11, 575328(2020)
10. Omori S., Wang T., Johmura Y., Kanai T.,
Nakano Y., Kido T., Susaki E.A., Nakajima T.,
Shichino S., Ueha S., Ozawa M, Yokote K.,
Kumamoto S., Nishiyama A., Sakamoto T.,
Yamaguchi K., Hatakeyama S., Shimizu E.,
Katayama K., Yamada Y., Yamazaki S., IwasakiK., Miyoshi C., Funato H., Yanagisawa M., Ueno
H., Imoto S., Furukawa Y., Yoshida N.,
Matsushima K., Ueda H.R., Miyajima A.,
Nakanishi M. Generation of a p16 Reporter
Mouse and Its Use to Characterize and Target
p16high Cells In Vivo. Cell Metab. 32, 814-828(2020)

Pathology, Immunology andMicrobiology
1. Pathology

44

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, MD, PhD.
Masako Ikemura, M.D., Ph.D. (Office for “Promotion of CPC Education and General
Integrative Medicine”)
Hiroyuki Abe, M.D., Ph.D.

Associate
Naoko Yamauchi, M.D., Ph.D. (Hospital Lecturer), Mariko Tanaka, M.D., Ph.D. (Hospital
Lecturer), Akiko Kunita, Ph.D., Naohiro Makise, M.D., Ph.D., Akiko Iwasaki, M.D., Ph.D.,
Hirofumi Rokutan, M.D., Ph.D.(Hospital), Munetoshi Hinata, M.D., Ph.D. (Hospital), Sho
Yamazawa, M.D., Ph.D. (Hospital)
Project Research Associate
Ruri Saito, M.D., Ph.D. ("Tsunagu"- Fukushima-Kanto Pathology- Forensic Pathology
Cooperation Program)Technical Support Specialist
Kei Sakuma, Kimiko Takeshita, M.T.

Homepage

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

Introduction and Organization
Department of Pathology and Diagnostic Pathology is
responsible for the practice of diagnostic pathology,
education, and research in cooperation with Divisionof Diagnostic 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. Miyama moved to Saitama Medical
University International Medical Center. Dr. Domoto
moved to Nippon medical school hospital. Dr. Tateishi
became a lecture of the department and Dr. Iwasaki
became an associate of the department.
Dr. Shinozaki-Ushiku became an associate
professor of Division of Integrative Genomics on June45

1st, 2020, and Dr. Tanaka become a lecturer on
February 1st, 2021.
Five postgraduate students (Kume, Fukazawa,
Furuya, Hoshi, and Yasunaga) finished the course andreceived Ph.D. In the new fiscal year, 2021, six newstudents will enter the postgraduate course, and there
will be 22 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. For the four
years since FY2018, in graduate school education, weplan to train pathologists, who are specialized in"death investigation, remote pathology diagnosis, andgenomic medicine" with the training system oriented
to region support by making them rotate among
universities.

Teaching activities
We provide General Pathology Course for the 1st
grade of undergraduate students, especially in its
morphologic field.
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.
Concerning the exercises of Systemic Pathology
Course, we have established a web system to accesswhole slide imaging by which students can look at
pathology slides online.

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 findtherapeutic targets. We are also working on research
projects of digestive system cancers, such as cancer
immunemicroenvironment,
Epstein-Barrvirus-positive 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 Saito),
Epstein-Barr virus-associated neoplasms (Drs.
Shinozaki-Ushiku, Abe and Hinata), pancreatobiliary
tumors (Drs. Tanaka and Yamauchi), bone and soft
tissue tumors (Dr. Makise). 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 Diagnostic
Pathology Division)
1. Bailey MH, Meyerson WU, Dursi LJ, Wang LB,
Dong G, Liang WW, Weerasinghe A, Li S, Li Y,
Kelso S; MC3 Working Group; PCAWG novel
somatic mutation calling methods working group,
Saksena G, Ellrott K, Wendl MC, Wheeler DA,

46

2.

3.

4.

5.

6.

7.

8.

Getz G, Simpson JT, Gerstein MB, Ding L;
PCAWG Consortium. ICGC/TCGA Pan-Cancer
Analysis of Whole Genomes Consortium(including Rokutan H and Ushiku T). Retrospective evaluation of whole exome and genome
mutation calls in 746 cancer samples. Nat
Commun. 2020-9;11(1):4748.
Halimi SA, Maeda D, Ushiku-Shinozaki A, Goto
A, Oda K, Osuga Y, Fujii T, Ushiku T,
Fukayama M. Comprehensive immunohistochemical analysis of the gastrointestinal andMüllerian phenotypes of 139 ovarian mucinous
cystadenomas. Hum Pathol. 2020-12;109:21-30.
Hinata M, Kunita A, Abe H, Morishita Y,
Sakuma K, Yamashita H, Seto Y, Ushiku T,
Fukayama M. Exosomes of Epstein-Barr
Virus-Associated Gastric Carcinoma Suppress
Dendritic Cell Maturation. Microorganisms
2020-11;8(11):1776.
Kashima J, Yoshida M, Jimbo K, Izutsu K,
Ushiku T, Yonemori K, Yoshida A.
ALK-positive Histiocytosis of the Breast: A
Clinicopathologic Study Highlighting Spindle
Cell Histology. Am J Surg Pathol. 2021-3;45(3)347-355.
Koyama Y, Morikawa T, Miyama Y, Miyakawa J,
Kawai T, Kume H, Sawabe M, Ushiku T. B7-H3
expression in upper tract urothelial carcinoma
associates with adverse clinicopathologicalfeatures and poor survival. Pathol Res Pract.
2020-9;216(12):153219.
Li CH, Prokopec SD, Sun RX, Yousif F, Schmitz
N; PCAWG Tumour Subtypes and ClinicalTranslation, Boutros PC; PCAWG Consortium.
ICGC/TCGA Pan-Cancer Analysis of Whole
Genomes Consortium (including Rokutan H and
Ushiku T). Sex differences in oncogenic
mutational processes. Nat Commun. 2020-8;
11(1):4330.
Makise N, Mori T, Motoi T, Shibahara J, Ushiku
T, Yoshida A. Recurrent FOS rearrangement inproliferative
fasciitis/proliferative
myositis.
Modern pathology. 2020-12;Online ahead ofprint.
Makise N, Mori T, Kobayashi H, Nakagawa K,
Ryo E, Nakajima J, Kohsaka S, Mano H,
Aburatani H, Yoshida A, Ushiku T.

9.

10.

11.

12.

13.

14.

Mesenchymal tumours with RREB1-MRTFB
fusion involving the mediastinum: extra-glossal
ectomesenchymal chondromyxoid tumours?
Histopathology. 2020-6;76(7):1023-1031.
Ogawa M, Shintani-Domoto Y, Nagashima Y,
Ode KL, Sato A, Shimizu Y, Ohashi K, Roehrl
MHA, Ushiku T, Ueda HR, Fukayama M. Mass
spectrometry-based absolute quantification ofamyloid proteins in pathology tissue specimens:
Merits and limitations. PLoS One. 2020-6;15(7):e0235143.
Okabe A, Huang KK, Matsusaka K, Fukuyo M,
Xing M, Ong X, Hoshii T, Usui G, Seki M, Mano
Y, Rahmutulla B, Kanda T, Suzuki T, Rha SY,
Ushiku T, Fukayama M, Tan P, Kaneda A.
Cross-species chromatin interactions drive
transcriptional rewiring in Epstein-Barr viruspositive gastric adenocarcinoma. Nat Genet.
2020-9;52(9):919-930.
Suzuki A, Katoh H, Komura D, Kakiuchi M,
Tagashira A, Yamamoto S, Tatsuno K, Ueda H,
Nagae G, Fukuda S, Umeda T, Totoki Y, Abe H,
Ushiku T, Matsuura T, Sakai E, Ohshima T,
Nomura S, Seto Y, Shibata T, Rino Y, Nakajima
A, Fukayama M, Ishikawa S, Aburatani H.
Defined lifestyle and germline factors predispose
Asian populations to gastric cancer. Sci Adv.
2020-5;6:eaav9778.
Yasui M, Kunita A, Numakura S, Uozaki H,
Ushiku T, Fukayama M. Cancer Stem Cells in
Epstein-Barr
Virus-AssociatedGastric
Carcinoma. Cancer Sci. 2020-7;111(7):25982607. doi:10.1111/cas.14435. PMID:32338409.
Kumarasinghe MP, Bourke MJ, Brown I,
Draganov PV, McLeod D, Streutker C,
Raftopoulos S, Ushiku T, Lauwers GY.
Pathological assessment of endoscopic resectionsof the gastrointestinal tract: a comprehensive
clinicopathologic review. Mod Pathol. 2020-6;
33(6):986-1006.
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. (2020) Carcinoma of the
Stomach Histopathology Reporting Guide.
International Collaboration on Cancer Reporting;
Sydney, Australia. ISBN: 978-1-922324-04-7.

47

15. Shi C, Bourke M, Hong S, Kumarasinghe P, Lam
A, Lauwers G, O’Donovan M, Ushiku T, van derPost C, Vieth M, Nagtegaal ID. (2020)
Endoscopic Resection of the
StomachHistopathology Reporting Guide. International
Collaboration on Cancer Reporting; Sydney,
Australia. ISBN: 978-1-922324-05-4.
16. Usui G, Matsusaka K, Mano Y, Urabe M, Funata
S, Fukayama M, Ushiku T, Kaneda A. DNA
Methylation and Genetic Aberrations in Gastric
Cancer. Digestion. 2020-10;16:1-8.
17. Asaoka Y, Tateishi R, Hayashi A, Ushiku T,
Shibahara J, Kinoshita J, Ouchi Y, Koike M,
Fukayama M, Shiina S, Koike K. Expression ofc-Met in Primary and Recurrent Hepatocellular
Carcinoma. Oncology. 2020;98:186-194.
18. ICGC/TCGA Pan-Cancer Analysis of Whole
Genomes Consortium (including Rokutan H,
Ushiku T）Pan-cancer analysis of whole genomes.
Nature 2020-2;578(7793).
19. Kurokawa R, Nakai Y, Gonoi W, Mori H,
Tsuruga T, Makise N, Ushiku T, Abe O.
Differentiation between ovarian metastasis fromcolorectal carcinoma and primary ovariancarcinoma: Evaluation of tumour markers and“mille-feuille sign” on computed tomography/
magnetic resonance imaging. Eur J Radiol 20203;124:108823.
20. Ushiku T, Kunita A, Kuroda R, ShinozakiUshiku A, Yamazawa S, Tsuji Y, Fujishiro M,
Fukayama M. Oxyntic gland neoplasm of thestomach: expanding the spectrum and proposal of
terminology. Modern Pathology 2020-2;33(2):206-216.

48

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)

Assistant Professors
Masato Morikawa, M.D., Ph.D.; Yoko Katsuno, Ph.D.;
Kei Takahashi, Ph.D. (Medical Scientist Training Program)

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. In March
2021, the Department consists of a professor, two
associate professors, three assistant professors,
technical assistants, and some research fellows,
including four graduate students, a master course
student, and two post-doctoral fellows.

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. Teaching responsibilities include lectures on General Pathology related
to the mechanisms of diseases. Since we believe itvery important for medical students to study basic
oncology, we teach a basic tumor biology course in
our lectures of General Pathology. All lecture courses
were conducted 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”
twice a month and “Monday Seminar” once a month.
We have been doing collaboration with Prof.
Carl-Henrik Heldin’s group, Uppsala University,
Sweden for more than 25 years.
From 2018, World-leading INnovative Graduate
School Program for Life Science and Technology(WINGS-LST) has started and some of our graduate
students are supported by this program. This program
will stimulate interaction between students andscientists in the programs as well as those from otherlaboratories (square.umin.ac.jp/wings-lf/).

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
Cellular Diversity (17H06326) from MEXT. From
2020, our research is also supported by a Grant-in-Aid49

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).
Followings are some research results obtained at
our laboratory in 2020.
1) Epigenetic remodeling shapes inflammatory renal
cancer and neutrophil-dependent metastasis
Advanced clear cell renal cell carcinoma (ccRCC)
often causes systemic inflammatory responses. Cancer
cells reshape the immune landscape by secreting
various cytokines or chemokines. This phenotype,known as cancer-cell-intrinsic inflammation, triggers ametastatic cascade. By multiple cycles of orthotopic
transplantation of human ccRCC cells into the mouse
kidney and establishment of highly malignant ccRCC
sublines, we investigated the functional roles andregulatory mechanisms of inflammation driven by thehighly malignant ccRCC cells. The inflammatory
responses of advanced ccRCC were recapitulated in
the highly malignant ccRCC. Amplification ofcancer-cell-intrinsic inflammation during ccRCC
progression triggered neutrophil-dependent lungmetastasis. Massive expression of inflammationrelated genes was transcriptionally activated by
epigenetic remodeling through mechanisms such as
DNA demethylation and super-enhancer formation. A
bromodomain and extra-terminal motif (BET)
inhibitor synchronously suppressed C-X-C-type
chemokines in the highly malignant ccRCC cells anddecreased neutrophil-dependent lung metastasis.
These findings demonstrate the nature of
inflammatory ccRCC, which triggers metastaticcascades, and suggest a potential therapeutic strategy
for advanced ccRCC (Nishida et al. Nat Cell Biol
2020).
2) NTSR1 (neurotensin receptor 1) signaling promotes
pancreatic cancer progression
Pancreatic cancer is one of the cancers with thepoorest prognosis, with a 5-year survival rate of
approximately 5-10%. Using multiple cycles oftransplantations in a mouse pancreatic orthotopic
inoculation model, we previously generated highly
malignant pancreatic cancer sublines with increased
tumor-forming abilities in vivo. Using these cells, we

screened potential molecular targets for the treatmentof pancreatic cancer. Among the genes with increased
expression levels in the pancreatic cancer sublines, we
picked up the genes encoding cell surface receptors
that may play important roles in the interactions
between cancer cells and the tumor microenvironment.
By searching our previous RNA-sequence analysis
data, we found increased expression levels of NTSR1
in highly malignant pancreatic cancer sublines.
Analysis of clinical databases showed that theexpression level of NTSR1 was increased in advanced
pancreatic cancer. Moreover, high NTSR1 levels werecorrelated with a poor prognosis. Overexpression of
NTSR1 in human pancreatic cancer cells accelerated
the tumorigenic and metastatic abilities in vivo.
RNA-sequence analysis showed that MAPK and
NF-κB signaling pathways were activated uponneurotensin stimulation in highly malignant cancer
sublines. Neurotensin stimulation increased theexpression of MMP-9 and other pro-inflammatory
cytokines and chemokines in pancreatic cancer cells.
Furthermore, treatment with SR48692, an NTSR1
antagonist, suppressed the activation of the MAPK
and NF-κB signaling pathways and induction of target
genes in pancreatic cancer cells in vitro, and theadministrationof
SR48692
suppressedthetumorigenicity of pancreatic cancer cells in vivo.
NTSR1 may thus be a prognostic marker and amolecular target for pancreatic cancer treatment(Takahashi et al. Mol Oncol 2020).
3) Whole-organ analysis of TGF-β-mediatedremodeling of the tumor microenvironment by tissue
clearing
Tissue clearing is one of the most powerful strategies
for a comprehensive analysis of disease progression.
We established an integrated pipeline that combines
tissue clearing, 3D imaging, and machine learning.
This pipeline provided the spatial information of thetumor microenvironment. We explored the role of
TGF-β in cancer metastasis using human lungadenocarcinoma A549 cells. TGF-β-stimulated cancer
cells
enhanced
metastaticcolonizationof
unstimulated-cancer cells in vivo when these cells
were mixed. RNA-sequencing analysis showed that
expression of the genes related to blood coagulationand inflammation were up-regulated in TGF-βstimulated cancer cells. Further, whole-organ analysis

50

showed the accumulation of platelets or macrophages
with TGF-β-stimulated cancer cells, suggesting that
TGF-β might remodel the tumor microenvironment,enhancing the metastatic colonization of cancer cells.
Our integrated pipeline for 3D profiling will help theunderstanding of the tumor microenvironment during
the process of cancer metastasis (Kubota et al.
Commun Biol 2020).

References
1. Nishida, J., Momoi, Y., Miyakuni, K., Tamura, Y.,
Takahashi, K., Koinuma, D., Miyazono, K., andEhata, S. (2020) Epigenetic remodelling shapes
inflammatory renal cancer and neutrophildependent metastasis. Nature Cell Biology 22 (4),465-475. doi: 10.1038/ s41556-020-0491-2
2. Sundqvist, A., Vasilaki, E., Voytyuk, O., Bai, Y.,
Morikawa, M., Moustakas, A., Miyazono, K.,
Heldin, C.-H., ten Dijke, P., and van Dam, H.
(2020) TGF-β and EGF signaling orchestrates theAP-1- and p63 transcriptional regulation of breast
cancer invasiveness. Oncogene 39 (22), 44364449. doi: 10.1038/s41388-020-1299-z
3. Yoshimatsu, Y., Wakabayashi, I., Kimuro, S.,
Takahashi, N., Takahashi, K., Kobayashi, M.,
Maishi, N., Podyma-Inoue, K.A., Hida, K.,
Miyazono, K., and Watabe, T. (2020) TNF-αenhances
TGF-β-induced
endothelial-tomesenchymal transition via TGF-β signal
augmentation. Cancer Science 111 (7), 23852399. doi: 10.1111/cas.14455
4. Sato, T., Sekimata, K., Sakai, N., Watanabe, H.,
Mishima-Tsumagari, C., Taguri, T., Matsumoto, T.,
Fujii, Y., Handa, N., Tanaka, A., Shirouzu, M.,
Yokoyama, S., Hashizume, Y., Miyazono, K.,
Koyama, H., and Honma T. (2020) Structural
basis of activin receptor-like kinase 2 (R206H)
inhibition by bis-heteroaryl pyrazole-based
inhibitors for the treatment of fibrodysplasia
ossificans progressiva identified by the integrationof ligand-based and structure-based drug design
approaches. ACS Omega 5 (20), 11411-11423.
doi: 10.1021/acsomega.9b04245

5. Takahashi, K., Akatsu, Y., Podyma-Inoue, K.A.,
Matsumoto, T., Takahashi, H., Yoshimatsu, Y.,
Koinuma, D., Shirouzu, M., Miyazono, K., and
Watabe, T. (2020) Targeting all transforming
growth factor-β isoforms with an Fc chimeric
receptor impairs tumor growth and angiogenesisof oral squamous cell cancer. Journal of
Biological Chemistry 295 (36), 12559-12572. doi:
10.1074/jbc.RA120.012492
6. Yahiro, Y., Maeda, S., Morikawa, M., Koinuma,
D., Jokoji, G., Ijuin, T., Komiya, S., Kageyama,R., Miyazono, K., and Taniguchi, N. (2020)
BMP-induced Atoh8 attenuates osteoclastogenesis
by suppressing Runx2 transcriptional activity andreducing the Rankl/Opg expression ratio in
osteoblasts. Bone Research 8, 32. doi: 10.1038/
s41413-020-00106-0
7. Murayama, K., Kato-Murayama, M., Itoh, Y.,
Miyazono, K., Miyazawa, K., and Shirouzu, M.
(2020) Structural basis for inhibitory effects of
Smad7 on TGF-β family signaling. Journal of
Structural Biology 212 (3), 107661. doi: 10.1016/
j.jsb.2020.107661
8. Fukuda, T., Fukuda, R., Tanabe, R., Koinuma, D.,
Koyama, H., Hashizume, Y., Moustakas, A.,
Miyazono, K., and Heldin, C.-H. (2020) BMP
signaling is a therapeutic target in ovarian cancer.
Cell Death and Discovery 6 (1), 139. doi:
10.1038/s41420-020-00377-w
9. Takahashi, K., Kubota, S.I., Ehata, S., Ueda, H.R.,
and Miyazono, K. (2020) Protocol for imaging
and analysis of mouse tumor models with CUBIC
tissue clearing. STAR Protocols 1 (3), 100191.
doi: 10.1016/j.xpro.2020.100191
10. Doi, K., Ikeda, M., Hayase, N., Moriya, K.,
Morimura, N., and COVID-UTH Study Group(2020) Nafamostat mesylate treatment in
combination with favipiravir for patients criticallyill with Covid-19: a case series. Critical Care 24(1), 392. doi: 10.1186/s13054-020-03078-z

Pathology, Immunology andMicrobiology
2. Microbiology

52

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

Lecturer
Naoko Kamiya, Ph.D.

Research Associate
Atsushi Takahashi, 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. Takahashi 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,
50,000 peoples are killed by gastric cancer each year.
Thus, establishment of new strategies for prevention
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 mechanismsof the bacterial CagA protein. These researches will
provide an opportunity to develop molecular-targeting
methods that effectively prevent the development ofgastric cancer. We made substantial progress in thefollowing research during the current year.
1. Helicobacter pylori CagA oncoprotein interacts
with SHIP2 to increase its delivery into gastricepithelial cells
Most if not all human gastric cancers are caused by

53

chronic infection of the stomach lining with H. pylori
strains that possess the cagA gene. The CagA protein,encoded by the cagA gene, is directly injected into
gastric epithelial cells through the type IV secretion
system (T4SS). Inside the host cells, CagA undergoes
tyrosine phosphorylation by Src family kinases(SFKs) or c-Abl kinase at the Glu-Pro-Ile-Tyr-Ala(EPIYA) motif. Tyrosine-phosphorylated CagA
acquires the ability to specifically bind to andaberrantly activate SHP2 tyrosine phosphatase,causing aberrant activation of the RAS-ERK MAP
kinase signaling pathway. SHP2 has been recognized
as a pro-oncogenic phosphatase and activating
mutations of SHP2 have been found in a variety ofhuman malignancies.
The EPIYA motif-containing region of individual
CagA consists of various combinations of 4 distinct
segments (termed EPIYA-A, EPIYA-B, EPIYA-C, and
EPIYA-D), each of which is defined by differences in
the amino acid sequences surrounding the EPIYA
motif. H. pylori strains isolated in East Asian
countries comprise EPIYA-A, EPIYA-B, and
EPIYA-D segments (East Asian CagA). In contrast, H.
pylori strains isolated all over the world except East
Asian countries comprise EPIYA-A, EPIYA-B, and
EPIYA-C segments (Western CagA). CagA binds to
SHP2 through tyrosine-phosphorylated EPIYA-C or
EPIYA-D segments. Notably, SHP2 binds to EPIYA-D
with 2 order of magnitude stronger affinity than to
EPIYA-C.
In this study, we found that SHIP2, an SH2 domaincontaining phosphatidylinositol 5'-phosphatase, is ahitherto undiscovered CagA-binding host protein.
Similar to SHP2, SHIP2 binds to the Western
CagA-specific EPIYA-C segment or East Asian
CagA-specific EPIYA-D segment through the SH2
domain in a tyrosine phosphorylation-dependent
manner. In contrast to the case of SHP2, however,SHIP2 binds more strongly to EPIYA-C than to
EPIYA-D. Interaction with CagA tethers SHIP2 to theplasma membrane, where it mediates production ofphosphatidylinositol 3,4-diphosphate [PI(3,4)P2 ]. The
CagA-SHIP2 interaction also potentiates themorphogenetic activity of CagA, which is caused by
CagA-deregulated SHP2. This study indicates that
initially delivered CagA interacts with SHIP2 andthereby strengthens H. pylori-host cell attachment byaltering membrane phosphatidylinositol compositions,which potentiates subsequent delivery of CagA thatbinds to and thereby deregulates the prooncogenic
phosphatase SHP2. In addition, this study indicatesthat CagA-SHIP2 interaction plays an important rolein quantitatively increasing the pathological activity ofWestern CagA, which is qualitatively less bioactive
then East Asian CagA, by facilitating CagA delivery.
2. Alternative splicing reverses the cell-intrinsic
and cell-extrinsic prooncogenic potentials of
YAP1
YAP1 is a transcriptional co-activator that interacts
with a number of transcription factors, most notably
TEADs, and thereby transactivates downstream target
genes, which stimulates cell proliferation while
preventing cell death. YAP1 shuttles between thecytoplasm and nucleus in response to various signals
including the Hippo signal, which plays an importantrole in restricting organ size by controlling cellproliferation and apoptosis. The Hippo pathway
contains two core serine/threonine kinases: MST and
LATS.
When theHippo signal is off,nonphosphorylated YAP1 enters the nucleus, where it
acts as a transcriptional co-activator by binding with
TEADs. When the Hippo signal is on, however,
MST-activated LATS phosphorylates cytoplasmic
YAP1 to prevent its nuclear translocalization. Thus,
impaired Hippo signaling also contributes toneoplastic transformation of cells by deregulating
YAP1.
In addition to acting as a transcriptional co-activator,
YAP1 directly mediates translocalization of the
pro-oncogenic phosphatase SHP2 from the cytoplasm
to nucleus. In the cytoplasm, SHP2 potentiates RAS–ERK signaling, which promotes cell proliferation andcell motility, whereas in the nucleus, it mediates gene
regulation. YAP1 comprises multiple splicing
isoforms defined in part by the presence (as in
YAP1-2γ) or absence (as in YAP1-2α) of a γ-segment
encoded by exon 6 that disrupts a critical leucine
zipper. Although the disruptive segment is known to
reduce co-activator function, it is unclear how thiselement impacts the physical and functional
relationships between YAP1 and SHP2.
To explore this question, we first demonstrated that
YAP1-2γ cannot bind SHP2. Nevertheless, YAP1-2γ

54

exhibits stronger mitogenic and motogenic activities
than does YAP1-2α because the YAP1-2α–mediateddelivery of SHP2 to the nucleus weakens cytoplasmic
RAS–ERK signaling. However, YAP1-2γ confers lessin vivo tumorigenicity than does YA1-2α by recruiting
tumor-inhibitory
macrophages.
Mechanistically,
YAP1-2γ transactivates and the YAP1-2α–SHP2
complex transrepresses the monocyte/macrophage
chemoattractant CCL2. Thus, cell-intrinsic and cellextrinsic pro-oncogenic YAP1 activities are inversely
regulated by alternative splicing of exon 6. Notably,
oncogenic KRAS down-regulates the SRSF3 splicing
factor that prevents exon 6 skipping, thereby creating
a YAP1-2α–dominant situation that supports a “cold”
immune microenvironment.

Publications
1. Ben, C., Wu, X., Takahashi-Kanemitsu, A.,
Knight, C.T., Hayashi, T., Hatakeyama, M.
Alternative splicing reverses the cell-intrinsic andcell-extrinsic prooncogenic potentials of YAP1. J.
Biol. Chem. 295(41): 13965-13980 (2020)
2. Ooki,T.,
Hatakeyama,M.
Hyaluronan
Degradation Promotes Cancer via Hippo-YAP
Signaling: An Intervention Point for Cancer
Therapy. Bioessays, 42(7): e2000005 (2020)
3. Fujii, Y., Murata-Kamiya, N., Hatakeyama, M.
Helicobacter pylori CagA oncoprotein interacts
with SHIP2 to increase its delivery into gastricepithelial cells. Cancer Sci. 111(5): 1596-1606(2020)
4. Takahashi-Kanemitsu,
A.,
Knight,C.T.,
Hatakeyama, M. Molecular anatomy andpathogenic actions of Helicobacter pylori CagA
that underpins gastric carcinogenesis. Cell. Mol.
Immunol. 17(1): 50-63 (2020)

55

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

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

Project Lecturer
Mahoko Ikeda, M.D., Ph.D.
Kazuya Okushin, M.D., Ph.D.

Research Associate
Yuta Okada, MD., Ph.D.
Mayo Tsuboi, MD., Ph.D.
Daisuke Ohki, 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.

Mizoguchi M, Matsumoto Y, Saito R, Sato T,
Moriya K. Direct antibiotic susceptibility testing ofblood cultures of gram-negative bacilli using the
Drug Susceptibility Testing Microfluidic (DSTM)
device. J Infect Chemother. 2020;26(6):554-562.
Jia F, Diao P, Wang X, Hu X, Kimura T, Nakamuta
M, Nakamura I, Shirotori S, Sato Y, Moriya K,
Koike K, Gonzalez FJ, Nakayama J, Aoyama T,
Tanaka N. Dietary Restriction Suppresses SteatosisAssociated Hepatic Tumorigenesis in Hepatitis C

Virus Core Gene Transgenic Mice. Liver Cancer.
2020;9(5):529-548.
3. Okushin K, Tsutsumi T, Ikeuchi K, Kado A,
Enooku K, Fujinaga H, Yamauchi N, Ushiku T,
Moriya K, Yotsuyanagi H, Koike K. Heterozygous
knockout of Bile salt export pump ameliorates liver
steatosis in mice fed a high-fat diet. PLoS One.
2020;15(8):e0234750.
4. Shiraya T, Araki F, Ueta T, Fukunaga H, Totsuka K,
Arai T, Uemura A, Moriya K, Kato S.
Ursodeoxycholic Acid Attenuates the Retinal
Vascular
Abnormalities
inAnti-PDGFR-β
Antibody-Induced Pericyte Depletion Mouse
Models. Sci Rep. 2020;10(1):977.
5. Kitaura S, Wakabayashi Y, Okazaki A, Okada Y,
Okamoto K, Ikeda M, Okugawa S, Moriya K. The
First Case Report of Acute Symptomatic HEVGenotype 4 Infection in an HIV-positive Patient inJapan. Intern Med. 2020;59(13):1655-1658.
6. Diao P, Wang X, Jia F, Kimura T, Hu X, Shirotori S,
Nakamura I, Sato Y, Nakayama J, Moriya K, Koike
K, Gonzalez FJ, Aoyama T, Tanaka N. A saturated
fatty acid-rich diet enhances hepatic lipogenesis andtumorigenesis in HCV core gene transgenic mice. J
Nutr Biochem. 2020;85:108460.
7. Shinohara T, Otani A, Yamashita M, Wakimoto Y,
Jubishi D, Okamoto K, Kanno Y, Ikeda M, Ishigaki
K, Nakai Y, Harada S, Okugawa S, Koike K,
Moriya K. Acute Pancreatitis During COVID-19
Pneumonia. Pancreas. 2020;49(10):e106-e108.
8. Doi K, Ikeda M, Hayase N, Moriya K, Morimura
N; COVID-UTH Study Group. Nafamostat
mesylate treatment in combination with favipiravir
for patients critically ill with Covid-19: a case series.
Crit Care. 2020;24(1):392.
9. Usui Y, Ayibieke A, Kamiichi Y, Okugawa S,
Moriya K, Tohda S, Saito R. Impact of
deoxycholate on Clostridioides difficile growth,
toxin production, and sporulation. Heliyon. 2020;
6(4):e03717.
10. Kitaura S, Wakabayashi Y, Okazaki A, Okada Y,
Okamoto K, Ikeda M, Okugawa S, Moriya K. The
First Case Report of Acute Symptomatic HEVGenotype 4 Infection in an HIV-positive Patient inJapan. Intern Med. 2020;59(13):1655-1658.
11. Kitaura S, Okamoto K, Wakabayashi Y, Okada Y,
Okazaki A, Ikeda M, Hakuta R, Nakai Y, Okugawa

57

12.

13.

14.

15.

16.

S, Koike K, Moriya K. Vibrio fluvialis Liver
Abscess and Bacteremia in a Sashimi Lover: A
Case Report and Review of the Literature. Open
Forum Infect Dis. 2020;7(6):ofaa212.
Okada Y, Okugawa S, Ikeda M, Kobayashi T, Saito
R, Higurashi Y, Moriya K. Genetic diversity andepidemiology of accessory gene regulator loci in
Clostridioides difficile. Access Microbiol. 2020;2(7):acmi000134.
Ayibieke A, Kobayashi A, Suzuki M, Sato W,
Mahazu S, Prah I, Mizoguchi M, Moriya K,
Hayashi T, Suzuki T, Iwanaga S, Ablordey A, Saito
R. Prevalence and Characterization of CarbapenemHydrolyzing Class D β-Lactamase-Producing
Acinetobacter Isolates From Ghana. Front
Microbiol. 2020;11:587398.
Harada S, Shibue Y, Aoki K, Ishii Y, Tateda K.
Prevalence of High-Level Aminoglycoside
Resistance and Genes Encoding AminoglycosideModifying Enzymes in Enterococcus faecalis andEnterococcus faecium Isolated in a University
Hospital in Tokyo. Jpn J Infect Dis. 2020;73(6):476-480.
Sasaki T, Harada S, Yamamoto S, Ohkushi D,
Hayama B, Takeda K, Hoashi K, Shiotani J,
Takehana K, Doi Y. Clinical characteristics ofperipheral venous catheter-associated gramnegative bloodstream infection among patients withmalignancy. PLoS One. 2020;15(1):e0228396.
Harada S, Ohkushi D, Nakano K, Mitani H,
Yamamoto Y, Kamei K, Hayama B. Fatal invasive
pulmonary aspergillosis caused by voriconazoleresistant Aspergillus tubingensis in a patient withsolid tumor. J Infect Chemother. 2020;26(3):301304.

Pathology, Immunology andMicrobiology
3. Immunology

59

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 and chairin 1977. Through his innovative research and great
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- 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 cuttingedge questions confronting the research field of
immunology. We also offer a special training course(called ‘free quarter’) of basic and advanced biologicaland immunological techniques to medical students. We
are also accepting undergraduate students as Medical
Scientist Training Program in faculty of medicine. In
fiscal year 2020, special lectures for undergraduate
students were given by internationally recognizedscientists, 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 study

60

is to develop epoch-making strategies for the treatmentof immune disorders such as autoimmune diseases andsevere 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 in immune cell
development. The crucial stromal cell types that
support hematopoietic cell development in the bonemarrow have not been clarified. We reported the crucialrole of osteoblasts in supporting lymphoid lineage
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 reciprocal interaction
between the immune and bone systems, in which acuteinflammation induces a defect in bone cells resulting inlymphopenia-associated immunodeficiency, suggesting that osteoblasts are a potential therapeutic target of
the treatment of inflammatory 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 Fc receptors(Negishi-Koga et al., Nat Commun., 2015). To
understand the precise mechanisms underlying cell fatespecification 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 T cells are the major source of IL17 produced in the bone injury site (Ono et al., Nat
Commun., 2016). Although it has been known that IL17 enhances osteoclastic bone resorption in certain
pathological situations, our current results clearly show
the promoting effect of IL-17 on bone formation,
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 by removing the tooth. Thus, exFoxp3Th17 cells
play a beneficial role in the host defense against oral

61bacteria. This investigation highlighted the notion that
T-cell-mediated bone damage, which was considered to
be an adverse consequence of inflammation, may havedeveloped 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, skeletalrelated events by bone metastasis and bone destruction
in rheumatoid arthritis. We have demonstrated thatoral administration of the novel small-molecule
inhibitor against RANKL suppressed bone metastasis
using the mouse models, indicating the great efficacy
of RANKL inhibition with a small-molecule compoundin bone metastasis (Nakai et al., Bone Res., 2019).
RANKL is synthesized as membrane-bound molecule,and cleaved into its soluble form by proteases. We havereported that soluble RANKL is dispensable forphysiological regulation of bone and immune systems,
but has a distinct and pivotal role in the promotion ofbone metastasis (Asano et al., Nat Metab., 2019). TheRANKL system plays a central role in bone andimmune homeostasis, but the source of OPG, the decoy
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 newparadigm 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 the thymus is mainlycomposed 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-

tolerance by producing a unique set of self-antigens(Nitta et al, Nat Immunol., 2020). Fibroblasts havebeen attracting much attention in recent years due totheir functional 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.
We have reported that the genetic variations ofhuman PSMB11 gene, which encodes 5t, a thymusspecific proteasome subunit, affected the MHC class Ibound 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 high frequency,
was associated with a higher risk of Sjögren’s
syndrome. These results suggested that, in addition to
the MHC haplotype, genetic variations of proteasome
influence T cell repertoire selection and susceptibility
to autoimmunity. Elucidation of the principles of T-cell
repertoire selection is one of most important 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 (Muro et al, Methods Mol Biol.,2020).
We have also been studying on thymic developmentof T cells. We showed that the TCR signal
mediated by the Syk-PI3K pathway is essential forthymic development of IL-17-producing T cells(Muro et al., J Clin Invest., 2018). These findings
suggest that the Syk-PI3K pathway might be atherapeutic 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 T cell development (Narita et al., Int
Immunol., 2018). These mice exhibited a marked
reduction of V5V1 T cells in the thymus and skin,
but had normal development of other T cell subsets
and leukocytes. This study indicates an exclusivefunction of Skint family genes in the development ofV5V1 T cells and provides a useful animal modelto analyze the mechanism for thymic education of Tcells.
Much attention has been paid to the development and62function 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 and directlyinteracted 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 a decrease in microbial
diversity, indicating that subepithelial RANKLexpressing mesenchymal cells (M cell inducer (MCi)cells) are key players in the maintenance of hostmicrobe symbiosis. Furthermore, we reported that
Col6a1-Cre driver mice are useful to study the functionof MCi cells (Nagashima et al., Biochem Biophys Res
Commun., 2017). Manipulation of MCi cells may
provide a molecular basis for novel treatments ofintestinal 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 cellspecific deficiency of the arginine methyltransferase
PRMT5 led to a decrease in the number of peripheral
CD4, CD8 and regulatory T cells, and an almost
complete loss of iNKT cells.
PRMT5-mediatedarginine methylation was essential for the expression of
the cytokine-signal-transducing components, thecommon 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 thesplicing 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 (Th17 cell)
plays critical roles in several autoimmune diseasemodels such as collagen induced arthritis (CIA) andexperimental encephalomyelitis (EAE). We haveidentified IB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 that robustly
produces IL-17 and RANKL and exacerbates bothinflammation 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. These results show that the targetingthese cells and/or molecules could be effective inpreventing bone destruction in RA (Danks et al., Ann
Rheum Dis., 2016).
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
EAE, indicating that RANKL is a potential therapeutictarget for treatment of multiple sclerosis (Guerrini et al.,Immunity, 2015).
We have also been studying the mechanism of T cell
tolerance induction, because a breakdown of T cell
tolerance induces autoimmune diseases. Self-toleranceof T cells is primarily established during theirdevelopment in the thymic medulla, where medullary
thymic epithelial cells (mTECs) ectopically express avariety of tissue-restricted antigens (TRAs) and thereby
TRA-reactive immature T cells are deleted. It has been
known that expression of a set of TRAs is regulated by
the transcriptional regulator Aire, although how theremaining TRAs are regulated has been unclear. We
identified a novel key transcription factor Fezf2, which
is highly expressed in mTECs and controls theexpression of a large fraction of Aire-independent
TRAs (Takaba et al., Cell, 2015). Mice lacking Fezf2
in mTECs exhibited severe autoimmune disorders in63peripheral organs, and the spectrum of autoimmunity in
Fezf2-deficient mice differed from that in Airedeficient mice. These results indicate that two
independent factors, Fezf2 and Aire, play nonredundant and mutually complementary roles in the
TRA expression to ensure T cell tolerance induction. In
addition, we identified Chd4 as chromatin remodelerinteracting 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, thesestudies represented important advance in our
understanding of the mechanisms underlying theimmune tolerance and autoimmune diseases.

References
1.

2.

3.
4.

5.

6.

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)
Nitta et al., Fibroblasts as a source of selfantigens for central immune tolerance. Nat
Immunol., 21: 1172–1180 (2020)
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)
Tomofuji et al., Chd4 choreographs self-antigen
expression for central immune tolerance. Nat
Immunol., 21: 892–901 (2020)

Radiology and Biomedical
Engineering
1. Radiology

65

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

Associate Professor
Keiichi Nakagawa, M.D., Ph.D., Hidemasa Takao, M.D., Ph.D.,
Takeyuki Watadani, M.D., Ph.D.

Lecturer
Hideomi Yamashita M.D., Ph.D., Toshihiro Furuta, M.D., Ph.D.,
Shouhei Hanaoka, M.D., Ph.D.

Project Associate Professor
Shiori Amemiya, M.D., Ph.D.

Assistant Professor
Mami Ogita, M.D., Wataru Gonoi, M.D., Ph.D.
Naotoshi Ishida, M.D., Ph.D., Ryousuke Takenaka, M.D., Ph.D.,
Eisuke Shibata, M.D., Ph.D., Yusuke Watanabe, M.D., Ph.D., Atsuto Katano, M.D., Ph.D.,
Yudai Nakai, M.D., Ph.D., Takatoshi Kubo, M.D., Ph.D., Ryu Miyagawa, Ph.D.

Project Assistant Professor
Ryo Kurokawa, M.D., Ph.D., Yuta Ohtake, M.D.

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.

66

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.

Teaching activities
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.

Research activities
Research 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,

67

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.

2)

3)

4)

5)

6)

7)

References
1) Akai H, Yasaka K, Kunimatsu A, Ohtomo K,
Abe O, Kiryu S.

8)Application of Ct Texture Analysis to Assess
the Localization of Primary Aldosteronism.
Sci Rep 10(1): 472, 2020
Amemiya S, Takao H, Abe O.
Origin of the Time Lag Phenomenon and the
Global Signal in Resting-State fMRI.
Front Neurosci 14: 596084, 2020
Amemiya S, Takao H, Kato S, Yamashita H,
Sakamoto N, Abe O.
Automatic detection of brain metastases oncontrast-enhanced CT with deep-learningfeature-fused single-shot detectors.
Eur J Radiol 136: 109577, 2021
Aoki S, Yamashita H, Takahashi W, Nawa K,
Ota T, Imae T, Ozaki S, Nozawa Y, Nakajima J,
Sato M, Anraku M, Nitadori J, Karasaki T, Abe
O, Nakagawa K.
Salvage stereotactic body radiotherapy forpost-operative oligo-recurrence of non-small
cell lung cancer: A single-institution analysis of
59 patients.
Oncol Lett 19(4): 2695-704, 2020
Baba A, Kessoku H, Akutsu T, Shimura E,
Matsushima S, Kurokawa R, Ota Y, Suzuki T,
Kawasumi Y, Yamauchi H, Ikeda K, Ojiri H.
Pre-treatment MRI predictor of high-grademalignant parotid gland cancer.
Oral Radiol: Epub ahead of print, 2021
Baba A, Kurihara S, Fukuda T, Yamauchi H,
Matsushima S, Ikeda K, Kurokawa R, Ota Y,
Takahashi M, Sakurai Y, Motegi M, Komori M,
Yamamoto K, Yamamoto Y, Kojima H, Ojiri H.
Non-echoplanar diffusion weighed imaging and
T1-weighted imaging for cholesteatoma
mastoid extension.
Auris Nasus Larynx: Epub ahead of print, 2021
Baba A, Kurihara S, Ogihara A, Matsushima S,
Yamauchi H, Ikeda K, Kurokawa R, Ota Y,
Takahashi M, Sakurai Y, Motegi M, Komori M,
Yamamoto K, Yamamoto Y, Kojima H, Ojiri H.
Preoperative predictive criteria for mastoid
extension in pars flaccida cholesteatoma inassessmentsusing
temporalbonehigh-resolution computed tomography.
Auris Nasus Larynx: Epub ahead of print, 2020
Benner S, Aoki Y, Watanabe T, Endo N, Abe O,
Kuroda M, Kuwabara H, Kawakubo Y, Takao H,

68

Kunimatsu A, Kasai K, Bito H, Kakeyama M,
Yamasue H.
Neurochemical Evidence for Differential
Effects of Acute and Repeated Oxytocin
Administration.
Mol Psychiatry 26(2): 710-20, 2021
9) Fujita N, Kurokawa R, Kaneshima R, Machida
M, Kawai G, Wada T, Takahashi M, Nakaya M,
Sakamoto N, Cho S, Abe O, Matsuoka Y.
Patient with penile metastasis from prostatecancer and survival over 5 years: A case reportwith longitudinal evaluation using computed
tomography and magnetic resonance imaging.
Radiol Case Rep 16(6): 1255-8, 2021
10) Fujita S, Buonincontri G, Cencini M, Fukunaga
I, Takei N, Schulte RF, Hagiwara A, Uchida W,
Hori M, Kamagata K, Abe O, Aoki S.
Repeatability and Reproducibility of Human
Brain Morphometry Using Three-Dimensional
Magnetic Resonance Fingerprinting.
Hum Brain Mapp 42(2): 275-85, 2021
11) Fujita S, Hagiwara A, Otsuka Y, Hori M, Takei
N, Hwang KP, Irie R, Andica C, Kamagata K,
Akashi T, Kunishima Kumamaru K, Suzuki M,
Wada A, Abe O, Aoki S.
Deep Learning Approach for Generating Mra
Images from 3d Quantitative Synthetic MRI
without Additional Scans.
Invest Radiol 55(4): 249-56, 2020
12) Fujita S, Hagiwara A, Takei N, Hwang KP,
Fukunaga I, Kato S, Andica C, Kamagata K,
Yokoyama K, Hattori N, Abe O, Aoki S.
Accelerated Isotropic Multiparametric Imaging
by High Spatial Resolution 3D-QALAS With
Compressed Sensing: A Phantom, Volunteer,
and Patient Study.
Invest Radiol: Epub ahead of print, 2020
13) Fujita S, Yokoyama K, Hagiwara A, Kato S,
Andica C, Kamagata K, Hattori N, Abe O, Aoki
S.
3d Quantitative Synthetic MRI in the
Evaluation of Multiple Sclerosis Lesions.
AJNR Am J Neuroradiol 42(3): 471-8, 2021
14) Furuta T, Yamaguchi M, Minami M, Abe O,
Fujii H.
Treatment Margins in Radiotherapy for Liver
Tumors Visualized as T2*-Hypointense Areason Spio-Enhanced Mri at 9.4 T.
MAGMA 33(5): 701-12, 2020
15) Gonoi W, Watanabe Y, Shirota G, Abe H,
Okuma H, Shintani-Domoto Y, Tajima T,
Fukayama M, Abe O, Ishida M.
Pulmonary Postmortem Computed Tomographyof Bacterial Pneumonia and Pulmonary Edema
in
Patients
Following
Non-Traumatic
in-Hospital Death.
Leg Med (Tokyo) 45: 101716, 202016) Goto M, Hagiwara A, Fujita S, Hori M,
Kamagata K, Aoki S, Abe O, Sakamoto H,
Sakano Y, Kyogoku S, Daida H.
Influence of Mild White Matter Lesions on
Voxel-Based Morphometry.
Magn Reson Med Sci 20(1): 40-6, 2021
17) Goto M, Hagiwara A, Kato A, Fujita S, Hori M,
Kamagata K, Sugano H, Arai H, Aoki S, Abe O,
Sakamoto H, Sakano Y, Kyogoku S, Daida H.
Estimation of Intracranial Volume: A
Comparative Study between Synthetic Mri and
Fsl-Brain Extraction Tool (Bet)2.
J Clin Neurosci 79: 178-82, 2020
18) Goto M, Kamatgata K, Saito A, Abe O, Motoi Y,
Miyajima M, Nakajima M.
Detection of Lesions Depends on the Dartel
Template Used in Group Comparisons with
Voxel-Based Morphometry.
Acta Radiol 61(2): 236-43, 2020
19) Goto M, Karima R, Hagiwara A, Hori M,
Kamagata K, Aoki S, Abe O.
Measured Volumes Using Segmented Tissue
Probability Data Obtained Using StatisticalParametric Mapping 12 Were Not Influenced
by the Contrasts of Analyzed Images.
J Clin Neurosci 74: 69-75, 202020) Hagiwara A, Hori M, Andica C, Abe O, Aoki S.
Myelin Imaging Can Be Affected by a Numberof Factors.
AJNR Am J Neuroradiol 41(6): E43-4, 202021) Hakuta R, Hamada T, Nakai Y, Oyama H,
Kanai S, Suzuki T, Sato T, Ishigaki K, Saito K,
Saito T, Takahara N, Mizuno S, Kogure H,
Watadani T, Tsujino T, Tada M, Abe O, Isayama
H, Koike K.
Natural History of Asymptomatic Bile Duct
Stones and Association of Endoscopic

69

Treatment with Clinical Outcomes.
J Gastroenterol 55(1): 78-85, 202022) Han C, Rundo L, Murao K, Noguchi T,
Shimahara Y, Milacski Z, Koshino S, Sala E,
Nakayama H, Satoh S.
MADGAN: unsupervised Medical Anomaly
Detection GAN using multiple adjacent brain
MRI slice reconstruction.
BMC Bioinformatics: Epub ahead of print,
202023) Ikegame T, Bundo M, Okada N, Murata Y,
Koike S, Sugawara H, Saito T, Ikeda M, Owada
K, Fukunaga M, Yamashita F, Koshiyama D,
Natsubori T, Iwashiro N, Asai T, Yoshikawa A,
Nishimura F, Kawamura Y, Ishigooka J,
Kakiuchi C, Sasaki T, Abe O, Hashimoto R,
Iwata N, Yamasue H, Kato T, Kasai K, Iwamoto
K.
Promoter
Activity-Based
Case-Control
Association Study on Slc6a4 Highlighting
Hypermethylation and Altered Amygdala
Volume in Male Patients with Schizophrenia.
Schizophr Bull 46(6): 1577-86, 202024) Imae T, Haga A, Watanabe Y, Takenaka S,
Shiraki T, Nawa K, Ogita M, Takahashi W,
Yamashita H, Nakagawa K, Abe O.
Retrospective dose reconstruction of prostate
stereotactic body radiotherapy using cone-beam
CT and a log file during VMAT delivery withflattening-filter-free mode.
Radiol Phys Technol 13(3): 238-48, 202025) Imae T, Takenaka S, Watanabe Y, Aoki A,
Matsuda K, Sasaki K, Saegusa S, Nawa K,
Nakagawa K, Abe O.
Surface and build-up dose comparison between
Elekta 6 MV flattening filter and flatteningfilter-free beams using an advanced Markus
ionization chamber and a solid water-equivalentphantom.
J Appl Clin Med Phys 21(12): 334-9, 2020
26) Imamura Y, Okada-Ogawa A, Noma N,
Shinozaki T, Watanabe K, Kohashi R, Shinoda
M, Wada A, Abe O, Iwata K.
A Perspective from Experimental Studies of
Burning Mouth Syndrome.
J Oral Sci 62(2): 165-9, 202027) Inui S, Fujikawa A, Jitsu M, Kunishima N,

Watanabe S, Suzuki Y, Umeda S, Uwabe Y.
Erratum: chest CT findings in cases from thecruise ship “Diamond Princess” withcoronavirus disease 2019 (COVID-19).
Radiol Cardiothorac Imaging 2(2): e204002,
202028) Inui S, Kondo H, Tanahashi Y, Fukukura Y,
Sano K, Morisaka H, Saito K, Kondo F,
Fukusato T, Furui S, Oba H.
Steatohepatitic
hepatocellular
carcinoma:
imaging findings with clinicopathologicalcorrelation.
Clin Radiol 76(2): 160.e15-160.e25, 2021
29) Inui S, Kurokawa R, Nakai Y, Watanabe Y,
Kurokawa M, Sakurai K, Fujikasa A, Sugiura H,
Kawahara T, Yoon SH, Uwabe Y, Uchida Y,
Gonoi W, Abe O.
Comparison of Chest CT Grading Systems inCoronavirus Disease 2019 (COVID-19)
Pneumonia.
Radiol Cardiothorac Imaging 2(6): e200492,
202030) Irie R, Amemiya S, Ueyama T, Suzuki Y,
Kamiya K, Takao H, Mori H, Abe O.
Accelerated acquisition of carotid MR
angiography using 3D gradient-echo imaging
with two-point Dixon.
Neuroradiology 62(10): 1345-9, 202031) Irie R, Otsuka Y, Hagiwara A, Kamagata K,
Kamiya K, Suzuki M, Wada A, Maekawa T,
Fujita S, Kato S, Nakajima M, Miyajima M,
Motoi Y, Abe O, Aoki S.
A Novel Deep Learning Approach with a 3d
Convolutional Ladder Network for Differential
Diagnosis of Idiopathic Normal Pressure
Hydrocephalus and Alzheimer's Disease.
Magn Reson Med Sci 19(4): 351-8, 202032) Ishida M, Gonoi W, Shirota G, Abe H,
Shintani-Domoto Y, Ikemura M, Ushiku T, AbeO.
Utility of unenhanced postmortem computed
tomography for investigation of in-hospital
nontraumatic death in children up to 3 years ofage at a single Japanese tertiary care hospital.
Medicine 99(19): e20130, 202033) Ishida M, Gonoi W, Abe H, Shirota G,
Fujimoto K, Okimoto N, Ushiku T, Abe O.

70

Longitudinal
Comparison
ofAscites
Attenuation
betweenAntemortem
andPostmortem Computed Tomography.
Forensic Sci Int 321: 110727, 2021
34) Isikbay M, Hope MD, Raptis CA, Shah A,
Bierhals AJ, Bhalla S, Hammer MM,
Klingerman SJ, Jeudy J, Filev PD, Henry TS,
Inui S, Fujikawa A, Jitsu M, Kunishima N,
Watanabe S, Suzuki Y, Umeda S, Uwabe Y.
Response: Dual Role of Radiologists in theFace of COVID-19.
Radiol Cardiothorac Imaging 2(2): e200192,
202035) Kakeda S, Watanabe K, Nguyen H, Katsuki A,
Sugimoto K, Igata N, Abe O, Yoshimura R,
Korogi Y.
An Independent Component Analysis Reveals
Brain Structural Networks Related to
Tnf-Alpha in Drug-Naive, First-Episode Major
Depressive
Disorder:A
Source-Based
Morphometric Study.
Transl Psychiatry 10(1): 187, 202036) Kamiya K, Kamagata K, Ogaki K, Hatano T,
Ogawa T, Takeshige-Amano H, Murata S,
Andica C, Murata K, Feiweier T, Hori M,
Hattori N, Aoki S.
Brain white-Matter degeneration due to aging
and Parkinson disease as revealed by double
diffusion encoding.
Front Neurosci 14: 584510, 2020
Eighty three English articles in total, including
another 47, have been published from ourdepartment in 2020. Please refer to our homepage,
http://www.ut-radiology.umin.jp/publication/2020.h
tml

Radiology and Biomedical
Engineering
2. Biomedical Engineering

72

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

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

Homepage

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

Introduction and Organization
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.

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.

Research activities
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.
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
1. Cell responses to hemodynamic forces
Our studies have demonstrated that ECs havefunctional responses to hemodynamic forces, shear

73

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 force-induced cell differentiation
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,
a new hybrid type of artificial blood vessel, in which
ES cells were cultured on the surface of polymer tubes

74

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 methyl-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

75

Vascular endothelial cells (ECs) sense andrespond to hemodynamic shear stress, which is
critical for circulatory homeostasis and thepathophysiology of vascular diseases. The
mechanisms of shear stress mechanotransduction,
however,remainelusive.
We
previously
demonstrated a direct role of mitochondria in thepurinergic signaling of shear stress: shear stressincreases mitochondrial ATP production, triggering
ATP release and Ca2+ signaling via EC
purinoceptors. Here, we showed that shear stressrapidly decreases cholesterol in the plasma
membrane, thereby activating mitochondrial ATP
production. Imaging using D4 mutant-derived
cholesterol biosensors showed that the applicationof shear stress to cultured ECs markedly decreasedcholesterol levels in both the outer and inner plasma
membrane bilayers. Flow cytometry showed thatthe cholesterol levels in the outer bilayer began todecrease 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 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
that
shear
stresssignificantly
increased
mitochondrial ATP production. Similarly, thetreatment of cells with methyl--cyclodextrin(MCD), a membrane-cholesterol-depleting agent,increased mitochondrial ATP production. The
addition of cholesterol to cells inhibited theincreasing effects of both shear stress and MCD on
mitochondrial ATP production in a dose-dependent
manner. These findings indicate that plasma
membrane cholesterol dynamics are closely coupled
to mitochondrial oxidative phosphorylation in ECs.

References
1. K. Yamamoto, Y. Nogimori, H. Imamura, and J.
Ando. Shear stress activates mitochondrial
oxidative phosphorylation by reducing plasma
membrane cholesterol in vascular endothelial
cells. Proc. Natl. Acad. Sci. USA. 117: 3366033667, 2020.

2. K. Yoshida, M. Ito, N. Sato, K. Obayashi, K.
Yamamoto, S. Koizumi, S. Tanaka, K. Furuta and
I. Matsuoka. Extracellular ATP Augments AntigenInduced Murine Mast Cell Degranulation and Allergic
Responses via P2X4 Receptor Activation. J
Immunol. 204:3077-3085, 2020.
3. H. Koseki, H. Miyata, S. Shimo, N. Ohno, K.
Mifune, K. Shimano, K. Yamamoto, K. Nozaki, H.
Kasuya, S. Narumiya, T. Aoki. Two diverse
hemodynamic forces, a mechanical stretch and ahigh wall shear stress, determine intracranial
aneurysm formation. Transl. Stroke Res. 11:8092, 2020.
4. M. Fukuda, S. Fukuda, J. Ando, K. Yamamoto, N.
Yonemoto, T. Suzuki, Y. Niwa, T. Inoue, N.
Satoh-Asahara, K. Hasegawa, A. Shimatsu, and T.
Tsukahara. Disruption of P2X4 purinoceptor
suppresses the inflammation associated withcerebral aneurysm formation. J. Neurosurg.
134:102-114, 2021.
5. A. Aoki, K. Shimizu, K. Yamamoto.
Mechanobiology in Intracranial Aneurysm.
Experimental Medicine. 38(7):1096-1104、2020.
6. J. Ando and K. Yamamoto. Impairment ofendothelial cell responses to blood flow induces
vascular diseases. Clinical Imagiology. 36(1):4-12, 2020.

76

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 -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

77probes 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-mannose showed good results and that the target
enzyme was -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.

78[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.

79

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.

80

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 P control) was developed byreforming the 1/R control function. At present, P
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81components 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

82

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, and will be to the
Department of Next-Generation Precision Medicine
Development Laboratory. We focus on both basic
research and translational research in the field ofgenomics (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 and NGS-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 to 2020).
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
research by integrated genome-wide analysis”

83This 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 is predicted bywhole-exome sequencing of fresh-frozen 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

6.

7.

Clinical activities are described in the section of“Department of Clinical Genomics”.

Publications
1.

2.

3.

4.

5.

Shinozaki-Ushiku A, Kohsaka S, Kage H, Oda K,
Miyagawa K, Nakajima J, Aburatani H, Mano H,
Ushiku T. Genomic profiling of multiple primarycancers
includingsynchronouslung
adenocarcinoma
andbilateralmalignantmesotheliomas: Identification of a novel BAP1
germline variant. Pathol Int 70:775-780, 2020.
Shinozaki-Ushiku A, Ishikawa S, Komura D,
Seto Y, Aburatani H, Ushiku T. The first case ofgastric carcinoma with NTRK rearrangement:
identification of a novel ATP1B-NTRK1 fusion.
Gastric Cancer 23:944-947, 2020.
Ando M, Kobayashi H, Shinozaki-Ushiku A,
Chikuda H, Matsubayashi Y, Yoshida M, Saito Y,
Kohsaka S, Oda K, Miyagawa K, Aburatani H,
Mano H, Yamasoba T. Spinal solitary fibroustumor of the neck: Next-generation sequencingbased analysis of genomic aberrations. Auris
Nasus Larynx 47:1058-1063, 2020.
Kobayashi H, Shin M, Makise N, ShinozakiUshiku A, Ikegami M, Taniguchi Y, Shinoda Y,
Kohsaka S, Ushiku T, Oda K, Miyagawa K,
Aburatani H, Mano H, Tanaka S. Genetic TestingDistinguishes Multiple Chondroid Chordomas
with Neuraxial Bone Metastases from Multicentric Tumors. Case Rep Genet 2020:8877722,
2020.
Shiiya H, Sato M, Shinozaki-Ushiku A, Konoeda
C, Kitano K, Nakajima J. Exacerbation of

8.

9.

10.

11.

12.

13.

Secondary Pulmonary Hypertension by Flat
Chest after Lung Transplantation. Ann Thorac
Cardiovasc Surg:, 2020.
Sekine A, Seo K, Matsukura S, Sato M,
Shinozaki-Ushiku A, Ogura T, Kitami A,
Kadokura M, Dohi S, Ichizuka K, Nagatsuka M.
A case report of idiopathic pleuroparenchymal
fibroelastosis with severe respiratory failure inpregnancy. BMC Pulm Med 20:264, 2020.
Kato T, Hiraishi Y, Kaseda K, Suzuki S, Tanaka
G, Yamauchi Y, Yasui M, Shinozaki-Ushiku A,
Ushiku T, Yamaji O, O'Neal WK, Nagase T. A
79-Year-Old Man With Progressive Dyspnea andMultiple Pulmonary Nodules. Chest 158:e79-e84,
2020.
Ito Y, Takaoka K, Toyama K, Taoka K,
Wakabayashi Y, Shinozaki-Ushiku A, Okazaki A,
Chikamatsu K, Mitarai S, Ushiku T, Kurokawa
M. The First Case of Concomitant Mycobacterium Genavense Lymphadenitis and EBVPositive Lymphoproliferative Disorder. Mediterr
J Hematol Infect Dis 12:e2020035, 2020.
Yamauchi H, Bando M, Shinozaki-Ushiku A,
Ogura T, Takemura T, Sato M, Hagiwara K. Is
unclassifiable idiopathic interstitial pneumonia a
result of idiopathic pleuroparenchymal fibroelastosis? Respir Investig [EPUB ahead of print]
Watanabe K, Kage H, Nagoshi S, Toyama K,
Ohno Y, Shinozaki-Ushiku A, Nakazaki K,
Suzuki H, Kurokawa M, Nagase T. Dual EGFR
and ABL Tyrosine Kinase Inhibitor Treatment ina Patient with Concomitant EGFR-Mutated Lung
Adenocarcinoma and BCR-ABL1-Positive CML.
Case Rep Oncol Med 2020:4201727, 2020.
Aizawa H, Karasaki T, Nagayama K, ShinozakiUshiku A, Aburatani H, Mano H, Nakajima J.
ClinicalApplicationof
Next-generation
Sequencing for the Diagnosis of Lung Squamous
Cell Carcinoma: Is It Primary or Secondary?
Intern Med 59:1299-1302, 2020.
Kurihara M, Sasaki T, Sakuishi K, Terao Y,
Murakawa T, Shinozaki-Ushiku A, Okada S,
Toda T, Tsuji S. Isolated seizure as initialpresentation of GABA(A) receptor antibodyassociated encephalitis. J Neurol Sci 410:116666,
2020.
Fukayama M, Abe H, Kunita A, Shinozaki-

84

14.

15.

16.

17.

18.

19.

Ushiku A, Matsusaka K, Ushiku T, Kaneda A.
Thirty years of Epstein-Barr virus-associatedgastric carcinoma. Virchows Arch 476:353-365,
2020.
Taguchi A, Nagasaka K, Plessy C, Nakamura H,
Kawata Y, Kato S, Hashimoto K, Nagamatsu T,
Oda K, Kukimoto I, Kawana K, Carninci P,
Osuga Y, Fujii T. Use of Cap Analysis Gene
Expression to detect human papillomavirus
promoter activity patterns at different diseasestages. Sci Rep 10:17991, 2020.
Kojima M, Sone K, Oda K, Hamamoto R,
Kaneko S, Oki S, Kukita A, Kawata A, Honjoh
H, Kawata Y, Kashiyama T, Sato M, Taguchi A,
Miyamoto Y, Tanikawa M, Tsuruga T, Nagasaka
K, Wada-Hiraike O, Osuga Y, Fujii T. The
histone methyltransferase SMYD2 is a novel
therapeutic target for the induction of apoptosis
in ovarian clear cell carcinoma cells. Oncol Lett
20:153, 2020.
Toyohara Y, Sone K, Nishida H, Taguchi A,
Miyamoto Y, Tanikawa M, Mori M, Tsuruga T,
Matsumoto Y, Oda K, Osuga Y, Fujii T.
Desensitization strategy for hypersensitivity
reactions to carboplatin in five patients withgynecological cancer. J Obstet Gynaecol Res 46:
2298-2304, 2020.
Sone K, Eguchi S, Asada K, Inoue F, Miyamoto
Y, Tanikawa M, Tsuruga T, Mori-Uchino M,
Matsumoto Y, Hiraike-Wada O, Oda K, Osuga Y,
Fujii T. Usefulness of biopsy by officehysteroscopy for endometrial cancer: A casereport. Mol Clin Oncol 13:141-145, 2020.
Kawata Y, Nagasaka K, Oda K, Makii C,
Takeuchi M, Oki S, Honjo H, Kojima M,
Miyagawa Y, Taguchi A, Tanikawa M, Sone K,
Hiraike H, Matsumoto Y, Wada-Hiraike O,
Ayabe T, Osuga Y, Fujii T. Effect of murine
double-minute 2 inhibitors in preclinical modelsof advanced clear cell carcinomas originatingfrom ovaries and kidneys. Cancer Sci 111:38243834, 2020.
Maru Y, Kawata A, Taguchi A, Ishii Y, Baba S,
Mori M, Nagamatsu T, Oda K, Kukimoto I,
Osuga Y, Fujii T, Hippo Y. Establishment andMolecular Phenotyping of Organoids from theSquamocolumnar Junction Region of the Uterine

Cervix. Cancers (Basel) 12(3):694, 2020.
20. Baba S, Taguchi A, Kawata A, Hara K, Eguchi S,
Mori M, Adachi K, Mori S, Iwata T, Mitsuhashi
A, Maeda D, Komatsu A, Nagamatsu T, Oda K,
Kukimoto I, Osuga Y, Fujii T, Kawana K.
Differential expression of human papillomavirus
16-, 18-, 52-, and 58-derived transcripts incervical intraepithelial neoplasia. Virol J 17:32,
2020.
21. Taguchi A, Hara K, Tomio J, Kawana K, Tanaka
T, Baba S, Kawata A, Eguchi S, Tsuruga T, Mori
M, Adachi K, Nagamatsu T, Oda K, Yasugi T,
Osuga Y, Fujii T. Multistate Markov Model toPredict the Prognosis of High-Risk Human
Papillomavirus-Related
CervicalLesions.
Cancers (Basel) 22;12(2):270, 2020.
22. Nakajima T, Kasuga A, Hara-Yamashita A, Ikeda
Y, Asai-Sato M, Nakao T, Hayashi C, Takeya C,
Adachi K, Tsuruga T, Matsumoto Y, Arimoto T,
Nagamatsu T, Oda K, Komatsu A, Chishima F,
Osuga Y, Fujii T, Kawana K. Reconstructed
uterine length is critical for the prevention of
cervicalstenosis
following
abdominal
trachelectomy in cervical cancer patients. J
Obstet Gynaecol Res 46:328-336, 2020.

Neuroscience
1. Basic Neuroscience86

Department of Neuropathology
Professor
Takeshi Iwatsubo, M.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,
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

87

Mol Psychiatr, 2004; Curr Opin Neurobiol, 2004). His
group has also shown by establishing in vitro
γ-secretase assays that sulindac sulfide, a major
non-steroidal anti-inflammatory drugs, directly acts on
γ-secretase and selectively reduce Aβ42-generating
activities (Takahashi et al., J Biol Chem, 2003),
providing important implications to the therapeuticstrategies of AD by γ-secretase modulation. Recently,
he has established a novel method for an efficient invitro reconstituion of γ-secretase complex, paving theway towards the structural analysis of active
γ-secretase (Hayashi et al. J Biol Chem, 2004), andusing thus highly purified γ-secretase particles, they
have partially unveiled the submolecular structure ofthis complex by single-particle EM analysis (Ogura etal. BBRC, 2006). Very recently, his group has
established an elegant strategy to analyze thestructure-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. Japanese ADNI: clinical studies for the identification of surrogate imaging and biomarkers of AD

88

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).

References
1)

2)

3)

Okada Y, Kato T, Iwata K, Kimura Y, Nakamura
A, Hattori H, Toyama H, Ishii K, Ishii K, Senda
M, Ito K, Iwatsubo T: Evaluation of PiB visualinterpretation with CSF Aβ and longitudinal
SUVR in J-ADNI study. Ann Nucl Med 34:
108-118, 2020
Suzuki K, Hirakawa A, Ihara R, Iwata A, Ishii K,
Ikeuchi T, Sun C-K, Donohue M, Iwatsubo T:
Effect of apolipoprotein E ε4 allele on the progression of cognitive decline in the early stage of
Alzheimer’s disease. Alzheimers Dementia:
Translational Research & Clinical Interventions
6:e12007, 2020
Abe Y, Ikegawa N, Yoshida K, Muramatsu K,
Hattori S, Kawai K, Murakami M, Tanaka T,
Goda W, Goto M, Yamamoto T, Hashimoto T,
Yamada K, Shibata T, Misawa H, Mimura M,
Tanaka KF, Miyakawa T, Iwatsubo T, Hata J-i,
Niikura T, Yasui M: Behavioral and electrophysiological evidence for a neuroprotective role ofaquaporin-4 in the 5xFAD transgenic mice model.
Acta Neuropathol Comm 8:67, 2020

4)

5)

6)

Sato K, Mano T, Suzuki K, Toda T, Iwatsubo T,
Iwata A: Attempt to predict A/T/N-based Alzheimer's disease cerebrospinal fluid biomarkers
using a peripheral blood DNA methylation clock.
J Alzheimers Dis Rep 4:287-296, 2020
Kuwahara T, Funakawa K, Komori T, Sakurai M,
Yoshii G, Eguchi T, Iwatsubo T: Roles of lysosomotropic agents on LRRK2 activation andRab10 phosphorylation. Neurobiol Dis 145:
105081, 2020
Hashimoto
T,
Fujii
D,
Naka
Y,
Kashiwagi-Hakozaki M, Matsuo Y, Matsuura Y,
Wakabayashi T, Iwatsubo T: Collagenous
Alzheimer amyloid plaque component impacts
on the compaction of amyloid-β plaques. Acta
Neuropathol Comm 8:212, 2020

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, four postdoctoral
scholars, one technical staff, five 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/
CaMKI) 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/
CaMKI 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-1 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-1 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 2020- December 2020)
1. Imoto T, Kawase A, Minoshima M, Yokoyama T,
Bito H, Kikuchi K. Photolytic Release of a Caged
Inhibitor of an Endogenous Transcription Factor
Enables Optochemical Control of CREBMediated Gene Expression. Org Lett. 2020 Jan 3;
22(1):22-25. doi: 10.1021/acs.orglett.9b03568.
2. Fujita H, Oikawa R, Hayakawa M, Tomoike F,
Kimura Y, Okuno H, Hatashita Y, Fiallos
Oliveros C, Bito H, Ohshima T, Tsuneda S, Abe
H, Inoue T. Quantification of native mRNA

94

3.

4.

5.

6.

dynamics in living neurons using fluorescencecorrelation spectroscopy and reduction-triggered
fluorescent probes. J Biol Chem. 2020 Jun 5;295(23):7923-7940. doi: 10.1074/jbc.RA119.
010921.
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 theradial migration of cortical excitatory neurons.
Neurosci Res. 2021 Aug;169:17-26. doi: 10.
1016/j.neures.2020.06.003.
Kojima K, Kurihara R, Sakamoto M, Takanashi T,
Kuramochi H, Zhang XM, Bito H, Tahara T,
Sudo Y. Comparative Studies of the Fluorescence
Properties of Microbial Rhodopsins: SpontaneousEmission Versus Photointermediate Fluorescence.
J Phys Chem B. 2020 Aug 27;124(34):7361-7367.
doi: 10.1021/acs.jpcb.0c06560.
Imoto T, Minoshima M, Yokoyama T, Emery BP,
Bull
SD,
Bito
H,
KikuchiK.
A
Photodeactivatable Antagonist for Controlling
CREB-Dependent Gene Expression. ACS Cent
Sci. 2020 Oct 28;6(10):1813-1818. doi: 10.1021/
acscentsci.0c00736.
Horiai M, Otsuka A, Hidema S, Hiraoka Y,
Hayashi R, Miyazaki S, Furuse T, Mizukami H,
Teruyama R, Tamura M, Bito H, Maejima Y,
Shimomura K, Nishimori K. Targeting oxytocin
receptor (Oxtr)-expressing neurons in the lateral
septum to restore social novelty in autism
spectrum disorder mouse models. Sci Rep. 2020
Dec 17;10(1):22173. doi: 10.1038/s41598-02079109-0.

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., Ayaka Ishii-Takahashi, M.D., Ph.D.

Homepage

http://childpsy.umin.jp/

Introduction and Organization
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.

Teaching activities
In the year of 2020, we had 6 graduate students. In
addition to research training, educational program
including case conference was implemented withfurther improvement.

Research activities
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 2020 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 autisticpreschoolers and group cognitive behavior therapy
for adults with high-functioning ASD
・Investigation on clinical evaluation and psychological education for adults with developmental

97

disorders

References
1. Kano Y, Fujio M, Kaji N, Matsuda N, Nonaka M,
Kono T. Changes in Sensory Phenomena, Tics,
Obsessive-Compulsive Symptoms, and Global
Functioning of Tourette Syndrome: A Follow-Up
After Four Years. Front Psychiatry, 11: 619, 2020.
2. Matsuda N, Nonaka M, Kono T, Fujio M,
Nobuyoshi M, Kano Y. Premonitory Awareness
Facilitates Tic Suppression: Subscales of thePremonitory Urge for Tics Scale and a New
Self-Report Questionnaire for Tic-AssociatedSensations. Front Psychiatry, 11: 592, 2020.
3. Yassin W, Nakatani H, Zhu Y, Kojima M, Owada
K, Kuwabara H, Gonoi W, Aoki Y, Takao H,
Natsubori T, Iwashiro N, Kasai K, Kano Y, Abe O,
Yamasue H, Koike S. Machine-learningclassification using neuroimaging data in
schizophrenia, autism, ultra-high risk and firstepisode psychosis. Transl Psychiatry, 10(1): 278,
2020.
4. Koshiyama D, Okada N, Ando S, Koike S, Yahata
N, Morita K, Sawada K, Morita S, Kawakami S,
Kanata S, Fujikawa S, Sugimoto N, Toriyama R,
Masaoka M, Araki T, Kano Y, Endo K, Yamasaki
S, Nishida A, Hiraiwa-Hasegawa M, Kasai K.
Association between duration of breastfeeding
based on maternal reports and dorsal and ventral
striatum and medial orbital gyrus volumes in earlyadolescence. Neuroimage, 220: 117083, 2020.
5. Okada N, Yahata N, 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, Edden RAE, Sawa A,
Kasai K. Neurometabolic underpinning of theintergenerational transmission of prosociality.
Neuroimage, 218: 116965, 2020.
6. Okada N, Yahata N, 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, Kasai K. Smaller anterior
subgenual cingulate volume mediates the effect ofgirls' early sexual maturation on negative

psychobehavioral outcome. Neuroimage, 209:
116478, 2020.
7. Yamasaki M, Makino T, Khor SS, Toyoda H,
Miyagawa T, Liu X, Kuwabara H, Kano Y,
Shimada T, Sugiyama T, Nishida H, Sugaya N,
Tochigi M, Otowa T, Okazaki Y, Kaiya H,
Kawamura Y, Miyashita A, Kuwano R, Kasai K,
Tanii H, Sasaki T, Honda M, Tokunaga K.
Sensitivity to gene dosage and gene expression
affects genes with copy number variants observed
among neuropsychiatric diseases. BMC Med
Genomics, 13(1): 55, 2020.
8. Kimura Y, Iijima K, Takayama Y, Yokosako S,
Kaneko Y, Omori M, Kaido T, Kano Y, Iwasaki M.
Deep Brain Stimulation for Refractory TouretteSyndrome: Electrode Position and Clinical
Outcome. Neurol Med Chir (Tokyo), 61(1): 33-39,2021.
9. Eriguchi Y, Aoki N, Kano Y, Kasai K. Rotational
plane-wise analysis of angular movement of neckmotor tics in Tourette's syndrome. Prog
Neuropsychopharmacol Biol Psychiatry, 108:
110092, 2020.
10. Tamune H, Kumakura Y, Morishima R, Kanehara
A, Tanaka M, Okochi N, Nakajima N, Hamada J,
Ogawa T, Nakahara M, Jinde S, Kano Y, Tanaka
K, Hirata Y, Oka A, Kasai K. Toward
co-production of research in 22q11.2 deletion
syndrome: Research needs from the caregiver's
perspective. Psychiatry Clin Neurosci, 74(11):626-627, 2020.
11. 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 changes in
oxytocin efficacy for autism social core symptoms.
Mol Autism, 12(1):15, 2021.
12. Yamasue H, Okada T, Munesue T, Kuroda M,
Fujioka T, Uno Y, Matsumoto K, Kuwabara H,
Mori D, Okamoto Y, Yoshimura Y, Kawakubo Y,
Arioka Y, Kojima M, Yuhi T, Owada K, Yassin W,
Kushima I, Benner S, Ogawa N, Eriguchi Y,
Kawano N, Uemura Y, Yamamoto M, Kano Y,
Kasai K, Higashida H, Ozaki N, Kosaka H. Effectof intranasal oxytocin on the core social

98

symptoms of autism spectrum disorder: arandomized clinical trial. Mol Psychiatry, 25(8):1849-1858, 2020..
13. 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.
14. Oshima F, William M, Takahashi N,
Tsuchiyagaito A, Kuwabara H, Shiina A, Seto M,
Hongo M, Iwama Y, Hirano Y, Sutoh C, Taguchi
K, Yoshida T, Kawasaki Y, Ozawa Y, Masuya J,
Sato N, Nakamura S, Kuno M, Takahashi J,
Ohtani T, Matsuzawa D, Inada N, Kuroda M,
Ando M, Hori A, Nakagawa A, Shimizu E.
Cognitive-behavioral
familytherapyaspsychoeducation for adolescents with highfunctioning autism spectrum disorders: Aware andCare for my Autistic Traits (ACAT) program
study protocol for a pragmatic multisite
randomized controlled trial. Trials. 21(1): 814,2020.

Neuroscience
3. Clinical Neuroscience100

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

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

Lecturer
Tsuyoshi Araki, M.D., Ph.D.

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

Yoshihiro Satomura, 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.

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

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

Kohei Echizen, MD.

Fumikazu Hiyoshi, MD.

Shimon Tonsho, MD.

Homepage

http://npsy.umin.jp/

Introduction and Organization

Clinical activities

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.

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 outpatients

101with schizophrenia in 1974, and the patients areengaged in rehabilitation and re-work programs.

disorder).

Publications
Education
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.

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

1. Yamashita A, Sakai Y, Yamada T, Yahata N,
Kunimatsu A, Okada N, Itahashi T, Hashimoto R,
Mizuta H, Ichikawa N, Takamura M, Okada G,
Yamagata H, Harada K, Matsuo K, Tanaka SC,
Kawato M, Kasai K, Kato N, Takahashi H,
Okamoto Y, Yamashita O, Imamizu H:
Generalizable brain network markers of major
depressive disorder across multiple imaging sites.
PLoS Biol 18: e3000966, 2020. (Dec) doi:
10.1371/journal.pbio.3000966. PMID: 33284797
2. Ikegame T, Bundo M, Okada N, Murata Y, Koike
S, Sugawara H, Saito T, Ikeda M, Owada K,
Fukunaga M, Yamashita F, Koshiyama D,
Natsubori T, Iwashiro N, Asai T, Yoshikawa A,
Nishimura F, Kawamura Y, Ishigooka J, Kakiuchi
C, Sasaki T, Abe O, Hashimoto R, Iwata N,
Yamasue H, Kato T, Kasai K, Iwamoto K:
Promoter activity-based case-control association
study on SLC6A4 highlighting hypermethylation
and altered amygdala volume in male patientswith schizophrenia. Schizophr Bull 46: 1577-1586,
2020. (Dec) doi: 10.1093/schbul/sbaa075. PMID:
32556264
3. Tamune H, Kumakura Y, Morishima R, Kanehara
A, Tanaka M, Okochi N, Nakajima N, Hamada J,
Ogawa T, Nakahara M, Jinde S, Kano Y, Tanaka
K, Hirata Y, Oka A, Kasai K. Toward
co-production of research in 22q11.2 deletion
syndrome: Research needs from the caregiver's
perspective. Psychiatry Clin Neurosci 74: 626-627,
2020. (Sep) doi: 10.1111/pcn.13141. Online aheadof print. PMID: 32902040
4. Huang Z, Endo K, Yamasaki S, Fujikawa S, Ando
S, Hiraiwa-Hasegawa M, Kasai K, Nishida A,
Koike S: Bi-directional relationships between
psychological symptoms and environmental
factors in early adolescence. Front. Psychiatry 11:574182, 2020. (Sep) https://doi.org/10.3389/fpsyt.
2020.57418211:574182
5. Koshiyama D, Fukunaga M, Okada N, Morita K,
Nemoto K, Yamashita F, Yamamori H, Yasuda Y,
Matsumoto J, Fujimoto M, Kudo N, Azechi H,
Watanabe Y, Kasai K, Hashimoto R. Association

102

between the superior longitudinal fasciculus andperceptual organization and working memory: A
diffusion tensor imaging study. Neurosci Lett 738:
135349, 2020. (Sep) doi: 10.1016/j.neulet.2020.
135349. PMID: 32889005
6. Morishima R, Yamasaki S, Ando S, Shimodera S,
Ojio Y, Okazaki Y, Kasai K, Sasaki T, Nishida A.
Long and short sleep duration and psychotic
symptoms in adolescents: Findings from a crosssectional survey of 15,786 Japanese students.
Psychiatry Res 293:113440, 2020. (Aug) doi:
10.1016/j.psychres.2020.113440. Online ahead ofprint. PMID: 32920526
7. Nakamura Y, Okada N, Ando S, Ohta K, Ojio Y,
Abe O, Kunimatsu A, Yamaguchi S, Kasai K,
Koike S: The association between amygdala
subfield-related functional connectivity andstigma reduction 12 months after social contacts:
A functional neuroimaging study in a subgroup ofa randomized controlled trial. Front. Hum.
Neurosci 14:356, 2020. (Aug) | https://doi.org/10.
3389/fnhum.2020.00356
8. Tada M, Suda Y, Kirihara K, Koshiyama D,
Fujioka M, Usui K, Araki T, Kasai K, Uka T.
Translatability of scalp EEG recordings ofduration-deviant mismatch negativity between
macaques and humans: A pilot study. Front
Psychiatry 11:874, 2020. (Aug) doi: 10.
3389/fpsyt.2020.00874. eCollection 2020. PMID:
33005162
9. Fujioka M, Kirihara K, Koshiyama D, Tada M,
Nagai T, Usui K, Morita S, Kawakami S, Morita
K, Satomura Y, Koike S, Suga M, Araki T, Kasai
K. Mismatch negativity predicts remission andneurocognitive function in individuals at
ultra-high risk for psychosis. Front Psychiatry 11:
770, 2020. (Aug) doi: 10.3389/fpsyt.2020.00770.
eCollection 2020. PMID: 32848939
10. Koshiyama D, Okada N, Ando S, Koike S, Yahata
N, Morita K, Sawada K, Morita S, Kawakami S,
Kanata S, Fujikawa S, Sugimoto N, Toriyama R,
Masaoka M, Araki T, Kano Y, Endo K, Yamasaki
S, Nishida A, Hiraiwa-Hasegawa M, Kasai K.
Association between duration of breastfeeding
based on maternal reports and dorsal and ventral
striatum and medial orbital gyrus volumes in earlyadolescence. Neuroimage 220:117083, 2020 (Oct).

doi: 10.1016/j.neuroimage.2020.117083. Online
ahead of print. PMID: 32593803
11. Itahashi T, Okada N, Ando S, Yamasaki S,
Koshiyama D, Morita K, Yahata N, Koike S,
Nishida A, Kasai K, Hashimoto RI. Functional
connectomes linking child-parent relationships
with psychological problems in adolescence.
Neuroimage. 2020 Oct 1;219:117013. doi: 10.
1016/j.neuroimage.2020.117013. Epub 2020 Jun 3.
PMID: 32504815
12. Okada N, Yahata N, 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, Edden RAE, Sawa A,
Kasai K. Neurometabolic underpinning of theintergenerational transmission of prosociality.
Neuroimage. 2020 Sep; 218: 116965. doi: 10.
1016/j.neuroimage.2020.116965. Epub 2020 May
24. PMID: 32461150
13. Yassin W, Nakatani H, Zhu Y, Kojima M, Owada
K, Kuwabara H, Gonoi W, Aoki Y, Takao H,
Natsubori T, Iwashiro N, Kasai K, Kano Y, Abe O,
Yamasue H, Koike S. Machine-learningclassification using neuroimaging data in
schizophrenia, autism, ultra-high risk and firstepisode psychosis. Transl Psychiatry. 2020 Aug
17;10(1):278. doi: 10.1038/s41398-020-00965-5.
PMID: 32801298
14. Morishima R, Usami S, Ando S, Kiyono T, Morita
M, Fujikawa S, Araki T, Kasai K. Living in
temporary housing and later psychologicaldistress after the Great East Japan Earthquake of
2011: A cross-lagged panel model. SSM Popul
Health. 2020 Jul 4;11:100629. doi: 10.1016/j.
ssmph.2020.100629. eCollection 2020 Aug.
PMID: 32676534
15. Hayashi N, Ando S, Jinde S, Fujikawa S, Okada N,
Toriyama R, Masaoka M, Sugiyama H, Shirakawa
T, Yagi T, Morita M, Morishima R, Kiyono T,
Yamasaki S, Nishida A, Kasai K. Social
withdrawal and testosterone levels in earlyadolescent boys. Psychoneuroendocrinology. 2020
Jun;116:104596. doi: 10.1016/j.psyneuen.2020.
104596.Epub 2020 Feb 13.
16. Ozawa S, Iijima Y, Ando S, Okada N, Kawashima
T, Ohta K, Yamasaki S, Kasai K, Nishida A,

103

Nakatani H, Koike S: Development of the Brief
Personal Values Inventory for sense of values.
Japanese Psychological Research. 62(2):72-86.
doi: 10.1111/jpr.12277 (October 2020)
17. Koshiyama D, Kirihara K, Tada M, Nagai T,
Fujioka M, Usui K, Araki T, Kasai K. Reduced
auditory mismatch negativity reflects impaired
deviance detection in schizophrenia. Schizophr
Bull. 2020 Jul 8;46(4):937-946. doi: 10.1093/
schbul/sbaa006. PMID: 32072183
18. Yamasue H, Okada T, Munesue T, Kuroda M,
Fujioka T, Uno Y, Matsumoto K, Kuwabara H,
Mori D, Okamoto Y, Yoshimura Y, Kawakubo Y,
Arioka Y, Kojima M, Yuhi T, Owada K, Yassin
W,Kushima I, Benner S, Ogawa N, Eriguchi Y,
Kawano N, Uemura Y, Yamamoto M, Kano Y,
Kasai K,Higashida H, Ozaki N, Kosaka H. Effectof intranasal oxytocin on the core social
symptoms of autism spectrum disorder: arandomized clinical trial. Mol Psychiatry. 2020
Aug;25(8):1849-1858. doi: 10.1038/s41380-0180097-2. Epub 2018 Jun 29. PMID: 29955161
19. Takasago M, Kunii N, Komatsu M, Tada M,
Kirihara K, Uka T, Ishishita Y, Shimada S, Kasai
K, Saito N: Spatiotemporal differentiation of
MMN from N1 adaptation: a human ECoG study
Spatiotemporal differentiation of MMN from N1
adaptation: a human ECoG study. Frontiers in
Psychiatry, section Neuroimaging and Stimulation.
2020 Jun 26;11:586. doi: 10.3389/fpsyt.2020.
00586. eCollection 2020.
20. Taniguchi G, Masaki K, Kondo S, Yumoto M,
Kasai K: Long-term undiagnosed nonconvulsive
status epilepticus identified by urgent electroencephalography with hyperventilation activation.
Case Rep Neurol 12: 153-159, 2020. (May 28)
21. Sasabayashi D, Takayanagi Y, Takahashi T,
Katagiri N, Sakuma A, Obara C, Katsura M,
Okada N, Koike S, Yamasue H, Nakamura M,
Furuichi A, Kido M, Nishikawa Y, Noguchi K,
Matsumoto K, Mizuno M, Kasai K, Suzuki M.
Subcortical brain volume abnormalities inindividuals with an at-risk mental state. Schizophr
Bull. 2020. Jul 8;46(4):834-845doi: 10.1093/
schbul/sbaa011. PMID: 32162659
22. Yoshihara Y, Lisi G, Yahata N, Fujino J,
Matsumoto Y, Miyata J, Sugihara GI, Urayama SI,

Kubota M, Yamashita M, Hashimoto R, Ichikawa
N, Cahn W, van Haren NEM, Mori S, Okamoto Y,
Kasai K, Kato N, Imamizu H, Kahn RS, Sawa A,
Kawato M, Murai T, Morimoto J, Takahashi H.
Overlapping but Asymmetrical Relationships
Between Schizophrenia and Autism Revealed byBrain Connectivity. Schizophr Bull. 2020 Apr 17;
46(5):1210-1218. doi: 10.1093/schbul/sbaa021.
23. Kiyono T, Morita M, Morishima R, Fujikawa S,
Yamasaki S, Nishida A, Ando S, Kasai K: Theprevalence of psychotic experiences in autism
spectrum disorder and autistic traits: A systematic
review and meta-analysis. Schizophrenia Bulletin
Open 1: sgaa046, 2020 (Jan) https://doi.org/10.
1093/schizbullopen/sgaa046.
24. Yamasaki M, Makino T, Khor SS, Toyoda H,
Miyagawa T, Liu X, Kuwabara H, Kano Y,
Shimada T, Sugiyama T, Nishida H, Sugaya N,
Tochigi M, Otowa T, Okazaki Y, Kaiya H,
Kawamura Y, Miyashita A, Kuwano R, Kasai K,
Tanii H, Sasaki T, Honda M, Tokunaga K.
Sensitivity to gene dosage and gene expression
affects genes with copy number variants observed
among neuropsychiatric diseases. BMC Med
Genomics. 2020 Mar 29;13(1):55. doi: 10.1186/
s12920-020-0699-9. PMID: 32223758
25. Koshiyama D, Kirihara K, Usui K, Tada M,
Fujioka M, Morita S, Kawakami S, Yamagishi M,
Sakurada H, Sakakibara E, Satomura Y, Okada N,
Kondo S, Araki T, Jinde S, Kasai K. Resting-state
EEG beta band power predicts quality of life
outcomes in patients with depressive disorders: A
longitudinal investigation. J Affect Disord. 2020
Mar 15;265:416-422. doi: 10.1016/j.jad.2020.01.
030. PMID: 32090768
26. Iijima Y, Okumura Y, Yamasaki S, Ando S, Okada
K, Koike S, Endo K, Morimoto Y, Williams A,
Murai T, Tanaka SC, Hiraiwa-Hasegawa M, Kasai
K, Nishida A. Assessing the hierarchy of personalvalues among adolescents: A comparison of rating
scale and paired comparison methods. J Adolesc.
2020 Feb 13;80:53-59. doi: 10.1016/j.adolescence.
2020.02.003. PMID: 32062170
27. Kotake R, Kanehara A, Miyamoto Y, Kumakura Y,
Sawada U, Takano A, Chiba R, Ogawa M, Kondo
S, Kasai K, Kawakami N. Reliability and validityof the Japanese version of the INSPIRE measure

104of staff support for personal recovery incommunity mental health service users in Japan.
BMC Psychiatry. 2020 Feb 7;20(1):51. doi: 10.
1186/s12888-020-2467-y. PMID: 32028913
28. Sugimoto N, Nishida A, Ando S, Usami S,
Toriyama R, Morimoto Y, Koike S, Yamasaki S,
Kanata S, Fujikawa S, Furukawa TA, Sasaki T,
Hiraiwa-Hasegawa M, Kasai K. Use of social
networking sites and desire for slimness among
10-year-old girls and boys: A population-based
birth cohort study. Int J Eat Disord. 2020 Feb;
53(2):288-295. doi: 10.1002/eat.23202. PMID:
31743492
29. Ichikawa N, Lisi G, Yahata N, Okada G,
Takamura M, Hashimoto RI, Yamada T, YamadaM, Suhara T, Moriguchi S, Mimura M, Yoshihara
Y, Takahashi H, Kasai K, Kato N, Yamawaki S,
Seymour B, Kawato M, Morimoto J, Okamoto Y.
Primary functional brain connections associatedwith melancholic major depressive disorder andmodulation by antidepressants. Sci Rep. 2020 Feb
26;10(1):3542. doi: 10.1038/s41598-020-60527-z.
PMID: 32103088
30. Endo K, Yamasaki S, Ando S, Kikusui T, Mogi K,
Nagasawa M, Kamimura I, Ishihara J, Nakanishi
M, Usami S, Hiraiwa-Hasegawa M, Kasai K,
Nishida A. Dog and Cat Ownership Predicts
Adolescents' Mental Well-Being: A PopulationBased Longitudinal Study. Int J Environ Res
Public Health. 2020 Jan 31;17(3). pii: E884. doi:
10.3390/ijerph17030884. PMID: 32023841
31. Nakamura Y, Okada N, Koshiyama D, Kamiya K,
Abe O, Kunimatsu A, Okanoya K, Kasai K, Koike
S. Differences in functional connectivity networks
related to the midbrain dopaminergic systemrelated area in various psychiatric disorders.
Schizophr Bull. 2020 Jan 5;46(5):1239-1248. doi:
10.1093/schbul/sbz121.
32. Nemoto K, Shimokawa T, Fukunaga M,
Yamashita F, Tamura M, Yamamori H, Yasuda Y,
Azechi H, Kudo N, Watanabe Y, Kido M,
Takahashi T, Koike S, Okada N, Hirano Y,
Onitsuka T, Yamasue H, Suzuki M, Kasai K,
Hashimoto R, Arai T: Differentiation ofschizophrenia using structural MRI withconsideration of scanner differences: A real-world
multi-site study. Psychiatry Clin Neurosci. 2020

Jan;74(1):56-63. doi: 10.1111/pcn.12934. PMID:
31587444
33. Sawada K et al. Is Utena’s Brief Objective
Measures (UBOM) useful in real-world
behavioral assessment of functioning? Validity
and utility testing in patients with schizophrenia.
Psychiatry Clin Neurosci. 2020 Jan;74(1):40-48.
doi: 10.1111/pcn.12929. PMID: 31482653

105

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., 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 by Professors
Toru Mannen, Ichiro Kanazawa, and Shoji Tsuji. The
organization of the Brain Research Institute wasreorganized 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 the patients withhighly advanced clinical practice as well as on clinicalactivities 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 (Memory Clinic).
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 and 5th
grade medical students, and clinical clerkship for the
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 Neuropathology,

106

consultation for Neurology, rotation at ER and supervising of junior trainees. This program is integrated
with clinical practice at the affiliated hospitals whererich experience is obtained for numerous cases inClinical 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 eventuallydevelop 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 activities ofα-DG-associated diseases are involved in the synthesisof 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-DG-associated diseases
indicated that spatiotemporal persistence of functionally glycosylated α-DG may be crucial for brain
development. These findings provide insight into
pathogenesis and therapeutic strategies in α-DGassociated diseases. In addition, we have started a plan
to conduct a First In Human test of a novel antisense
nucleic acid in Fukuyama-type congenital muscular
dystrophy, which is common in Japan due todystroglycanopathy. (Toda, T., Kanagawa, M.,
Kobayashi, K., Sudo, A., Fujino, G., Kitamura, 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 of neurodegeneration in PD. We also identified genetic factors
responsible for the individual difference of the effectsof zonisamide by using GWAS. (Toda, T., Satake, W.,
Uenaka, T., Cha, P.C., Fujino, G.)
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 neurological diseases
including epilepsy, multiple system atrophy, amyotrophic lateral sclerosis, hereditary spastic paraplegia,
spinocerebellar atrophy, and adrenoleukodystrophy. As
for sporadic neurologic diseases, we perform casecontrol association studies in multiple system atrophy
and amyotrophic lateral sclerosis to identify genetic
factors underlying these diseases. On the basis of thefindings that mutations in COQ2 are associated withfamilial as well as sporadic multiple system atrophy, weare conducting an investigator-initiated clinical trial
using coenzyme Q10 for patients with multiple system
atrophy. After identifying expanded intronic TTTCA
and TTTTA repeats in three independent genes inpatients with benign adult familial myoclonic epilepsy,
which postulated a new disease mechanism in epilepsy,
we also identified expanded CGG repeats in three
genes are causes of neuronal intranuclear inclusion
disease, oculopharyngeal myopathy with leukoencephalopathy, and oculopharyngodistal myopathy.
We reported safety and efficacy of hematopoietic stem
cell transplantation for adolescent-/adulthood-onset
cerebral form/cerebello-brainstem form of 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.)
The human neurophysiology section specializes instudying 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 work
extends from the study of spinal systems to basal
ganglia and cerebral cortex. We are especiallyinterested in plasticity induction by non-invasive brain
stimulation (NIBS) techniques, offering potential for107

clinical application. Our lab has a long experience inthe use of transcranial magnetic stimulation (TMS)
which is able to stimulate neurons in intact human brain
and has devised a highly effective repetitive TMS
method to induce long-term effects (quadripulse
stimulation, QPS). We have recently started a clinical
trial of repetitive TMS to treat patients with Parkinson’s
disease. (Hamada, M., Shirota, Y., Kodama, S.,
Kainaga M, Seto E, Katsuse K, Tokimura R, andMiyano R.)
In the field of neuromuscular diseases, we provide
pathological diagnosis of biopsied materials frompatients with myopathy or neuropathy. We also provide
autoantibody testing for anti-ganglioside antibodies,muscle specific antibodies and paraneoplastic
neurological antibodies. In research field, using
biopsied muscles and collected serum samples, wehave been studying the mechanisms of inflammatory
myopathies from the view points of pathologicalchanges, myositis specific autoantibodies, serum
cytokines, and expression profiling of muscle samples.
Our aim is to increase understanding of the etiology andpathogenesis of neuromuscular diseases. (Shimizu, J.,
Kubota A., Maeda M.).
In the biochemistry laboratory, autopsy brain
analysis of Alzheimer's disease and Lewy body disease
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 the influenceof serum calcium level was discovered.
Other
activities include development of new imaging
techniques using Raman microspectroscopy. We
recently invented a novel high-sensitivity lipid imaging
methodology using delipidation technique for sample
preconditioning before Raman observation, which
successfully determined spatial distribution of minor
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 the sensitivity

surpassing ELISA. We newly developed a detection
device for our sensor chip, realizing automated, highthroughput measurement. We also developed a novel
preanalytical sample handling protocol for highsensitivity measurement. We are also participating inobservational studies of preclinical Alzheimer's disease(AMED Preclinical research) and DIAN-J studies.
（Atsushi Iwata, Yu Nagashima, Toji Miyagawa, 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-specific patho-mechanisms for better diagnosis
and treatment of immune-mediated CNS inflammation.
(Sakuishi K, Koguchi A, and Kawasaki R)

Publication
1.

2.

3.

4.

Kodama S, Tokushige SI, Sugiyama Y, Sato K,
Otsuka J, Shirota Y, Hamada M, Iwata A, Toda T,
Tsuji S, Terao Y. Rituximab improves not only
back stiffness but also "stiff eyes" in stiff person
syndrome: Implications for immune-mediatedtreatment. J Neurol Sci. 2020 Jan 15;408:116506.
doi: 10.1016/j.jns.2019.116506.
Kuwabara N, Imae R, Manya H, Tanaka T, Mizuno
M, Tsumoto H, Kanagawa M, Kobayashi K, Toda
T, Senda T, Endo T, Kato R. Crystal structures of
fukutin-related protein (FKRP), a ribitolphosphate transferase related to muscular
dystrophy. Nat Commun. 2020 Jan 16;11(1):303.
doi: 10.1038/s41467-019-14220-z.
Koshi-Mano K, Mano T, Morishima M,
Murayama S, Tamaoka A, Tsuji S, Toda T, Iwata
A. Neuron-specific analysis of histone
modifications with post-mortem brains. Sci Rep.
2020 Feb 28;10(1):3767. doi: 10.1038/s41598020-60775-z.
Seki T, Kanagawa M, Kobayashi K, Kowa H,
Yahata N, Maruyama K, Iwata N, Inoue H, Toda
T. Galectin 3-binding protein suppresses amyloidβ production by modulating β-cleavage of amyloid

108

precursor protein. J Biol Chem. 2020 Mar 13;295(11):3678-3691. doi: 10.1074/jbc. RA119.
008703.
5. Kurihara M, Sasaki T, Sakuishi K, Terao Y,
Murakawa T, Shinozaki-Ushiku A, Okada S,
Toda T, Tsuji S. Isolated seizure as initialpresentation of GABAA receptor antibodyassociated encephalitis. J Neurol Sci. 2020 Mar
15; 410:116666. doi: 10.1016/j.jns.2020.116666.
6. Nishizawa M, Onodera O, Hirakawa A, Shimizu Y,
Yamada M; Rovatirelin Study Group. Effect ofrovatirelin in patients with cerebellar ataxia: two
randomised double-blind placebo-controlled
phase 3 trials. J Neurol Neurosurg Psychiatry.
2020 Mar;91(3):254-262. doi: 10.1136/jnnp2019-322168.
7. Kurihara M, Ishiura H, Bannai T, Mitsui J,
Yoshimura J, Morishita S, Hayashi T, Shimizu J,
Toda T, Tsuji S. A Novel de novo KIF1A Mutation
in a Patient with Autism, Hyperactivity, Epilepsy,
Sensory Disturbance, and Spastic Paraplegia.
Intern Med. 2020 Mar 15;59(6):839-842. doi:
10.2169/internalmedicine.3661-19.
8. Oji Y, Hatano T, Ueno SI, Funayama M, Ishikawa
KI, Okuzumi A, Noda S, Sato S, Satake W, Toda
T, Li Y, Hino-Takai T, Kakuta S, Tsunemi T,
Yoshino H, Nishioka K, Hattori T, Mizutani Y,
Mutoh T, Yokochi F, Ichinose Y, Koh K, Shindo K,
Takiyama Y, Hamaguchi T, Yamada M, Farrer MJ,
Uchiyama Y, Akamatsu W, Wu YR, Matsuda J,
Hattori N. Variants in saposin D domain of
prosaposin gene linked to Parkinson's disease.
Brain. 2020 Apr 1;143(4):1190-1205. doi:
10.1093/brain/awaa064.
9. Song D, Fu X, Ge L, Chang X, Wei C, Liu J, Yang
H, Qu S, Bao X, Toda T, Wu X, Xiong H. A splicesite mutation c.1251G>A of ISPD gene is acommon cause of congenital muscular dystrophy
in Chinese patients. Clin Genet. 2020 May;
97(5):789-790. doi: 10.1111/cge.13695.
10. Sato K, Mano T, Iwata A, Toda T.
Neuropsychiatric adverse events of chloroquine: areal-world pharmacovigilance study using the
FDA Adverse Event Reporting System (FAERS)
database. Biosci Trends. 2020 May 21;14(2):139143. doi: 10.5582/bst.2020.03082.
11. Morioka S, Sakaguchi H, Mohri H, Taniguchi-

12.

13.

14.

15.

16.

Ikeda M, Kanagawa M, Suzuki T, MiyagoeSuzuki Y, Toda T, Saito N, Ueyama T. Congenital
hearing impairment associated with peripheral
cochlear nerve dysmyelination in glycosylationdeficient muscular dystrophy. PLoS Genet. 2020
May 26;16(5): e1008826. doi: 10.1371/journal.
pgen.1008826.
Minakawa EN, Popiel HA, Tada M, Takahashi T,
Yamane H, Saitoh Y, Takahashi Y, Ozawa D,
Takeda A, Takeuchi T, Okamoto Y, Yamamoto K,
Suzuki M, Fujita H, Ito C, Yagihara H, Saito Y,
Watase K, Adachi H, Katsuno M, Mochizuki H,
Shiraki K, Sobue G, Toda T, Wada K, Onodera O,
Nagai Y. Arginine is a disease modifier for polyQ
disease models that stabilizes polyQ protein
conformation. Brain. 2020 Jun 1;143(6):18111825. doi: 10.1093/brain/awaa115.
Foo JN, Chew EGY, Chung SJ, Peng R,
Blauwendraat C, Nalls MA, Mok KY, Satake W,
Toda T, Chao Y, Tan LCS, Tandiono M, Lian MM,
Ng EY, Prakash KM, Au WL, Meah WY, Mok SQ,
Annuar AA, Chan AYY, Chen L, Chen Y, Jeon BS,
Jiang L, Lim JL, Lin JJ, Liu C, Mao C, Mok V, Pei
Z, Shang HF, Shi CH, Song K, Tan AH, Wu YR,
Xu YM, Xu R, Yan Y, Yang J, Zhang B, Koh WP,
Lim SY, Khor CC, Liu J, Tan EK. Identification of
Risk Loci for Parkinson Disease in Asians andComparison of Risk Between Asians andEuropeans: A Genome-Wide Association Study.
JAMA Neurol. 2020 Jun 1;77(6):746-754. doi:
10.1001/jamaneurol.2020.0428.
Porto, K-J, Matsukawa T, Ishiura, H, Mitsui J,
Matic A, Yu J-M, Dominguez J, Damian L, Toda
T, Tsuji S. A novel mutation in ABCD1 gene in a
Filipino patient with Adult-Onset X-linked ALD.
Neurol Clin Neurosci. 2020 June21;8(5):329-331.
doi:10.1111/ncn3.12425.
Sato K, Mano T, Suzuki K, Toda T, Iwatsubo T,
Iwata A; for Alzheimer’s Disease Neuroimaging
Initiative. Attempt to Predict A/T/N-Based
Alzheimer's Disease Cerebrospinal Fluid
Biomarkers Using a Peripheral Blood DNA
Methylation Clock. J Alzheimers Dis Rep. 2020
Jul 23;4(1):287-296. doi: 10.3233/ADR-200205.
Tamura T, Kodama S, Kitamura A, Toda T.
Transient Peri-ictal Edema around Calcified
Neurocysticercosis Lesions. Intern Med. 2020

109

17.

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Aug
1;59(15):1921-1922.
doi:
10.2169/
internalmedicine.4486-20.
Cha PC, Satake W, Ando-Kanagawa Y, Yamamoto
K, Murata M, Toda T. Genome-wide association
study identifies zonisamide responsive gene in
Parkinson's disease patients. J Hum Genet. 2020
Aug;65(8):693-704. doi: 10.1038/s10038-0200760-8.
Nakamura N, Tsunoda K, Mitsutake A, Shibata S,
Mano T, Nagashima Y, Ishiura H, Iwata A, Toda
T, Tsuji S, Sawamura H. Clinical Characteristics
of Neuronal Intranuclear Inclusion DiseaseRelated Retinopathy With CGG Repeat
Expansions in the NOTCH2NLC Gene. Invest
Ophthalmol Vis Sci. 2020 Sep 1;61(11):27. doi:
10.1167/iovs.61.11.27.
Uchio N, Unuma A, Kakumoto T, Osaki M, Zenke
Y, Sakuta K, Kubota A, Uesaka Y, Toda T,
Shimizu J. Pembrolizumab on pre-existing
inclusion body myositis: a case report. BMC
Rheumatol. 2020 Sep 16; 4:48. doi: 10.1186/
s41927-020-00144-5.
Porto K-J, Mitsui, J , Ishiura H, Kubota A, Luspian,
Kathleen Jaye; Emmanuel E, Ludwig D, Toda T,
Tsuji S. A novel multi-exon deletion in thedysferlin gene of a limb-girdle musculat dystrophy
type 2B Filipino patient. Neurol Clin Neurosci.
2020 Sep26;8(6):419-421. doi:10.1111/ncn3.
12453.
Matsukawa T, Shoji H, Urasaki Y, Ishiura H,
Mitsui J, Oguri S, Tsuji S, Toda T. Novel variantof CSF1R in a sporadic case with early-onset
cognitive impairment. Neurol Clin Neurosci.
2020 Sep26; 8(6):430-432. doi:10.1111/ncn3.
12452.
Tsuji Y, Ueda T, Sekiguchi K, Nishiyama M,
Kanda F, Nishigori C, Toda T, Matsumoto R.
Progressive length-dependent polyneuropathy inxeroderma pigmentosum group A. Muscle Nerve.
2020 Oct;62(4):534-540. doi: 10.1002/mus.27028.
Hirano M, Satake W, Moriyama N, Saida K,
Okamoto N, Cha PC, Suzuki Y, Kusunoki S, Toda
T. Bardet-Biedl syndrome and related disorders inJapan. J Hum Genet. 2020 Oct;65(10):847-853.
doi: 10.1038/s10038-020-0778-y.
Sato K, Mano T, Iwata A, Toda T.
Autocorrelation-based method to identify

25.

26.

27.

28.

29.

30.

31.

disordered rhythm in Parkinson's disease tasks: A
novel approach applicable to multimodal devices.
PLoS One. 2020 Oct 8;15(10):e0238486. doi:
10.1371/journal.pone.0238486. eCollection 2020.
Kawai M, Mano T, Naito T, Honda A, Nakai Y,
Toyama K, Fujioka Y, Makise N, Hasegawa
H,Sakuishi K, Kurokawa M, Toda T.
Disseminated necrotizing leukoencephalopathy
after allogeneic peripheral blood stem celltransplantation and methotrexate administration.
Neurol Clin Neurosci. 2020Nov05;9(1):155-156.
doi:10.1111/ncn3.12466.
Mitsutake A, Matsukawa T, Porto KJL, Sato T,
Katsumata J, Seki T, Maekawa R, Hideyama T,
Tanaka M, Ishiura H, Toda T, Tsuji S, Shiio Y. A
Japanese family with primary familial brain
calcification
presenting
withparoxysmal
kinesigenic dyskinesia - A comprehensive
mutational analysis. J Neurol Sci. J Neurol Sci.
2020 Nov 15;418:117091. doi: 10.1016/j.jns.2020.
117091.
Ueda K, Seto A, Mano T, Toda T. Isolated Body
Lateropulsion in Supplementary Motor Area
Infarction. Intern Med. 2 2020 Dec 1;59(23):3113-3114. doi: 10.2169/internalmedicine.532020.
Kobayashi R, Naruse H, Koyama S, Kawakatsu S,
Hayashi H, Ishiura H, Mitsui J, Ohta Y, Toda T,
Tsuji S, Otani K. Familial dementia with Lewy
bodies with VPS13C mutations. Parkinsonism
Relat Disord. 2020 Dec; 81:31-33. doi: 10.1016/
j.parkreldis.2020.10.008.
Chen XY, Song DY, Fan YB, Tan DD, Chang XZ,
Xiao JX, Toda T, Xiong H. Novel mutations in
B3GALNT2 gene causing α-dystroglycanopathy
in Chinese patients. Chin Med J (Engl). 2020 Dec
7. doi: 10.1097/CM9.0000000000001283.
Chikada A, Mitsui J, Matsukawa T, Ishiura H,
Toda T, Ogata K, Goto J ,Wenning GK, Tsuji S.
Reliability and validity of Japanese version ofUnified Multiple System Atrophy Rating Scale.
Neurol Clin Neurosci. 2020 Dec31;9(2):171180.doi:10.1111/ncn3.12477.
Sakurai Y, Kakumoto T, Takenaka Y, Matsumoto
H. Asymmetric Bálint's syndrome withmultimodal agnosia, bilateral agraphesthesia, andineffective kinesthetic reading due to subcortical

110

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34.

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36.

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hemorrhage in the left parieto-occipito-temporal
area. Neurocase. 2020 Dec;26(6):328-339. doi: 10.
1080/13554794.2020.1831546. PMID: 33103577.
Odake Y, Koh K, Takiyama Y, Ishiura H, Tsuji S,
Yamada M, Yoshita M. Identification of a novel
mutation in ATP13A2 associated with acomplicated form of hereditary spastic paraplegia.
Neurol Genet 2020;6:e514.
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 case report andliterature review. J Hum Genet 2020 in press. doi:
10.1038/s10038-020-00866-x.
Hosoe J, Miya F, Kadowaki H, Fujiwara T, Suzuki
K, Kato T, Waki H, Sasako T, Aizu K, Yamamura
N, Sasaki F, Kurano M, Hara K, Tanaka M, Ishiura
H, Tsuji S, Honda K, Yoshimura J, Morishita S,
Matsuzawa F, Aikawa SI, Boroevich KA,
Nangaku M, Okada Y, Tsunoda T, Shojima N,
Yamauchi T, Kadowaki T. Clinical usefulness ofmultigene screening with phenotype-driven
bioinformatics analysis for the diagnosis ofpatients with monogenic diabetes or severe insulin
resistance. Diabetes Res Clin Pract 2020;169:
108461.
Hongo H, Miyawaki S, Imai H, Shimizu M, Yagi
S, Mitsui J, Ishiura H, Yoshimura J, Doi K, Qu W,
Teranishi Y, Okano A, Ono H, Nakatomi H,
Shimizu T, Morishita S, Tsuji S, Saito N.
Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranialartery stenosis. Sci Rep 2020;10:11942.
Yoshida M, Hayashi T, Fujii K, Ishiura H, Tsuji S,
Sakurai Y. Selective impairment of On-reading(Chinese-style pronunciation) in alexia withagraphia for kanji due to subcortical hemorrhage
in the left posterior middle temporal gyrus.
Neurocase 2020;26:220–226.
Terao Y, Matsuda SI, Ishiura H, Tsuji S,
Yamamoto T, Fukuda H, Ugawa Y. Do eye
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Lim SY, Ishiura H, Ramli N, Shibata S, Almansour
MA, Tan AH, Houlden H, Lang AE, Tsuji S.
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Yanagisawa N, Adachi K, Nanba E, Ishiura H,
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Nishiyama K. An autopsy case of GM1
gangliosidosis type II in a patient who survived along duration with artificial respiratory support.
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Ishihara S, Okamoto Y, Tanabe H, Yoshimura A,
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Koh K, Ishiura H, Shimazaki H, Tsutsumiuchi M,
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spastic paraplegia. Mol Genet Genomic Med
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Matsukawa T, Shoji H, Urasaki Y, Ishiura H,
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Department of Neurosurgery
Professor
Nobuhito Saito, M.D., Ph.D.

Lecturer
Masahiro Shin, M.D., Ph.D.

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

Project Lecturer
Shota Tanaka, M.D.,Ph.D.
Naoto Kunii, M.D., Ph.D.

Associate
Taichi Kin, M.D., Ph.D.

Shunsaku Takayanagi, M.D., Ph.D.

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

Mariko Kawashima, M.D.

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

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

Satoshi Koizumi,M.D.,Ph.D.

Yuki Shinya, M.D.

Homepage

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

Introduction and Organization

Clinical activities

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, 2 lecturers, 2 project lectures,and
8 associates.
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.

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 isopen for patients with brain tumor, pituitary disease,spinal disease, cerebrovascular disease, endovascularintervention, epilepsy, and gamma knife treatment.
From April 2020 to March 2020, 16,509 patients weretreated at the outpatient clinics.
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

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surgery and pre- and intra-operative functional mapping in epilepsy surgery are frequently used to preserve
brain function as much as possible. Endoscopic
endonasal surgery is also frequently utilized as aminimally invasive therapeutic option for skull baselesions. State-of-the-art techniques including intraoperative computer-aided navigation and intravascular
procedures help our continuous effort to increase thesafety of surgical treatment. Some endovascular
procedures are performed in our hybrid operating roomwith the cooperation of the operation department andthe 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 case studies
and bedside teaching are scheduled in the third andfourth 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 hospitaland affiliated hospitals to experience every aspect ofneurosurgical practice for five years on average. Our
residency training is finalized after the sixth year, when
the finishing residents serve as senior residents at theuniversity hospital for 6 months. Academic training isprovided through numerous intramural clinical andresearch conferences, journal clubs, seminars as well as
quarterly regional meetings of the Japan NeurosurgicalSociety. After or during residency training, ourresidents can choose to be admitted into the Ph.D.
course at the Graduate School of Medicine, theUniversity of Tokyo, to be involved in advanced basic

research activities for 4 years. Upon completion oftraining, our graduates stay in the department to be
associates in our university hospital or become clinicalstaffs 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 aswell 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 adult neurogenesis
are currently investigated using various models toenhance post-ischemic regeneration. By extending the
research into primate model, we are pursuing clinicalapplication in the future.
2) 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

113

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
rateofsomatic
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 with whole exome
sequencing, RNA sequencing, and methylation analysis.
The current focus of our genome study is on spinal
astrocytoma and ependymoma. Our particular interest
also lies in heterogeneity and malignant progression ofglioma,especiallyfrom
immune-oncologicalperspectives.
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.

We have been collaborating with a basic research lab
in our university and developing novel fluorescenceprobes specifically detecting glioma with a hope thatfluorescence-guided surgery may result in greater
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 MRInegative cases, we are seeking to increase the accuracyof localizing epileptic focus using intracranialelectrodes. In addition to the state-of-art technologies
such as time-frequency analysis and cortico-corticalevoked potentials, we are developing next-generation
intracranial electrodes and accelerating research toidentify epileptogenic network. At the same time, we
aim to evaluate the effectiveness of function-preserving
procedures such as multiple hippocampal transection,
which has been originally developed in Japan. Also, as
the first facility to introduce vagus nerve stimulation(VNS) therapy in Japan, we are participating in aninternational collaborative research on the verificationof the effectiveness of VNS in the real world.
5) 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 withmuch higher spatial resolution and SN ratio. We aim tounderstand brain mechanisms as complicated network
systems and to improve the reliability of non-invasive
techniques. Since ECoG is a strong candidate for a
decoding source of brain-computer interface (BCI), weare planning to expand the research on this field toclinical implementation of BCI for communication andmotor control in cooperation with other brain researchlaboratories and engineering laboratories.
6) Clinical applications of the functional brain
imaging and operative simulation using three-114

dimensional 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 the multimodalities 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 (2020)
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doi: 10.3389/fpsyt.2020.00586
Tanaka S., Sato I., Takahashi M., Armstrong T. S.,
Cleeland C. S., Mendoza T. R., Mukasa A.,
Takayanagi S., Narita Y., Kamibeppu K., Saito N.
Validation study of the Japanese version of MD
Anderson Symptom Inventory for Brain Tumor
module. Jpn J Clin Oncol 50(7):787-793, 2020
doi: 10.1093/jjco/hyaa036
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. Journal of medical
genetics, 2020 doi: 10.1136/jmedgenet-2020106973
14. Yanai K., Shimada S., Kunii N., Takasago M.,
Takabatake K., Saito N. Earlier tachycardia forseizures originating from the right versus left
hemisphere in a patient with bilateral mesial
temporal lobe epilepsy. Clin Neurophysiol
131(9):2168-2170, 2020 doi: 10.1016/j.clinph.
2020.06.011
15. Yoshida S., Shin M., Kin T., Saito N. 3dimensional computer graphics model elucidating
involvement of intraparenchymal venous
malformation in trigeminal nucleus of brachium
pontis with intractable trigeminal neuralgia. J
Clin Neurosci 76:205-207, 2020 doi: 10.1016/j.
jocn.2020.04.042

Social Medicine
1. Occupational, Environmental
and Preventive Medicine

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

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

Assistant Professor
Daisuke Komura, M.D.,Ph.D.
Shuto Hayashi, 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 from time
to time, like infectious diseases and occupational healthto name a few, to meet the expectations of the society.
Eventually, in response to the completion of the Human
Genome Project and the recent advancement inmolecular biology, the laboratory had changed its nameto the Department of Molecular Preventive Medicine.
Under Professor Koji Matsushima, the 8th director of
the laboratory, research was actively 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 the nameof the department back to Preventive Medicine.
Currently, our lab includes (besides the professor, theassociate professor, and the assistant professors) 9

students (1 are from outside of UTokyo), 2 technicalstaffs, 10 technical assistants, 1 collaboration
researcher, 1 academic support staff, and 1 assistantclerk. Also, three collaborative researchers fromprivate companies have joined our laboratory.

Teaching activities
We give “Preventive Medicine” lecture course tothird-year undergraduate students in the school of
medicine,
practical
coursestofourth-year
undergraduate students, and “Introduction toPreventive Medicine” in medical science master’s
program. 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
science to explore the appropriate points ofintervention for various health issues, in particular,

118

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 in lymphocyte
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 andfoods that the individual has encountered, and byinternal factors, e.g., self-antigens and cancer antigens.
In the department of Preventive Medicine, we aretrying to develop a method to extract not only current
disease conditions but also other relevant healthinformation, such as past disease history and lifestyles,
by analyzing immune repertoires. In particular, in
immune repertoire analysis using gastric cancer andgastric mucosa tissues, we combine the results withcancer genome and microbiome analyses to decipher
immune history with regard to cancer antigens and H.
pylori in its entirety, and revealed that the sulfatedglycosaminoglycans 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.
Also, we are applying the obtained immune repertoire
data to design antibodies and use them in cancer

treatment and prevention.
2. Cancer
Genome Analysis
toExploreCarcinogenic Factors and Point of Intervention
We are combining human clinical cancer tissues with
NGS to achieve a comprehensive understanding of thecancer genome. Whole cancer genome sequencing will
provide numerous information, such as the driver genes,
which would serve direct therapeutic targets, and thegenetic background of an individual related tocarcinogenic predispositions. It also enables mutation
signature analysis to reveal environmental factors
which are also possible carcinogenic predispositions.
The obtained 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
and showed that its mutation signature differs from theintestinal-type gastric adenocarcinoma, suggesting thatcarcinogenic factors are different in these two types ofcancer. We are looking at cancer tissues as a whole, byapplying genomics point of view, i.e., single-cell
analysis, to cancer cells, immune cells, and vascularstroma cells that comprise cancer tissue, to elucidate
carcinogenic and progression factors and points ofintervention 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) of cancerfrom cancer histopathological images. Our goal is todevelop tools to achieve a uniform pathologicaldiagnosis and to help eliminate regional medical caredisparities. We developed Luigi, a content-based image
retrieval system for cancer histopathological images,
and made it available to pathologists and researchers in
Web (https://luigi-pathology.com/) and smartphone
application. The database in Luigi contains

119histopathologial images and their deep texture from
more than 7,000 cases of 32 cancer types in The Cancer
Genome Atlas. By uploading images, histopathologicalsimilar cases in the database are presented. Our current
focus is on the development of contents which would
seamlessly connect routine lab tests performed in small
clinics and cancer genome medicine given in large core
hospitals by integrated analysis of histopathologicalinformation and cancer genome information.

Publications
1.

2.

3.

4.

5.

6.

Atsumi, S., Katoh, H., Komura, D., Hashimoto, I.,
Furuya, G., Koda, H., Konishi, H., Suzuki, R.,
Yamamoto, A., Yuba, S., Abe, H., Rino, Y.,
Oshima, T., Ushiku, T., Fukayama, M., Seto, Y.,
Ishikawa,
S.,
2020.
Focal
adhesion
ribonucleoprotein complex proteins are major
humoral cancer antigens and targets in
autoimmune diseases. Communications Biology
3, 1–15.
Bailey, M.H., Meyerson, W.U., Dursi, L.J., Wang,
L.-B., Dong, G., Liang, W.-W., Weerasinghe, A.,
Li, S., Kelso, S., MC3 Working Group, PCAWG
novel somatic mutation calling methods working
group, Saksena, G., Ellrott, K., Wendl, M.C.,
Wheeler, D.A., Getz, G., Simpson, J.T., Gerstein,M.B., Ding, L., PCAWG Consortium, 2020.
Retrospective evaluation of whole exome andgenome mutation calls in 746 cancer samples. Nat
Commun 11, 4748.
Hiroshima, Y., Kasajima, R., Kimura, Y., Komura,D., Ishikawa, S., Ichikawa, Y., Bouvet, M.,
Yamamoto, N., Oshima, T., Morinaga, S., Singh,
S.R., Hoffman, R.M., Endo, I., Miyagi, Y., 2020.
Novel targets identified by integrated cancerstromal interactome analysis of pancreatic
adenocarcinoma. Cancer Lett. 469, 217–227.
ICGC/TCGA Pan-Cancer Analysis of Whole
Genomes Consortium, 2020. Pan-cancer analysisof whole genomes. Nature 578, 82–93.
Ikeda, H., Muroi, M., Kondoh, Y., Ishikawa, S.,
Kakeya, H., Osada, H., Imoto, M., 2020. Miclxin,
a Novel MIC60 Inhibitor, Induces Apoptosis via
Mitochondrial Stress in β-Catenin Mutant Tumor
Cells. ACS Chem Biol 15, 2195–2204.
Komura, D., Kawabe, A., Fukuta, K., Sano, K.,

Umezaki, T., Koda, H., Suzuki, R., Tominaga, K.,
Konishi, H., Nishida, S., Furuya, G., Katoh, H.,
Ushiku, T., Fukayama, M., Ishikawa, S., 2020.
Deep Texture Representations as a Universal
Encoder for Pan-cancer Histology. bioRxiv 2020.
07.28.224253.
7. Koyama, K., Maeda, D., Kito, M., Tamura, D.,
Kudo-Asabe, Y., Katoh, H., Ishikawa, S., Nanjo,
H., Terada, Y., Goto, A., 2020. Clinicopathological and molecular analyses of linearly
expanded epithelial cells with β-cateninalterations, “β-catenin signature”, in the normal
fallopian tube. Histopathology 77, 880–889.
8. Li, C.H., Prokopec, S.D., Sun, R.X., Yousif, F.,
Schmitz, N., PCAWG Tumour Subtypes andClinical Translation, Boutros, P.C., PCAWG
Consortium, 2020. Sex differences in oncogenic
mutational processes. Nat Commun 11, 4330.
9. Matsubara, D., Yoshimoto, T., Soda, M., Amano,Y., Kihara, A., Funaki, T., Ito, T., Sakuma, Y.,
Shibano, T., Endo, S., Hagiwara, K., Ishikawa, S.,
Fukayama, M., Murakami, Y., Mano, H., Niki, T.,
2020. Reciprocal expression of trefoil factor-1 andthyroidtranscription
factor-1
inlungadenocarcinomas. Cancer Sci 111, 2183–2195.
10. Midorikawa, Y., Yamamoto, S., Tatsuno, K.,
Renard-Guillet, C., Tsuji, S., Hayashi, A., Ueda,
H., Fukuda, S., Fujita, T., Katoh, H., Ishikawa, S.,
Covington, K.R., Creighton, C.J., Sugitani, M.,
Wheeler, D.A., Shibata, T., Nagae, G., Takayama,T., Aburatani, H., 2020. Accumulation of
Molecular
Aberrations
Distinctive
toHepatocellular Carcinoma Progression. Cancer
Res 80, 3810–3819.
11. Ohkuma, R., Yada, E., Ishikawa, S., Komura, D.,
Ishizaki, H., Tamada, K., Kubota, Y., Hamada, K.,
Ishida, H., Hirasawa, Y., Ariizumi, H., Satoh, E.,
Shida, M., Watanabe, M., Onoue, R., Ando, K.,
Tsurutani, J., Yoshimura, K., Yokobori, T.,
Sasada, T., Aoki, T., Murakami, M., Norose, T.,
Ohike, N., Takimoto, M., Izumizaki, M.,
Kobayashi, S., Tsunoda, T., Wada, S., 2020a.
High expression of olfactomedin-4 is correlatedwith chemoresistance and poor prognosis inpancreatic cancer. PLoS ONE 15, e0226707.
12. Ohkuma, R., Yada, E., Ishikawa, S., Komura, D.,
Kubota, Y., Hamada, K., Horiike, A., Ishiguro, T.,

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13.

14.

15.

16.

17.

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., 2020b. High expression
levels of polymeric immunoglobulin receptor are
correlated with chemoresistance and poor
prognosis in pancreatic cancer. Oncology
Reports. 44, 252-262
Sano, K., Matsuda, S., Tohyama, S., Komura, D.,
Shimizu, E., Sutoh, C., 2020. Deep learning-basedclassification of the mouse estrous cycle stages.
Scientific Reports 10, 11714.
Shinozaki-Ushiku, A., Ishikawa, S., Komura, D.,
Seto, Y., Aburatani, H., Ushiku, T., 2020. The firstcase of gastric carcinoma with NTRK
rearrangement: identification of a novel ATP1BNTRK1 fusion. Gastric Cancer 23, 944–947.
Suzuki, A., Katoh, H., Komura, D., Kakiuchi, M.,
Tagashira, A., Yamamoto, S., Tatsuno, K., Ueda,
H., Nagae, G., Fukuda, S., Umeda, T., Totoki, Y.,
Abe, H., Ushiku, T., Matsuura, T., Sakai, E.,
Ohshima, T., Nomura, S., Seto, Y., Shibata, T.,
Rino, Y., Nakajima, A., Fukayama, M., Ishikawa,
S., Aburatani, H., 2020. Defined lifestyle andgermline factors predispose Asian populations togastric cancer. Science Advances 6, eaav9778.
Takai, E., Maeda, D., Li, Z., Kudo-Asabe, Y.,
Totoki, Y., Nakamura, H., Nakamura, A.,
Nakamura, R., Kirikawa, M., Ito, Y., Yoshida, M.,
Inoue, T., Habuchi, T., Ikoma, S., Katoh, H., Kato,
M., Shibata, T., Ishikawa, S., Yachida, S., Goto,A., 2020. Post-mortem Plasma Cell-Free DNA
Sequencing: Proof-of-Concept Study for the“Liquid Autopsy.” Scientific Reports 10, 1–10.
Watabe, S., Kikuchi, Y., Morita, S., Komura, D.,
Numakura, S., Kumagai-Togashi, A., Watanabe,M., Matsutani, N., Kawamura, M., Yasuda, M.,
Uozaki,H.,
2020.
Clinicopathologicalsignificance of microRNA-21 in extracellular
vesicles of pleural lavage fluid of lungadenocarcinoma and its functions inducing themesothelial to mesenchymal transition. Cancer
Med 9, 2879–2890.

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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.

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, 4 project
researchers (part-time), 2 supporting staff members, 9
graduate students (3 in PhD program, 6 in professional
degree course), 16 part-time lecturers, and 36 visiting
fellows.

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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). Eachgroup conducts field practice, review work, orlaboratory work, and writes a report in the style oforiginal or review paper. However, because of the
COVID-19 pandemic, the above groups werereorganized into eight groups and the practice andwork was conducted online.
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
Other research activities include, (1) evaluation of

123

disaster 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.

8

References
1

2

3

4

5

6

7

Ikesu R, Miyawaki A, Kobayashi Y. Physician
distribution by specialty and practice setting:findings in Japan in 2000, 2010 and 2016. The
Tohoku Journal of Experimental Medicine,251(1): 1-8, 2020. doi: 10.1620/tjem.251.1
Lin C, Tomio J, Tanaka H, Sonoda M, Sano K,
Kobayashi Y. Diagnosis and medical care forcongenital
cytomegalovirus infection: anobservational study using claims data in Japan,
2010 to 2017. Medicine, 99: 10 (e19419), 2020.
http://dx.doi.org/10.1097/MD.000000000001941
9
Ito Y, Hara K, Kobayashi Y. The effect of inertia
on brand-name versus generic drug choices.
Journal of Economic Behavior and Organization,
172: 364-379, 2020. https://doi.org/10.1016/j.
jebo.2019.12.022
Fukunishi H, Nishiyama M, Luo Y, Kubo M,
Kobayashi
Y.
Alzheimer-typedementia
prediction by sparse logistic regression using
claim data. Computer Methods and Programs in
Biomedicine, 196: 105582, 2020. http://doi.org/
10.1016/j.cmpb.2020.105582
Abe K, Miyawaki A, Kobayashi Y, Watanabe T,
Tamiya N. Place of death associated with types oflong-term care services near the end-of-life forhome-dwelling older people in Japan: a pooled
cross-sectional study. BMC Palliative Care, 19(1):121, 2020. doi:10.1186/s12904-020-00622-0
Iba A, Tomio J, Ymana H, Sugiyama T,
Yoshiyama T, Kobayashi Y. Tuberculosis
screening and management of latent tuberculosis
infection prior to biologic treatment in patientswith immune-mediated inflammatory diseases: A
longitudinal population-based analysis using
claims data. Health Science Reports, 3: e216,
2020. https://doi.org/10.1002/hsr2.216
Kaneko R Sato Y, Kobayashi Y. Manufacturing

9

10

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12

13

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industry cancer risk in Japan: A multicenter
hospital-based case control study. Asian Pacific
Journal of Cancer Prevention 21 (9): 2697-2707,
2020. doi: 10.31557/APJCP.2020.21.9.2697
Adachi N, Kobayashi Y. One-year follow-up
study on associations between dental caries,
periodontitis, and metabolic syndrome. Journal of
Oral Science 62 (1): 52-56, 2020. doi.org/10.
2334/josnusd.18-0251
Zaitsu M, Lee HE, Lee S, Takeuchi T, Kobayashi
Y, Kawachi I. Occupational disparities in bladdercancer survival: A population-based cancer
registry study in Japan. Cancer Medicine 9:
894-901, 2020. doi: 10.1002/cam4.2768
Zaitsu M, Takeuchi T, Kobayashi Y, Kawachi I.
Light to moderate amount of lifetime alcohol
consumption and risk of cancer in Japan. Cancer
126 (5): 1031-1040, 2020. doi: 10.1002/cncr.
32590
Ihana-Sugiyama N, Sugiyama T, Tanaka H, Ueki
K, Kobayashi Y, Ohsugi M. Comparison ofeffectiveness and drug cost between dipeptidyl
peptidase‐4 inhibitor and biguanide as the first‐line anti‐hyperglycaemic medication among
Japanese working generation with type 2 diabetes.
Journal of Evaluation in Clinical Practice 26:299-307, 2020. doi.org/10.1111/jep.13171
Miyawaki A, Kobayashi Y, Kawachi I.
Self-reported hearing/visual loss and mortality in
middle-aged and older adults: Findings from the
Komo-Ise
Cohort,Japan.
Journalof
Epidemiology 30 (2): 67-73, 2020. https://doi.
org/10.2188/jea.JE20180198
Nakao M, Okumura A, Hasegawa J, Toyokawa S,
Ichizuka K, Kanayama N, Satoh S, Tamiya N,
Nakai A, Fujimori K, Maeda T, Suzuki H,
Iwashita M, Ikeda T. Fetal heart rate pattern interm or near-term cerebral palsy: a nationwide
cohort study. American Journal of Obstetrics &Gynecology, 233(6): 907(e1-e13), 2020. doi: 10.
1016/j.ajog.2020.05.059
Toyokawa S, Hasegawa J, Ikenoue T, Asano Y,
Jojima E, Satoh S, Ikeda T, Ichizuka K, Takeda S,
Tamiya N, Nakai10 A, Fujimori K, Maeda T,
Masuzaki H, Suzuki H, Ueda S. Weekend andoff-hour effects on the incidence of cerebral
palsy: contribution of consolidated perinatal care.

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15

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21

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Environmental Health and Perventive Medicine,
25: 52, 2020. doi:10.1186/s12199-020-00889-y
Okada F, Toyokawa S, Kaneko T, Furuhata T.
Frequency of going out and locomotive syndrome
among Japanese female elderlies. Global Journalof Health Science, 12(1): 80-85, 2020. doi:10.
5539/gjhs.v12n1p80
Okada F, Kaneko T, Toyokawa S, Furuhata T.
Contextual associations of interregional income
gap with physical constitution and dietaryenvironment in individual housebound elderly.
Global journal of health science, 12(4): 94-103,
2020. doi: 10.5539/gjhs.v12n4p94
Taguchi A, Hara K, Tomio J, Kawana K, Tanaka
T, Baba S, Kawata A, Eguchi S, Tsuruga T, Mori
M, Adachi K, Nagamatsu T, Oda K, Yasugi T,
Osuga Y, Fujii T. Multistate Markov model topredict the prognosis of high-risk humanpapillomavirus-related cervical lesions. Cancers(Basel), 12(2):270, 2020. doi:10.3390/cancers
12020270
Morioka N, Moriwaki M, Tomio J, Kashiwagi M,
Fushimi K, Ogata Y. Structure and process ofdementia care and patient outcomes after hip
surgery in elderly people with dementia: A
retrospective observational study in Japan.
International Journal of Nursing Studies, 102:103470,2020.
doi:10.1016/j.ijnurstu.2019.
103470Inada H, Tomio J, Nakahara S, Ichikawa M.
Area-wide traffic-calming zone 30 policy ofjapan and incidence of road traffic injuries among
cyclists and pedestrians. American Journal of
Public Health, 100(2):237-243, 2020. doi:10.
2105/AJPH.2019.305404
Oguma T, Watanabe E, Mori T, Fujino.
Autonomous continuation of community healthworkers' activities in Thegon Township, Bago
Region, Myanmar. Frontiers in Public Health 8:
201, 2020. https://doi.org/10.3389/fpubh.2020.
00201
Gero K, Miyawaki A, Kawachi I. Relative
income deprivation and all-cause mortality inJapan: Do life priorities matter? Annals of
Behavioral Medicine, 54(9):665-679, 2020. doi:
10.1093/abm/kaaa010
Kaneko S, Noguchi H, Fu R, Kang C, Kawamura

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A, Amano S, Miyawaki A. Differences in cancer
patients’work-cessation risk, based on gender andtype of job: Examination of middle-aged andolder adults in super-aged Japan. PLoS ONE,15(1): e0227792, 2020. doi:10.1371/journal.pone.
0227792
Miyawaki A, Hasegawa K, Figueroa JF, Tsugawa
Y. Hospital readmission and emergency
department revisits of homeless patients treatedat homeless-serving hospitals in the USA:
Observational study. The Journal of General
Internal Medicine, 35(9):2560-2568, 2020. doi:10.
1007/s11606-020-06029-0
Miyawaki A, Hasegawa K, Tsugawa Y. Lessons
from influenza outbreaks for potential impact of
COVID-19
outbreakonhospitalizations,ventilator use, and mortality among homelesspersons in New York State. The Journal of
General Internal Medicine, 35: 2781-2783, 2020.
doi:10.1007/s11606-020-05876-1
Miyawaki A, Kobayashi Y, Noguchi H, Watanabe
T, Takahashi H, Tamiya N. Effect of reduced
formal care availability on formal/informal carepatterns and caregiver health: a quasiexperimental study using the Japanese long-termcare insurance reform. BMC Geriatrics, 20(1):207, 2020. doi:10.1186/s12877-020-01588-7
Miyawaki A, Tsugawa Y. Association between
Newsweek’s Global Hospital Ranking and patient
outcomes in the USA. The Journal of General
Internal Medicine, 35(4):1343-1344, 2020. doi:
10.1007/s11606-019-05212-2
Goto T, Hara K, Hashimoto K, Soeno S,
Shirakawa T, Sonoo T, Nakamura K. Validationof chief complaints, medical history, medications,and physician diagnoses structured with an
integrated emergency department information
system in Japan: the Next Stage ER system.
Acute Medicine & Surgery, 7(1):1-8, 2020. doi:
10.1002/ams2.554
Kinoshita Y, Yagisawa T, Sugihara T, Hara K,
Takeshima S, Kubo T, Shinzato T, Shimizu T,
Suzuki M, Maeshima A, Kamei J, Fujisaki A,
Ando S, Suzuki M, Kume H, Fujimura T. Clinicaloutcomes in donors and recipients of kidneytransplantations involving medically complex
living donors – a retrospective study. Transplant

125

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31

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1111/tri.13699
Shimizuguchi T, Sekiya N, Hara K, Taguchi A,
Nakajima Y, Miyake Y, Shibata Y, Taguchi K,
Ogawa H, Ito K, Karasawa K. Radiation therapy
and the risk of herpes zoster in patients withcancer. Cancer, 126(15):3552-3559, 2020. doi:10.
1002/cncr.32926
Kaito S, Nakajima Y, Hara K, Toya T, Nishida T,
Uchida N, Mukae J, Fukuda T, Ozawa Y, Tanaka
M, Ikegame K, Katayama Y, Kuriyama T, Kanda
J, Atsuta Y, Ogata M, Taguchi A, Ohashi K.
Heterogeneous impact of cytomegalovirus
reactivation on nonrelapse mortality inhematopoietic stem cell transplantation. Blood
Advances, 4(6):1051-1061, 2020. doi:10.1182/
bloodadvances.2019000814
Baba S, Taguchi A, Kawata A, Hara K, Eguchi S,
Mori M, Adachi K, Mori S, Iwata T, Mitsuhashi
A, Maeda D, Komatsu A, Nagamatsu T, Oda K,
Kukimoto I, Osuga Y, Fujii T, Kawana K.
Differential expression of human papillomavirus
16-, 18-, 52-, and 58-derived transcripts incervical intraepithelial neoplasia. Virology
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Taguchi A, Furusawa A, Ito K, Nakajima Y,
Shimizuguchi T, Hara K, Takao M, Kashiyama T,
Kino N, Karasawa K, Yasugi T. Postradiotherapy
persistent lymphopenia as a poor prognostic
factor in patients with cervical cancer receiving
radiotherapy: a single-center, retrospective study.
International Journal of Clinical Oncology,
25(5):955–962, 2020. doi:10.1007/s10147-02001623-y
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, 2020
[Epub ahead of print]. https://journals.lww.com/
10.1097/SLA.0000000000004528
Tanaka H, Mackenbach JP, Kobayashi Y.
Widening socioeconomic inequalities in smoking
in Japan, 2001-2016. Journal of Epidemiology,
2020 [Epub ahead of print]. https://doi.org/10.
2188/jea.JE20200025

35 Abe K, Miyawaki A, Nakamura M, Ninomiya H,
Kobayashi Y. Trends in hospitalizations forasthma during the COVID-19 outbreak in Japan.
The Journal of Allergy and Clinical Immunology:
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https://doi.org/10.1016/j.jaip.2020.09.060
36 Yamana H, Iba A, Tomio J, Ono S, Jo T,
Yasunaga H. Treatment of latent tuberculosis
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37 Maeda Y, Nakamura M, Ninomiya H, Ogawa K,
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39 Taniguchi Y, Iwagami M, Sakata N, Watanabe T,
Abe K, Tamiya N. Epidemiology of food choking
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20200057

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

127

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., Ayumi Motomura, M.D., Ph.D., Fumiko Chiba, M.D., Ph.D.

Homepage

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 fingerprinting 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,
toxicological, and blood type tests. Finally, forensic

128

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) started. Infection
control in dissection has become a hot topic, but with
the introduction of the laminar-flow autopsy tablefollowing the seismic retrofitting carried out last year,
it has become possible to accept SARS-CoV2-infected bodies. While all cases were tested by the
Department of Infection Control and Prevention of the
University of Tokyo Hospital at the beginning of thepandemic, now that we have newly introduced ourown real-time PCR system in our laboratory,
conducting a SARS-CoV-2 PCR test in all cases.

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
Clerkship learning, each student experiences theprocess 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 and Tokyo Medical and Dental
University, researches in 6 sections (forensic
pathology, clinical forensic medicine, forensic
toxicology, forensic radiology, forensic odontology
and forensic genetics) have proceeded.

1. Forensic Pathology
In autopsy, it is difficult to examine a vertebral
artery. We therefore conduct study on a method of
the artery using angioscopy. We also conduct
research about the usefulness of coronary
angiography using 3D-CT. As to pathologicalresearch, we investigate about the lipid peroxidationin the cases of stimulant intoxication and crash
syndrome.
2. Clinical Forensic Medicine
We have started to liaise with child consultation
centers to examine children suspected of suffering
abuse. We will also collaborate with otherinstitutions to establish a framework for child abuse
examinations in Chiba Prefecture. Through these
activities, we will continue to work to establish thepractice of clinical forensic medicine while
educating students and conducting research on theprevention of child abuse, with the objective of
laying the foundations for the discipline of clinicalforensic medicine in Japan.
3. Forensic Toxicology
Using LC/MS/MS and LC/QTOF-MS themethods to detect illegal drugs are investigated. We
also conduct study on the post-mortem
redistribution of some drugs by experiments using
animals. We try to figure out the standardized
method of drug testing in the field of Japanese
forensic medicine.
4. Forensic Odontology
A new method of personal identification (ageestimation and DNA testing) and drug analysis
using a single tooth at once is developed.
5. Forensic Genetics
We try to find gene alterations that cause asudden death of an individual. We also try to figureout new methods to predict the birth place of the
cadaver by analyzing the DNA types of parasites.
6. Forensic Radiology
Using 3D-CT, we develop new methods toperform stature and sex estimation using themeasurements of various bones. We investigate the129merit and demerit of post-mortem imaging todetermine the cause of death.

Publications
1.

2.

3.

4.

5.

6.

7.

8.

9.

Haragi M, Yamaguchi R, Okuhara T, Kiuchi T.
Interviewing forensic specialists regarding
medical-legal illustration methods to replace
gruesome graphic evidence. J Vis Commun Med.
2020; 43 (1): 27-34.
Haragi M, Yamaguchi R, Okuhara T, Kiuchi T.
Questionnaire survey of a mock jury on theirimpressions of medical-legal illustrations aimed
at reducing trauma and PTSD of jurors. J Vis
Commun Med. 2020; 43 (2): 67-75.
Torimitsu S, Abe H, Ikemura M, Gonoi W, Ishida
M, Makino Y, Iwase H. Multiple intracerebral
hemorrhages associated with lipohyalinosis: acase report. Forensic Imaging. 2020; 200375.
Inokuchi G, Chiba F, Makino Y, Tsuneya S, Iwase
H. Sudden death due to tension pneumothorax
associated with pulmonary tuberculosis. Forensic
Sci Med Pathol. 2021 ;17(1):152-156.
Ishihara K, Iwase H. Reform of the deathinvestigation system in Japan. Medicine, Scienceand the Law. 2020;60(3):216-222.
Hoshioka Y, Abe H, Yajima D, Makino Y,
Yamaguchi R, Saitoh H, Inokuchi G, Motomura
A, Nagasawa S, Iwase H. The composition ofchlorinated or oxidized phosphatidylcholine
products changes with hypochlorite concentration: Application to abscess lipid analysis. Leg
Med (Tokyo). 2020; 46: 101724.
Yoshida M, Makino Y, Hoshioka Y, Chiba F,
Inokuchi G, Torimitsu S, Yamaguchi R,
Motomura A, Abe H, Yajima D, Iwase H. Fatal
hemorrhage complicated with methamphetamine
poisoning and its post-mortem CT features.
Forensic Sci Med Pathol. 2020;16(4):577-585.
Yoshida M, Hoshioka Y, Makino Y, Kojima M,
Horikoshi T, Mukai Hikosaka K, Norose K,
Iwase H. Pseudo-'Pneumatosis intestinalis’ sign:
a case of parasite uniquely depicted on postmortem CT. Forensic Imaging.2020.
Monum T, Makino Y, Prasitwattanaseree S,
Yajima D, Chiba F, Torimitsu S, Hoshioka Y,
Yoshida M, Urabe S, Oya Y, Iwase H. Ageestimation from ossification of sternum and true
ribs using 3D post-mortem CT images in a
Japanese population. Leg Med (Tokyo). 2020; 43:
101663.
10. Helmrich E, Decker L, Adolphi N, Makino Y.
Postmortem CT lung findings in decedents with
Covid-19: A review of 14 decedents and potential
triage implications. Forensic Imaging, 2020; 23;200419.
11. Tanaka C, Utsuno H, Makino Y, Minegishi S, Ota
J, Iwase H, Sakurada K. Facial soft tissue
thickness of the Japanese population determinedusing post mortem computed tomography images.
Forensic Imaging. 2020; 23; 200423.
12. Makino Y, Kojima M, Yoshida M, Motomura A,
Inokuchi G, Chiba F, Torimitsu S, Hoshioka Y,
Yamaguchi R, Saito N, Urabe S, Tsuneya S,
Horikoshi T, Yajima D. Iwase H. Postmortem CT
and MRI findings of massive fat embolism.
International Journal of Legal Medicine, volume
134, pages 669–678.

130

Department of
Biomedical Informatics
Professor
Kazuhiko Ohe

Associate Professor
Kayo Waki, Yoshimasa Kawazoe, Ken Imai

Assistant Professor
Yusuke Ida, Shinichiro Yokota

Homepage

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

Introduction and Organization
The Department of Medical Informatics andEconomics aims to reform medical systems and makesocial contribution by applying information
technology to medical field such as medical
economics and hospital management. The department
develops basic methods that are applicable to medical
information systems in the boundary area of
healthcare and information science, establishes
infrastructures for information environment where
medical information are utilized effectively, andapplies knowledge and technique acquired throughthese efforts to medical and healthcare field.
The main keywords of the target domain are
medical and clinical information systems, nextgeneration electronic health record systems, virtual
health care environment, computer representations andstandardization of medical concepts, ontology,
medical knowledge engineering, hospital epidemiology, quality assessment of healthcare, clinical andbioinformatics engineering, privacy protection andencryption, analysis of hospital management, safety
management in healthcare.
The professor of the department also holds the
position of director of the department planning, information and management (DPIM) in the University ofTokyo Hospital. DPIM is the department that deals
with information analyses and future planning for the

University of Tokyo Hospital by using information
systems as well as the planning, design, development,
and operation of information systems for the whole
hospital. The DPIM was newly established on April 1,
2003, after integration of the Hospital Computer
Center and the project team for hospital development,
which separately existed until the end of March, 2003.
Since the professor runs the Department of Medical
Informatics and Economics with staffs of DPIM, they
are practically the same organization. Therefore,
educations and researches in the graduate course arepromoted together with DPIM activities. The origin of
the Department of Medical Informatics andEconomics dates back to 1983 when the hospitalcomputer center was officially approved as one of thecentral clinical service facilities in the hospital. At thesame time, the doctor’s course for medical informatics
was established. The first professor was Dr. Shigekoto
Kaihara, who is the founder of medical informatics inJapan. In accordance with the reform to the university
with graduate school curriculum in the university ofTokyo, the Department of Medical Informatics andeconomics was established in present division ofsocial medicine in 1997. Then, one professor and one
associate professor belonging to the hospital computer
center moved to the department. In 2000, medical
informatics field was set up in the Interfaculty
Initiative in Information Studies, Graduate School of131Interdisciplinary Information Studies. The department
is located on the fourth floor in Administration andResearch Building in the University of Tokyo
Hospital.

Teaching activities1). 4-year Ph.D. Course in the Department of Medical
Informatics and Economics at the Division ofSocial Medicine: The Department of Medical
Informatics and Economics at the Division ofSocial Medicine offers the Medical Sciences
doctoral course (4-year program) and admission is
open to those who graduate from a 6-year programat the Faculty of Medicine (the School of Medicine),
and those who complete the master course either in
the University of Tokyo or any other institutions(not necessary to be a doctor). Students will acquire
Doctoral Degree (Ph.D.) of Medical Science withcompletion of required units and passing a doctoral
thesis.
2). 3-year Ph.D. Course and 2-year M.H.S course in
the Department of Health Informatics at theDivision of Health Sciences and Nursing: The
Department of Medical Informatics and Economics
is a collaborating department with the Division of
Health Sciences and Nursing at the Graduate
School of Medicine, and it is called the Department
of Health Medical Informatics. At the Department
of Health Medical Informatics within the Divisionof Health Sciences and Nursing, the department
offers the Master course in Health Science andNursing (2-year program) and the Health Sciences
and Nursing doctoral course (3-year program). In
the master course, students will acquire Master of
Health Sciences with completion of required units
and passing a master’s thesis. In the doctoral course,
students will acquire Doctor of Health Sciences(Ph.D.) with completion of required units andpassing a doctoral thesis.
3). 2-year M.P.H and 1-year M.P.H in the Department
of Health Informatics in the Shool of Public Health:
We offer 2-year Master of Publics Health (M.P.H)
course and the 1-year M.P.H program in the Schoolof Publics Health. See the homepage of the Schoolof Publics Health.
4). 2-year M.M.S in the Department of Health

Medical Informatics in the Medical Science
Graduate Program: Graduate School of Medicine,the University of Tokyo, offers the master course in
Medical Sciences. The course was established forstudents who graduate from faculties other than a
6-year program at Faculty of Medicine andeventually wish to advance to the Medical Sciences
doctoral course of the University of Tokyo.
The students in FY2019 are eleven in doctor’s coursefor Biomedical Informatics.
The researches cover various topics; developmentof medical decision support system, analysis of
medical human resources in Japan, research for
medical and e-Phenotyping in large healthcare
database, etc.

Research activities
The research domains are 1) application studies ondevelopments of clinical information systems, hospital
information system and electronic health records
system, 2) medical knowledge discovery fromdatabases of hospital information system, 3) structured
representations and standardization of medical terms
and concepts, 4) privacy protection and security inhealthcare information systems, 5) mobile health that
supports self-management of lifestyle-related diseases.
In these domains, one of the major research topics
is joining the University of Tokyo COI (Center of
Innovation) Project named “Self Management of Your
Health”. The COI project aims to construct anddeliver an infrastructure for the enhancement ofclinical database research and the standardization ofnation-wide health information systems. The
department plays a role of the development as a
sub-project leader. The use of SS-MIX2 standard andextensive storage system is key technology forconverting vender-proprietary database format into theinternational standard format and facilitating easy
multi-purpose secondary use for clinical researches
and other researches in social medicine area.
Other various project for standardization of medical or
health information systems, creating big database inhealthcare domain, developing the national healthcare
information database (MID-NET database) for
detecting adverse event of drugs, etc.

132

Publications
1. Sofue T, Nakagawa N, Kanda E, Nagasu H,
Matsushita K, Nangaku M, Maruyama S, Wada T,
Terada Y, Yamagata K, Narita I, Yanagita M,
Sugiyama H, Shigematsu T, Ito T, Tamura K,
Isaka Y, Okada H, Tsuruya K, Yokoyama H,
Nakashima N, Kataoka H, Ohe K, Okada M,
Kashihara N.Prevalence of anemia in patientswith chronic kidney disease in Japan: A
nationwide, cross-sectional cohort study using
data from the Japan Chronic Kidney Disease
Database (J-CKD-DB).PLoS One. 2020 Jul 20;
15(7):e0236132.
2. Tanaka Y, Tajima T, Seyama M, Waki K.
Differential Continuous Wave Photoacoustic
Spectroscopy
for
Non-Invasive
GlucoseMonitoring. IEEE SENSORS JOURNAL. 2020
Apr; 20(8):4453-4458.
3. Yoshida Y, Patil SJ, Brownson RC, Boren SA,
Kim M, Dobson R, Waki K, Greenwood DA,
Torbjørnsen A, Ramachandran A, Masi C,
Fonseca VA, Simoes EJ. Using the RE-AIM
framework to evaluate internal and external
validity of mobile phone-based interventions indiabetes self-management education and support.
J Am Med Inform Assoc. 2020 May 7.
4. Adachi H, Kawamura Y, Nakagawa K, Horisaki R,
Sato I, Yamaguchi S, Fujiu K, Waki K, Noji H,
Ota S. Use of Ghost Cytometry to Differentiate
Cells
with
SimilarGross
Morphologic
Characteristics. Cytometry A. 2020 Apr;97(4):415-422.
5. Hirano R, Yamaguchi S, Waki K, Kimura Y, Chin
K, Nannya Y, Nangaku M, Kadowaki T, Ohe K.
Willingness of Patients Prescribed Medications
for Lifestyle-Related Diseases to Use Personal
Health Records: Questionnaire Study. J MedInternet Res. 2020 May 28;22(5):e13866.
6. Waki K, Sankoda A, Amano S, Ogawa M, Ohe K.
Responding to COVID-19: Agile Use ofInformation Technology to Serve Patients With
Diabetes. J Diabetes Sci Technol. 2020 Jul;
14(4):807-808.
7. Sudo K, Murasaki K, Kinebuchi T, Kimura S,
Waki K. Machine learning-based screening of
Healthy Meals from their Images. JMIR Form Res.

2020 Oct 26;4(10):e18507.
8. Kodama T, Ida Y, Miura H. A Nationwide Survey
on Working Hours and Working Environment
among Hospital Dentists in Japan. Int J Environ
Res Public Health. 2020;17(23):9048
9. Mitani T, Doi S, Yokota S, Imai T, Ohe K. Highly
accurate and explainable detection of specimen
mix-up using a machine learning model. Clinical
Chemistry and Laboratory Medicine. 2020;58(3):375–383.
10. Yamada K, Yamaguchi S, Fuji T, Sato K, Ohe T,
The COVID-19 outbreak limits physical activities
and increases sedentary behaviour: a possible
sedentary public health crisis for the elderly. J
Orthop Sci. 2020;25(6):1093-1094.
11. Yamada K, Yoichi M Ito, Akagi M, Chosa E, Fuji
T, Hirano K, Ikeda, S, Ishibashi H, Ishibashi Y,
Ishijima M, Itoi E, Iwasaki N, Izumida R, Kadoya
K, Kamimura M, Kanaji A, Kato H, Kishida S,
Mashima N, Matsuda S, Matsui Y,Matsunaga T,
Miyakoshi N, Mizuta H, Nakamura Y, Nakata
K,Omori G, Osuka K, Uchio Y, Ryu K,Sasaki N,
Sato K, Senda M, Sudo A, Takahira N, Tsumura
H, Yamaguchi S, Yamamoto N, Nakamura K,
Ohe T. Reference values for the Locomotive
Syndrome Risk Test quantifying mobility of 8681
adults aged 20 to 89 years: a cross-sectional
nationwide study in Japan. J Orthop Sci. 2020
Nov;25(6):1084-1092.

Internal Medicine
1. Medicine Ⅰ

134

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, the second
professor, the present professor Issei Komuro waselected in August, 2012. Our department comprises one
professor, 4 lecturers, 2 hospital lecturers, 15 research
assistants, 10 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 2020, a total of 1,653 patients were newly
admitted to our hospital ward of 61 beds. The average
duration of hospitalization was 11.1 days.

Because we are an authorized facility for heart transplantation, the use of left ventricular assist device incases 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 2019, 15
patients underwent heart transplant (total 153 cases). In
March 2014, our facility was also authorized to perform
lung transplantation. Coronary angiography was
performed in 1,875 patients, of which 371 patients
underwent percutaneous coronary interventions. CT
coronary angiography and cardiovascular MRI were
performed in 676 and 134 patients, respectively. With
regard to arrhythmias, there were 283 cases of catheter
ablation, 142 cases of implantation or replacement ofpacemakers and other specialized pacemaker devices,
including 27 cases of implantation or replacement of
implantable cardioverter-defibrillator and 24 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
162.6 patients visit 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

135

failure, pulmonary hypertension, congenital heartdisease, valvular heart disease, arrhythmia, Marfan
syndrome, cardiac amyloidosis, and onco-cardiology.
The department is also focused on acute cases ofcoronary heart disease and aortic disease, as emergent
catheterization is available on a 24-hour basis.

Education
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 clinical lecturesand 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.

10. New treatments for pulmonary hypertension
11. New treatments for congenital heart disease
12. Aerobic threshold and cardiac rehabilitation
13. Imaging techniques (echocardiography, MRI, CT,
and SPECT) in cardiovascular diseases
14. Epidemiology and prevention of cardiovasculardisease15. Artificial Intelligence in Cardiology

Publications (2020)
1.

2.

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 of interest
include the following:
1. Cardiac hypertrophy and heart failure: analyses ofpathogenic mechanisms and development of novel
therapies (e.g., gene therapy)
2. Interplay between organs, cells, and molecules inchronic inflammation
3. Mechanisms underlying cardiorenal association
4. Role of hypoxia signaling in cardiovascular diseases
5. Genetic analysis of inherited cardiomyopathy
6. Experiments on pathophysiology ofcardiomyopathy using human iPS cells
7. Investigation of disease pathophysiology anddevelopment of novel therapies (severe heart
failure, cardiac transplantation, congenital heartdisease, etc.)
8. New treatments for structural heart disease
9. Diagnosis and treatment of Marfan syndrome andadult congenital heart disease

3.

4.

5.

Fukuma N, Takimoto E, Ueda K, Liu P, Tajima M,
Otsu Y, Kariya T, Harada M, Toko H, Koga K,
Blanton RM Jr, Karas RH, Komuro I. Estrogen
receptor-α
non-nuclear
signaling
confers
cardioprotection and is essential to c GMP-PDE5
inhibition efficacy. JACC Basic Transl Sci. 2020;
5(3):282-295.
Itoh H, Kaneko H, Kiriyama H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yatomi Y, Yamamichi N, Komuro I. Effect of
metabolically healthy obesity on the developmentof carotid plaque in general population: acommunity-based cohort study. J Atheroscler
Thromb. 2020;27(2):155-163.
Kaneko H, Itoh H, Yotsumoto H, Kiriyama H,
Kamon T, Fujiu K, Morita K, Michihata N, Jo T,
Morita H, Yasunaga H, Komuro I. Association ofbody weight gain with subsequent cardiovascular
event in non-obese general population without
overt cardiovascular disease. Atherosclerosis.
2020;308:39-44.
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.
Association of isolated diastolic hypertension
based on the cutoff value in the 2017 American
Collegeof
Cardiology/American
Heart
Association Blood Pressure Guidelines withsubsequent cardiovascular events in the general
population. J Am Heart Assoc. 2020;9(19):e017963.
Kaneko H, Itoh H, Kiriyama H, Kamon T, Fujiu
K, Morita K, Michihata N, Jo T, Takeda N, Morita
H, Yasunaga H, Komuro I. Restfulness from sleep
and subsequent cardiovascular disease in thegeneral population. Sci Rep. 2020;10(1):19674.

136

6.

Kaneko H, Itoh H, Kamon T, Fujiu K, Morita K,
Michihata N, Jo T, Morita H, Yasunaga H,
Komuro I. Association of cardiovascular healthmetrics with subsequent cardiovascular disease inyoung adults. J Am Coll Cardiol. 2020;76(20):2414-2416.
7. Kaneko H, Itoh H, Yotsumoto H, Kiriyama H,
Kamon T, Fujiu K, Morita K, Michihata N, Jo T,
Morita H, Yasunaga H, Komuro I. Association
between the number of hospital admissions and inhospital outcomes in patients with heart failure.
Hypertens Res. 2020;43(12):1385-1391.
8. Kiriyama H, Kaneko H, Itoh H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yamamichi N, Komuro I. Effect of cigarettesmoking on carotid artery atherosclerosis: acommunity-based cohort study. Heart Vessels.
2020;35(1):22-29.
9. Ko T, Higashitani M, Uemura Y, Utsunomiya M,
Yamaguchi T, Matsui A, Ozaki S, Tobita K,
Kodama T, Morita H, Komuro I. Clinical outcome
and diverse risk factors for different therapeutictarget locations of peripheral artery disease. J
Atheroscler Thromb. 2020;27(8):769-779.
10. Koyama S, Ito K, Terao C, Akiyama M, Horikoshi
M, Momozawa Y, Matsunaga H, Ieki H, Ozaki K,
Onouchi Y, Takahashi A, Nomura S, Morita H,
Akazawa H, Kim C, Seo JS, Higasa K, Iwasaki M,
Yamaji T, Sawada N, Tsugane S, Koyama T,
Ikezaki H, Takashima N, Tanaka K, Arisawa K,
Kuriki K, Naito M, Wakai K, Suna S, Sakata Y,
Sato H, Hori M, Sakata Y, Matsuda K, Murakami
Y, Aburatani H, Kubo M, Matsuda F, Kamatani Y,
Komuro I. Population-specific and trans-ancestry
genome-wide analyses identify distinct and shared
genetic risk loci for coronary artery disease. Nat
Genet. 2020;52(11):1169-1177.
11. Matsubara TJ, Fujiu K, Shimizu Y, Oshima T,
Matsuda J, Matsunaga H, Oguri G, Hasumi E,
Kojima T, Komuro I. Fluoroless and contrast-freecatheter ablation without a lead apron in routine
clinical practice. Sci Rep. 2020;10(1):17096.
12. 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. Serum uric acid level and subclinicalleft ventricular dysfunction: a community-based

13.

14.

15.

16.

17.

18.

19.

20.

cohort study. ESC Heart Fail. 2020;7(3):10311038.
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. Carotid intima-media thickness andsubclinical left heart dysfunction in the general
population. Atherosclerosis. 2020;305:42-49.
Nakayama A, Nagayama M, Morita H, Tajima M,
Mahara K, Uemura Y, Tomoike H, Komuro I,
Isobe M. A large-scale cohort study of long-term
cardiac rehabilitation: A prospective crosssectional study. Int J Cardiol. 2020;309:1-7.
Nakayama Y, Fujiu K, Yuki R, Oishi Y, Morioka
MS, Isagawa T, Matsuda J, Oshima T, Matsubara
T, Sugita J, Kudo F, Kaneda A, Endo Y, Nakayama
T, Nagai R, Komuro I, Manabe I. A longnoncodingRNAregulates
inflammation
resolution by mouse macrophages through fatty
acid oxidation activation. Proc Natl Acad Sci U S
A. 2020;117(25):14365-14375.
Narita K, Amiya E, Hatano M, Ishida J, Maki H,
Minatsuki S, Tsuji M, Saito A, Bujo C, Ishii S,
Kakuda N, Shimbo M, Hosoya Y, Endo M,
Kagami Y, Imai H, Itoda Y, Ando M, Shimada S,
Kinoshita O, Ono M, Komuro I. Differences in the
prognoses of patients referred to an advanced
heart failure center from hospitals with different
bed volumes. Sci Rep. 2020;10(1):21071.
Oka T, Akazawa H, Sase K, Hatake K, Komuro I.
Cardio-oncology in japan: the rapidly rising sun.
JACC CardioOncology. 2020;815-818.
Saito Y, Nakayama A, Sato T, Morita H, Kawahara
T, Itoh H, Komuro I. Lipid-lowering statin therapy
is beneficial in elderly female patients withhypercholesterolaemia and diabetic retinopathy.
Eur J Prev Cardiol. 2020;2047487320920761.
Sawada N, Nakanishi K, Daimon M, Yoshida Y,
Ishiwata J, Hirokawa M, Nakao T, Morita H, Di
Tullio MR, Homma S, Komuro I. Influence ofvisceral adiposity accumulation on adverse left
and right ventricular mechanics in the community.
Eur J Prev Cardiol. 2020;27(18):2006-2015.
Shiraishi Y, Amiya E, Hatano M, Katsuki T, Bujo
C, Tsuji M, Nitta D, Maki H, Ishida J, Kagami Y,
Endo M, Kimura M, Ando M, Shimada S,
Kinoshita O, Ono M, Komuro I. Impact of

137

21.

22.

23.

24.

tacrolimus versus cyclosporin A on renal function
during the first year after heart transplant. ESC
Heart Fail. 2020;7(4):1842-1849.
Toko H, Morita H, Katakura M, Hashimoto M, Ko
T, Bujo S, Adachi Y, Ueda K, Murakami H,
Ishizuka M, Guo J, Zhao C, Fujiwara T, Hara H,
Takeda N, Takimoto E, Shido O, Harada M,
Komuro I. Omega -3 fatty acid prevents thedevelopment of heart failure by changing fatty
acid composition in the heart. Sci Rep. 2020;10(1):15553.
Watanabe A, Amiya E, Hatano M, Watanabe M,
Ozeki A, Nitta D, Maki H, Hosoya Y, Tsuji M,
Bujo C, Saito A, Endo M, Kagami Y, Nemoto M,
Nawata K, Kinoshita O, Kimura M, Ono M,
Komuro I. Significant impact of left ventricularassist device models on the value of flowmediated dilation: effects of LVAD on endothelial
function. Heart Vessels. 2020;35(2):207-213.
Yamaguchi T, Sumida TS, Nomura S, Satoh M,
Higo T, Ito M, Ko T, Fujita K, Sweet ME, Sanbe
A, Yoshimi K, Manabe I, Sasaoka T, Taylor MRG,
Toko H, Takimoto E, Naito AT, Komuro I.
Cardiac dopamine D1 receptor triggers ventriculararrhythmia in chronic heart failure. Nat Commun.
2020;11(1):4364.
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. Association of arterial stiffness withleft atrial structure and phasic function: acommunity-based cohort study. J Hypertens.
2020;38(6):1140-1148.

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

Lecturer
Goh Tanaka, M.D.,Ph.D., Hidenori Kage, M.D.,Ph.D.

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

Hiroyuki Tamiya, M.D.,Ph.D.

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

Yosuke Amano, M.D.,Ph.D.

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

Yoshihisa Hiraishi, M.D.,Ph.D.

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

Naoya Miyashita, 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

139

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 2020
1. Primary lung cancer
398
2. Other cancers
43
3. Abnormal lung shadows53
4. Interstitial pneumonia
64
5. Respiratory infections
35
6. Non-tuberculous
mycobacterial infections
9
7. COPD
11

8. Bronchial Asthma
9. Pneumothorax

1
7

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 isdesigned to facilitate the exposure to a wide range of

140

clinical practice both at The University of Tokyo
Hospital and at one of the affiliated hospitals for two
weeks each (although COVID-19 pandemic madethe latter unavairable in 2020). 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.



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
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

1. Ando, T., M. Kawashima, T. Jo, K. Masuda, Y.
Yamauchi, G. Tanaka, H. Kage, M. Suzukawa, H.
Nagai, H. Matsui, K. Fushimi, H. Yasunaga and T.
Nagase (2020). "Early Arterial Embolization andMortality in Mechanically Ventilated Patients
With Hemoptysis: A Nationwide Retrospective
Cohort Study." Crit Care Med 48(10): 1480-1486.
2. Fukuda, K., H. Matsuzaki, Y. Mikami, K. Makita,
K. Miyakawa, N. Miyashita, K. Hosoki, T. Ishii, S.
Noguchi, H. Urushiyama, M. Horie, A. Mitani, Y.
Yamauchi, E. Shimura, S. Nakae, A. Saito, T.
Nagase and Y. Hiraishi (2021). "A mouse modelof asthma-chronic obstructive pulmonary disease
overlap induced by intratracheal papain." Allergy
76(1): 390-394.
3. Hosoki, K., Y. Mikami, H. Urushiyama, K. Souma,
G. Kawamura, K. Uchida, T. Nagase and T. Jo(2020). "Predictors of postoperative acuteexacerbation of interstitial lung disease: acase-control study." BMJ Open Respir Res 7(1).
4. Isago, H., A. Mitani, S. Kohno, S. Nagoshi, T.
Ishimori, M. Saito, H. Tamiya, N. Miyashita, T.
Ishii, H. Matsuzaki, Y. Yatomi, T. Nagase and T.
Jo (2021). "The Japanese Herbal (Kampo)
Medicine
Hochuekkito
Attenuates
Lung
Inflammation in Lung Emphysema." Biol Pharm
Bull 44(1): 39-45.
5. Kato, T., Y. Hiraishi, K. Kaseda, S. Suzuki, G.
Tanaka, Y. Yamauchi, M. Yasui, A. ShinozakiUshiku, T. Ushiku, O. Yamaji, W. K. O'Neal and T.
Nagase (2020). "A 79-Year-Old Man With

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Progressive Dyspnea and Multiple Pulmonary
Nodules." Chest 158(2): e79-e84.
6. Miyashita, N., M. Horie, Y. Mikami, H.
Urushiyama, K. Fukuda, K. Miyakawa, H.
Matsuzaki, K. Makita, Y. Morishita, H. Harada, M.
Backman, C. Lindskog, H. Brunnström, P. Micke,
T. Nagase and A. Saito (2020). "ASCL1 promotes
tumor progression through cell-autonomous
signaling and immune modulation in a subset oflung adenocarcinoma." Cancer Lett 489: 121-132.
7. Miyashita, N., M. Horie, H. I. Suzuki, M. Saito, Y.
Mikami, K. Okuda, R. C. Boucher, M. Suzukawa,
A. Hebisawa, A. Saito and T. Nagase (2020).
"FOXL1 Regulates Lung Fibroblast Function via
Multiple Mechanisms." Am J Respir Cell Mol
Biol 63(6): 831-842.
8. Muroyama, Y., H. Tamiya, G. Tanaka, W. Tanaka,
A. C. Huang, D. A. Oldridge, K. Matsusaka, Y.
Takazawa, T. Jo, T. Ushiku and T. Nagase (2020).
"Alpha-Fetoprotein-Producing Lung Hepatoid
Adenocarcinoma with Brain Metastasis Treatedwith S-1." Case Rep Oncol 13(3): 1552-1559.
9. Oki, R., Y. Hirakawa, H. Kimura, K. Honda, M.
Hinata, H. Abe, Y. Domoto, G. Tanaka, T. Nagase
and M. Nangaku (2020). "Renal Effects after
Pembrolizumab Treatment for Non-small Cell
Lung Carcinoma." Intern Med 59(7): 977-981.
10. Saito, M., A. Mitani, T. Ishimori, N. Miyashita, H.
Isago, Y. Mikami, S. Noguchi, M. Tarui and T.
Nagase (2020). "Active mTOR in Lung
Epithelium Promotes Epithelial-Mesenchymal
Transition and Enhances Lung Fibrosis." Am J
Respir Cell Mol Biol 62(6): 699-708.
11. Watanabe, K., M. Suzukawa, O. Narumoto, M.
Kawashima, J. Suzuki, H. Matsui, H. Nagai, A.
Kurashima, T. Nagase and S. Tohma (2021).
"CD64 expression on neutrophils reflects theactivity of nontuberculous mycobacterial lungdisease." Respir Investig 59(1): 155-156.
12. Yotsumoto, T., K. Maemura, K. Watanabe, Y.
Amano, Y. Matsumoto, K. Zokumasu, T. Ando, M.
Kawakami, H. Kage, J. Nakajima, Y. Yatomi, T.
Nagase and D. Takai (2020). "NRXN1 as a novel
potential target of antibody-drug conjugates forsmall cell lung cancer." Oncotarget 11(39):3590-3600.

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Department of Gastroenterology
Professor
Kazuhiko Koike, M.D., Ph.D.

Lecturer
Keisuke Tateishi, M.D., Ph.D.
Motoyuki Otsuka, M.D., Ph.D.
Ryosuke Tateishi, M.D., Ph.D.

Associate
Yasuo Tanaka, M.D., Ph.D.

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

Hayato Nakagawa, M.D., Ph.D.

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

Atsuo Yamada, M.D., Ph.D.

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

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

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

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

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

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

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

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

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

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

Ryo Nakagomi, M.D., Ph.D.

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

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

Ryota Niikura, M.D., Ph.D.

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

Kazunaga Ishigaki, M.D., Ph.D.

Homepage

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

Introduction and Organization
The Department of Gastroenterology wasestablished through a reorganization of the Graduate
School of Medicine and that of the Division ofInternal Medicine of The University of Tokyo
Hospital in 1998. The department is responsible forclinical services, education, and research activities in
the liver, pancreato-biliary, and gastrointestinal tract.
It comprises a professor, three lecturers, 21 associates,
18 fellows, 68 graduates, and other visiting
researchers including students from abroad. Someothers are under a temporary transfer inside andoutside the country. The North and South wings on the
11th floor of Ward A have provided core hospitalrooms for the department. Laboratories of thedepartment are scattered on each floor, mainly ofClinical Research Center.

Clinical Activities
The Department of Gastroenterology is in chargeof about 80 inpatients on average, which are about
2,700 in total per year. We receive about 110 new
patients each week in and out of the hospital, with anaverage hospital stay of 10.6 days. Resident, juniorand senior staff members bear the responsibility forthe medical management of each inpatient in collaboration with subspecialty groups concerned. The staff
members examine about 4,600 outpatients with

143

various digestive diseases in a month. Specialty andsubspecialty clinical conferences are held on Monday
evening.
Hepatocellular carcinoma is the most common
disease in patients who are admitted to the department(~400 cases in 2020). The number of treatments forhepatocellular
carcinoma,
represented
bypercutaneous radiofrequency ablation, nearly 250
cases per year, showing one of the greatest achievements in the field. The number of cases undergoingradiofrequency ablation for metastatic liver tumors is
also increasing recent years. In addition, we aremaking efforts to develop an innovation for dailyclinical activities. For example, fibrosis progression inchronic liver disease is conventionally assessed byliver biopsy. Recently we can evaluate the stage ofliver fibrosis by FibroScan®, newly developed
equipment that measures liver stiffness by ultrasound,which is useful for evaluating increasing
non-alcoholic steatohepatitis patients. In addition,nearly 100% cure for HCV hepatitis can be achievedby using oral antiviral agents instead of IFN therapy.
This will be especially beneficial for elderly patientsand advanced fibrotic patients.
ERCP, the standard endoscopic treatment forbiliary and pancreatic diseases, is annually performedin about 1,000 cases. Various endoscopic treatments
such as endoscopic treatment of bile duct stones inover 1,400 cases and biliary drainage with metal stents
for malignant biliary strictures in over 1,000 cases
have been performed. We have reported thedevelopment and clinical studies of papillary balloon
dilation (EPBD) and papillary large balloon dilation(EPLBD) for the treatment of bile duct stones, andmany studies on covered metal stents for malignant aswell as benign biliary strictures. We have a lot ofexperience in providing advanced endoscopic
treatment for patients who are difficult to receive
standard treatment, such as ERCP using a balloon
endoscope and transluminal drainage and stonetherapy using endoscopic ultrasonography (EUS) for
surgically altered anatomy cases. We also perform
endoscopic treatment of chronic pancreatitis andpancreatic stone disease. We also provide preoperative
chemotherapy for resectable pancreatic cancer andnovel chemotherapy for unresectable pancreatic andbiliary 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 2020). 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.
Aiming at personalized medicine based on genetic
information, we are also actively conducting cancer
multi-gene panel testing.

144

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.

Educational Activities
The undergraduate medical students regularly
take the clinical 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 take the expert training of gastroenterology in the affiliated hospitals for several years.
The
students
oftheDepartment
ofGastroenterology in the Graduate School of Medicine
perform a high standard of medical research in thebasic or clinical field for four years. Currently, 68
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
profiling of clinical samples, organoids, or liquidbiopsy, we perform various experiments to translate
the basic results into clinics eventually.
Various clinical activities are recorded in database and analyzed. Studies oriented towardevidence-based medicine are highly appreciated.
Recent studies include radiofrequency ablation forliver metastasis of colorectal cancer, the impact of
metabolic factors in hepatocarcinogenesis. We havealso designed many clinical trials as follows; Effectsof various drug treatments on advanced hepatocellular
carcinoma, SNPs analyses for antiviral treatment for
hepatitis C, new chemotherapeutic regimens foradvanced pancreatic cancer or biliary tract cancer,
balloon endoscope-assisted ERCP for surgicallyaltered anatomy, the efficacy of polyglycolic acidsheets 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
and highest-level clinical activities, based on thevarious data of many patients, especially those
suffering from malignant diseases. Furthermore, we
aim to find the new aspects of diseases and create a
new strategy against them, which is based on clinical,
basic, and epidemiological studies in our area.

Selected References
1. Aoki T, Yamada A, Aoyama K, Saito H, Fujisawa
G, Odawara N, Kondo R, Tsuboi A, Ishibashi R,
Nakada A, Niikura R, Fujishiro M, Oka S,
Ishihara S, Matsuda T, Nakahori M, Tanaka S,
Koike K, Tada T. Clinical usefulness of a deeplearning-based system as the first screening on
small-bowel capsule endoscopy reading. Dig
Endosc. 2020;32(4):585-591

145

2. 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 blood
content in capsule endoscopy images based on a
deep
convolutional
neuralnetwork.
J
Gastroenterol Hepatol. 2020;35(7):1196-1200
3. Enooku K, Tsutsumi T, Kondo M, Fujiwara N,
Sasako T, Shibahara J, Kado A, Okushin K,
Fujinaga H, Nakagomi R, Minami T, Sato M,
Uchino K, Nakagawa H, Kondo Y, Asaoka Y,
Tateishi R, Ueki K, Ikeda H, Yoshida H, Moriya K,
Yotsuyanagi H, Kadowaki T, Koike K. Hepatic
FATP5 expression is associated with histologicalprogression and loss of hepatic fat in NAFLD
patients. J Gastroenterol. 2020;55(2):227-243
4. Fujiwara H, Takahara N, Tateishi K, Tanaka M,
Kanai S, Kato H, Nakatsuka T, Yamamoto K,
Kogure H, Arita J, Nakai Y, Kasuga M, Ushiku T,
Hasegawa K, Koike K. 5-Aminolevulinicacid-mediated photodynamic activity in patientderived cholangiocarcinoma organoids. Surg
Oncol. 2020;35:484-490
5. Hakuta R, Hamada T, Nakai Y, Oyama H, Kanai S,
Suzuki T, Sato T, Ishigaki K, Saito K, Saito T,
Takahara N, Mizuno S, Kogure H, Watadani T,
Tsujino T, Tada M, Abe O, Isayama H, Koike K.
Natural history of asymptomatic bile duct stones
and association of endoscopic treatment withclinical outcomes. J Gastroenterol. 2020;55(1):78-8
6. Hakuta R, Nakai Y, Hamada T, Suzuki Y, Inokuma
A, Oyama H, Kanai S, Nakamura T, Sato T,
Ishigaki K, Saito K, Saito T, Takahara N, Mizuno
S, Kogure H, Tada M, Koike K. Regular Statin
Use and Incidence of Postendoscopic Retrograde
Cholangiopancreatography Pancreatitis. J Clin
Gastroenterol. 2020;54(10):905-910
7. Hata M, Kinoshita H, Hayakawa Y, Konishi M,
Tsuboi M, Oya Y, Kurokawa K, Hayata Y,
Nakagawa H, Tateishi K, Fujiwara H, Hirata Y,
Worthley DL, Muranishi Y, Furukawa T, Kon S,
Tomita H, Wang TC, Koike K. GPR30-Expressing
Gastric Chief Cells Do Not Dedifferentiate But
Are Eliminated via PDK-Dependent Cell
Competition During Development of Metaplasia.
Gastroenterology. 2020;158(6):1650-1666

8. Hirata Y, Yamada A, Niikura R, Shichijo S,
Hayakawa Y, Koike K. Efficacy and safety of a
new rifabutin-based triple therapy withvonoprazan for refractory Helicobacter pylori
infection: A prospective single-arm study.
Helicobacter. 2020;25(5):e12719
9. Ishigaki K, Hamada T, Nakai Y, Isayama H, Sato
T, Hakuta R, Saito K, Saito T, Takahara N,
Mizuno S, Kogure H, Ito Y, Yagioka H, Matsubara
S, Akiyama D, Mohri D, Tada M, Koike K.
Retrospective Comparative Study of Side-by-Sideand Stent-in-Stent Metal Stent Placement for
Hilar Malignant Biliary Obstruction. Dig Dis Sci.
2020;65(12):3710-3718
10. Ishigaki K, Nakai Y, Oyama H, Kanai S, Suzuki T,
Nakamura T, Sato T, Hakuta R, Saito K, Saito T,
Takahara N, Hamada T, Mizuno S, Kogure H,
Tada M, Isayama H, Koike K. Endoscopic
Ultrasound-Guided Tissue Acquisition by
22-Gauge Franseen and Standard Needles for
Solid Pancreatic Lesions. Gut Liver. 2020;14(6):817-825
11. Kato H, Tateishi K, Fujiwara H, Ijichi H,
Yamamoto K, Nakatsuka T, Kakiuchi M, Sano M,
Kudo Y, Hayakawa Y, Nakagawa H, Tanaka Y,
Otsuka M, Hirata Y, Tachibana M, Shinkai Y,
Koike K. Deletion of Histone Methyltransferase
G9a Suppresses Mutant Kras-driven Pancreatic
Carcinogenesis. Cancer Genomics Proteomics.
2020;17(6):695-705
12. Kogure H, Kawahata S, Mukai T, Doi S, Iwashita
T, Ban T, Ito Y, Kawakami H, Hayashi T, SasahiraN, Kubota K, Togawa O, Kato H, Okabe Y,
Matsubara S, Yagioka H, Saito T, Nakai Y,
Isayama H. Multicenter randomized trial ofendoscopic papillary large balloon dilation
without sphincterotomy versus endoscopic
sphincterotomy for removal of bile duct stones:
MARVELOUS trial. Endoscopy. 2020;52(9):736744
13. Nagao S, Tsuji Y, Sakaguchi Y, Takahashi Y,
Minatsuki C, Niimi K, Yamashita H, Yamamichi
N, Seto Y, Tada T, Koike K. Highly accurate
artificial intelligence systems to predict theinvasion depth of gastric cancer: efficacy of
conventional white-light imaging, nonmagnifying
narrow-band imaging, and indigo-carmine dye

146contrast imaging. Gastrointest Endosc. 2020;
92(4):866-873
14. Nakai Y, Sato T, Hakuta R, Ishigaki K, Saito K,
Saito T, Takahara N, Hamada T, Mizuno S,
Kogure H, Nogchi K, Ito Y, Isayama H, Koike K.
Long-term outcomes of a long, partially covered
metal stent for EUS-guided hepaticogastrostomy
in patients with malignant biliary obstruction(with video). Gastrointest Endosc. 2020;92(3):623-631
15. Niikura R, Nagata N, Yamada A, Honda T,
Hasatani K, Ishii N, Shiratori Y, Doyama H,
Nishida T, Sumiyoshi T, Fujita T, Kiyotoki S,
Yada T, Yamamoto K, Shinozaki T, Takata M,
Mikami T, Mabe K, Hara K, Fujishiro M, Koike K.
Efficacy and Safety of Early vs Elective
Colonoscopy for Acute Lower Gastrointestinal
Bleeding. Gastroenterology. 2020;158(1):168-175
16. Noguchi K, Nakai Y, Mizuno S, Isayama H,
Hirano K, Kanai S, Nakamura T, Uchino R,
Takahara N, Kogure H, Tada M, Koike K. Insulin
secretion improvement during steroid therapy for
autoimmune pancreatitis according to the onset of
diabetes mellitus. J Gastroenterol. 2020;55(2):198-204
17. Ochi M, Otsuka M, Maruyama R, Koike K. HBx
increases EGFR expression by inhibiting
miR129-5p function. Biochem Biophys Res
Commun. 2020;529(2):198-203
18. Okushin K, Tsutsumi T, Ikeuchi K, Kado A,
Enooku K, Fujinaga H, Yamauchi N, Ushiku T,
Moriya K, Yotsuyanagi H, Koike K. Heterozygous
knockout of Bile salt export pump ameliorates
liver steatosis in mice fed a high-fat diet. PLoS
One. 2020;15(8):e0234750
19. Oyama H, Tada M, Takagi K, Tateishi K, Hamada
T, Nakai Y, Hakuta R, Ijichi H, Ishigaki K, Kanai
S, Kogure H, Mizuno S, Saito K, Saito T, Sato T,
Suzuki T, Takahara N, Morishita Y, Arita J,
Hasegawa K, Tanaka M, Fukayama M, Koike K.
Long-term Risk of Malignancy in Branch-Duct
Intraductal Papillary Mucinous Neoplasms.
Gastroenterology. 2020;158(1):226-237
20. Sakaguchi Y, Tsuji Y, Shinozaki T, Ohki D,
Mizutani H, Minatsuki C, Niimi K, Yamamichi N,
Koike K. Steroid injection and polyglycolic acidshielding to prevent stricture after esophageal

endoscopic submucosal dissection: a retrospective
comparative analysis (with video). Gastrointest
Endosc. 2020;92(6):1176-1186
21. Sato T, Kogure H, Nakai Y, Ishigaki K, Hakuta R,
Saito K, Saito T, Takahara N, Hamada T, Mizuno
S, Tada M, Isayama H, Koike K. A prospective
study of fully covered metal stents for different
types of refractory benign biliary strictures.
Endoscopy. 2020;52(5):368-376
22. Sato T, Kogure H, Nakai Y, Ishigaki K, Hakuta R,
Saito K, Saito T, Takahara N, Hamada T, Mizuno
S, Yamada A, Tada M, Isayama H, Koike K.
Double-balloon endoscopy-assisted treatment of
hepaticojejunostomy anastomotic strictures andpredictive factors for treatment success. Surg
Endosc. 2020;34(4):1612-1620
23. Sekiba K, Otsuka M, Seimiya T, Tanaka E, Funato
K, Miyakawa Y, Koike K. The fatty-acid amidehydrolase inhibitor URB597 inhibits MICA/B
shedding. Sci Rep. 2020;10(1):15556
24. Takahara N, Nakai Y, Saito K, Sasaki T, Suzuki Y,
Inokuma A, Oyama H, Kanai S, Suzuki T, Sato T,
Hakuta R, Ishigaki K, Saito T, Hamada T, Mizuno
S, Kogure H, Tada M, Isayama H, Koike K. The
impact of age and comorbidity in advanced orrecurrent biliary tract cancer receiving palliative
chemotherapy. J Gastroenterol Hepatol. 2020;35(10):1828-1835
25. Takahashi R, Ijichi H, Sano M, Miyabayashi K,
Mohri D, Kim J, Kimura G, Nakatsuka T,
Fujiwara H, Yamamoto K, Kudo Y, Tanaka Y,
Tateishi K, Nakai Y, Morishita Y, Soma K, Takeda
N, Moses HL, Isayama H, Koike K. Soluble
VCAM-1 promotes gemcitabine resistance via
macrophage infiltration and predicts therapeutic
response in pancreatic cancer. Sci Rep. 2020;10(1):21194
26. Takahashi Y, Tsutsumi Y, Takeuchi C, Shiogama
K, Mizutani Y, Inada KI, Yamamichi N, Koike K.
Nuclear staining of claudin-18 is a new
immunohistochemical marker for diagnosing
intramucosal
well-differentiatedgastric
adenocarcinoma. Pathol Int. 2020;70(9):644-652
27. Tsuboi A, Oka S, Aoyama K, Saito H, Aoki T,
Yamada A, Matsuda T, Fujishiro M, Ishihara S,
Nakahori M, Koike K, Tanaka S, Tada T. Artificial
intelligence using a convolutional neural network

147

for automatic detection of small-bowel
angioectasia in capsule endoscopy images. Dig
Endosc. 2020;32(3):382-390
28. Wake T, Tateishi R, Fukumoto T, Nakagomi R,
Kinoshita MN, Nakatsuka T, Sato M, Minami T,
Uchino K, Enooku K, Nakagawa H, Fujinaga H,
Asaoka Y, Tanaka Y, Otsuka M, Koike K.
Improved liver function in patients with cirrhosis
due to chronic hepatitis C virus who achievesustained virologic response is not accompanied
by increased liver volume. PLoS One. 2020;15(4):e0231836
29. Yamada T, Tateishi R, Iwai M, Koike K, Todo T.
Neoadjuvant Use of Oncolytic Herpes Virus G47Δ
Enhances the Antitumor Efficacy of Radiofrequency Ablation. Mol Ther Oncolytics. 2020;
18:535-545
30. Yamamichi N, Yamaji Y, Shimamoto T, Takahashi
Y, Majima K, Wada R, Mitsushima T, Koike K.
Inverse time trends of peptic ulcer and reflux
esophagitis show significant association with
reduced prevalence of Helicobacter pylori
infection. Ann Med. 2020;52(8):506-514

Internal Medicine
2. Medicine Ⅱ149

Department of Nephrology and
Endocrinology
Professor
Masaomi Nangaku, M.D., Ph.D.

Associate Professor
Noriko Makita, M.D., Ph.D.
Tetsuhiro Tanaka, M.D., Ph.D.

Lecturer

Hiroshi Nishi, M.D., Ph.D.
Yoshifumi Hamasaki, M.D., Ph.D.

Associate
Megumi Fujita, M.D., Ph.D.,

Nobuaki Ito, M.D., Ph.D.,

Motonobu Nakamura, M.D., Ph.D.,

Katsunori Manaka, M.D., Ph.D.,

Imari Mimura, M.D., Ph.D.,

Yosuke Hirakawa, 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.

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 30 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 30 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

150

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

151

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) Catheter Diversion Procedure With Exit-Site
Renewal Promotes Peritoneal Dialysis Catheter
Survival. Oki R, Hamasaki Y, Komaru Y,
Miyamoto Y, Matsuura R, Yamada D, Iwagami
M, Doi K, Kume H, Nangaku M. Kidney Int Rep.
2020 Dec 7;6(2):325-332.
(2) Cardiovascular and renal effectiveness of
empagliflozin in routine care in East Asia:
Results from the EMPRISE East Asia study.
Seino Y, Kim DJ, Yabe D, Tan EC, Chung WJ,
Ha KH, Nangaku M, et al.; EMPRISE East Asia
study group. Endocrinol Diabetes Metab. 2020
Sep 16;4(1):e00183.
(3) RRT Selection for AKI Patients With Critical
Illness. Matsuura R, Doi K, Hamasaki Y,
Nangaku M. Semin Nephrol. 2020 Sep;40(5):498-505.
(4) Esaxerenone (CS-3150) in Patients with Type 2
Diabetes and Microalbuminuria (ESAX-DN):
Phase 3 Randomized Controlled Clinical Trial.
Ito S, Kashihara N, Shikata K, Nangaku M, Wada
T, Okuda Y, Sawanobori T. Clin J Am Soc
Nephrol. 2020 Dec 7;15(12):1715-1727.
(5) Urinary
Neutrophil
Gelatinase-AssociatedLipocalin in Critically Ill Patients With
Coronavirus Disease 2019. Komaru Y, Doi K,
Nangaku M. Crit Care Explor. 2020 Aug 20;2(8):e0181.
(6) Hierarchical Clustering Analysis for Predicting
1-Year Mortality After Starting Hemodialysis.
Komaru Y, Yoshida T, Hamasaki Y, Nangaku M,
Doi K. Kidney Int Rep. 2020 May 23;5(8):11881195.

152(7) Vadadustat, an oral hypoxia-inducible factor
prolyl hydroxylase inhibitor, for treatment ofanemia of chronic kidney disease: two
randomized Phase 2 trials in Japanese patients.
Nangaku M, Farag YMK, deGoma E, Luo W,
Vargo D, Khawaja Z. Nephrol Dial Transplant.
2020 Jul 28:gfaa060.
(8) Association Between IV Thiamine and Mortality
in Patients With Septic Shock: A Nationwide
Observational Study. Miyamoto Y, Aso S,
Iwagami M, Yasunaga H, Matsui H, Fushimi K,
Hamasaki Y, Nangaku M, Doi K. Crit Care Med.
2020 Aug;48(8):1135-1139.
(9) Different Biomarker Kinetics in Critically Ill
Patients with High Lactate Levels. Matsuura R,
Komaru Y, Miyamoto Y, Yoshida T, Yoshimoto
K, Hamasaki Y, Nangaku M, Doi K. Diagnostics(Basel). 2020 Jul 4;10(7):454.
(10) The role of hypoxia in the pathogenesis of lupus
nephritis. Kurata Y, Tanaka T, Nangaku M.
Kidney Int. 2020 Oct;98(4):821-823.
(11) Randomized Clinical Trial on the Effect ofBardoxolone Methyl on GFR in Diabetic Kidney
Disease Patients (TSUBAKI Study). Nangaku M,
Kanda H, Takama H, Ichikawa T, Hase H,
Akizawa T. Kidney Int Rep. 2020 Apr 14;5(6):879-890.
(12) COVID-19 of dialysis patients in Japan: Current
status and guidance on preventive measures.
COVID-19 Task Force Committee of theJapanese Association of Dialysis Physicians;
Japanese Society for Dialysis Therapy; JapaneseSociety of Nephrology, Kikuchi K, Nangaku M,
Ryuzaki M, Yamakawa T, Hanafusa N, Sakai K,
et al. Ther Apher Dial. 2020 Aug;24(4):361-365.
(13) Hypoxia-inducible factor prolyl hydroxylase
inhibitor in the treatment of anemia in chronic
kidney disease. Kurata Y, Tanaka T, Nangaku M.
Curr Opin Nephrol Hypertens. 2020 Jul;29(4):414-422.
(14) J-CKD-DB: a nationwide multicentre electronic
health record-based chronic kidney disease
database in Japan. Nakagawa N, Sofue T, Kanda
E, Nagasu H, Matsushita K, Nangaku M, et al.
Sci Rep. 2020 Apr 30;10(1):7351.
(15) New insights into tubular cell recovery after
ischemic acute kidney injury. Sakashita M,

Tanaka T, Nangaku M. Kidney Int. 2020 May;
97(5):845-846.
(16) The Clinical Course of Acute Kidney Disease
after Cardiac Surgery: A Retrospective
Observational Study. Matsuura R, Iwagami M,
Moriya H, Ohtake T, Hamasaki Y, Nangaku M,
Doi K, Kobayashi S, Noiri E. Sci Rep. 2020 Apr
16;10(1):6490.
(17) Regional variance in the use of urine dipstick testfor outpatients in Japan. Nishi H, Yoshida Y,
Inoue R, Takemura K, Nangaku M. Nephrology(Carlton). 2020 Sep;25(9):676-682.
(18) A Simple Scoring Method for Predicting the Low
Risk of Persistent Acute Kidney Injury in
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Department of Diabetes andMetabolic Diseases
Professor
Toshimasa Yamauchi, M.D., Ph.D.

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

Lecturer
Masato Iwabu, M.D., Ph.D.

Assistant Professor
Hiroaki Okazaki, M.D., Ph.D.,

Satoru Takase, M.D., Ph.D.,

Tomohisa Aoyama, M.D., Ph.D.

Mikio Takanashi, M.D., Ph.D.,

Masaki Igarashi, M.D., Ph.D.

Yoshitaka Sakurai, M.D., Ph.D.

Takayoshi Sasako, M.D., Ph.D.

Jun Hosoe, M.D., Ph.D. (until Sep 2019)

Gotaro Toda, M.D., Ph.D. (since Jun 2019) Masakazu Aihara, M.D., Ph.D. (since Oct 2019)

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 25 beds mainly on the 12th floor of the North

Wing Ward A of the University of Tokyo Hospital, andtook care of 403 new inpatients per year. Besides thestaffs listed above, our division holds faculties inbranches, for example, Department of ClinicalNutrition Therapy (Associate Professor: Dr. Naoto
Kubota), Laboratory for Advanced Research on
Pathophysiology of Metabolic Diseases (Project
Associate Professor: Dr. Miki Okada-Iwabu, Project
Assistant Professor: Dr. Jun hosoe [until Oct 2020]),
Genomic Research Support Center (Project Associate
Professor: Dr. Nobuhiro Shojima), Department of
Healthcare Information Management (Associate
Professor: Dr. Kayo Waki, Project Assistant Professor:
Dr. Kana Miyake), Department of Clinical Laboratory(Associate Professor: Dr. Makoto Kurano [until Apr
2020]), 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

155

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 13 students of Graduate
School in our division. With all these 53 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 136 patients perday (total 33,026 patients per year). On the inpatientward, we not only take care of around 25 patients inour division as mentioned above, but also provide a
sophisticated management to all patients sufferingfrom metabolic diseases, especially diabetes mellitus.
Diabetes mellitus, metabolic syndrome, dyslipidemia
and obesity disease are becoming more prevalent inJapan, and lead to complications including nephropathy, retinopathy, neuropathy and cardiovasculardiseases. Thus, in collaboration with other departments, we optimize the treatment of each patient.
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
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 of156

insulin 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)", systematic reviews and metaanalyses with a focus on important issues such as
metabolic syndrome, and investigator initiated clinical
trials targeting for a new class of anti-diabetic agents.

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fueledbyhighphosphatidylinositol turnover. Gut. 2020 Apr 6:
gutjnl-2020-320646.

31. Toda G, Yamauchi T, Kadowaki T, Ueki K.
Preparation and culture of bone marrow-derived
macrophages from mice for functional analysis.
STAR Protoc. 2:100246, 2020
32. Toda G, Soeda K, Okazaki Y, Kobayashi N,
Masuda Y, Arakawa N, Suwanai H, Masamoto Y,
Izumida Y, Kamei N, Sasako T, Suzuki R, Kubota
T, Kubota N, Kurokawa M, Tobe K, Noda T,
Honda K, Accili D, Yamauchi T, Kadowaki T,
Ueki K. Insulin- and LipopolysaccharideMediated Signaling in Adipose Tissue
Macrophages Regulates Postprandial Glycemia
through Akt-mTOR Activation. Mol Cell. 79:43,
2020
33. Waki K, Sankoda A, Amano S, Ogawa M, Ohe
K. ：Responding to COVID-19: Agile Use ofInformation Technology to Serve Patients With
Diabetes. J Diabetes Sci Technol. 14(4):807-808,
2020
34. Yamada T, Yoneoka D, Hiraike Y, Hino K,
Toyoshiba H, Shishido A, Noma H, Shojima N,
Yamauchi T. Deep Neural Network for Reducing
the Screening Workload in Systematic Reviews
for Clinical Guidelines: Algorithm Validation
Study. J Med Internet Res. 22(12):e22422, 2020
35. Yoshida Y, Patil SJ, Brownson RC, Boren SA,
Kim M, Dobson R, Waki K, Greenwood DA,
Torbjørnsen A, Ramachandran A, Masi C,
Fonseca VA, Simoes EJ：Using the RE-AIM
framework to evaluate internal and external
validity of mobile phone-based interventions indiabetes self-management education and support.
J Am Med Inform Assoc. 27(6):946-956, 2020

160

Department of
Hematology and Oncology
Professor
Mineo Kurokawa, M.D., Ph.D.

Lecturer
Fumio Nakahara, M.D., Ph.D.

Yosuke Masamoto, M.D., Ph.D.

Assistant Professor
Kumi Nakazaki, M.D., Ph.D.,

Kazuki Taoka, M.D., Ph.D.,

Yosei Fujioka, M.D., Ph.D.,

Hiroaki Maki, M.D., Ph.D.,

Megumi Yasunaga, M.D., Ph.D.,

Arika Shimura, M.D., Ph.D.

Akira Honda, M.D., Ph.D.

Sho Yamazaki, M.D., Ph.D.

Hideaki Mizuno, 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

161

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.
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.

References
1.

Noura M, Morita K, Kiyose H, Matsuo H,
Nishinaka-Arai Y, Kurokawa M, Kamikubo Y,
Adachi S. Pivotal role of DPYSL2A in

162

2.

3.

4.

5.

6.

7.

KLF4-mediated monocytic differentiation of
acute myeloid leukemia cells. Sci Rep.20(1):20245, 2020.
Hirano Y, Miyawaki S, Satou M, Taoka K,
Toyama K, Ikemura M, Tanaka R, Takayanagi S,
Tanaka S, Nakatomi H, Kurokawa K, and Saito N.
Small cell variant of anaplastic lymphoma
kinase-positive anaplastic large cell lymphoma of
the dura mimicking tentorial meningioma.
World Neurosurgery 138: 169¬-173, 2020.
Ito Y, Takaoka K, Toyama K, Taoka K,
Wakabayashi Y, Shinozaki-Ushiku A, Okazaki A,
Chikamatsu K, Mitarai S, Ushiku T, Kurokawa
M. The First Case of Concomitant Mycobacterium Genavense Lymphadenitis and EBV-Positive Lymphoproliferative Disorder. Mediterr
J Hematol Infect Dis 12(1): e2020035, 2020.
Matsuda K, Taisuka J, Miyauchi M, Toyama K,
Nakazaki K, Matsui H, Fushimi K, Yasunaga H,
Kurokawa M. Primary prophylaxis with
pegfilgrastim in patients with newly-diagnosed
diffuse large B-cell lymphoma: propensity score
and instrumental variable analyses. Leuk
Lymphoma 61(10): 2435-2441, 2020.
Toda G, Soeda K, Okazaki Y, Kobayashi N,
Masuda Y, Arakawa N, Suwanai H, Masamoto Y,
Izumida Y, Kamei N, Sasako T, Suzuki R,
Kubota T, Kubota N, Kurokawa M. Tobe K,
Noda T, Honda K, Accili D, Yamauchi T,
Kadowaki
T,
Ueki
K.
Insulinand
Lipopolysaccharide-MediatedSignalingin
AdiposeTissueMacrophages
Regulates
Postprandial Glycemia through Akt-mTOR
Activation. Mol Cell 79(1): 43-53, 2020.
Sasaki K, Honda A, Shinozaki-Ushiku A, Fujioka
Y, Maki H, Toyama K, Ushiku T, Kurokawa M.
Insulinand
Lipopolysaccharide-MediatedSignaling in Adipose Tissue Macrophages
Regulates Postprandial Glycemia throughAkt-mTOR Activation. Ann Hematol 100(6):1621-1622, 2020.
Watanabe K, Kage H, Nagoshi S, Toyama K,
Ohno Y, Shinozaki-Ushiku A, Nakazaki K,
Suzuki H, Kurokawa M, Nagase T. Dual EGFR
and ABL Tyrosine Kinase Inhibitor Treatment ina Patient with Concomitant EGFR-Mutated Lung
Adenocarcinoma and BCR-ABL1-Positive CML.

Case Rep Oncol Med 4201727, 2020.
8. Iida T, Nozawa H, Sonoda H, Toyama K, Kawai
K, Hata K, Tanaka T, Nishikawa T, Sasaki K,
Shuno Y, Kaneko M, Murono K, Emoto S, Ishii
H, Kurokawa M, Ishihara S. Upfront Surgery for
Small Intestinal Non-Hodgkin's Lymphoma
40(4): 2372-2377, 2020.
9. Goyal G, Heaney ML, Collin M, Cohen-Aubart F,
Vaglio A, Durham BH, Hershkovitz-Rokah O,
Girschikofsky M, Jacobsen ED, Toyama K,
Goodman AM, Hendrie P, Cao XX, Estrada-Veras JI, Shpilberg O, Abdo A, Kurokawa M,
Dagna L, McClain KL, Mazor RD, Picarsic J,
Janku F, Go RS, Haroche J, Diamond EL.
Erdheim-Chester disease: consensus recommen
dations for evaluation, diagnosis, and treatmentin the molecular era. Blood 135(22): 1929-1945,
2020.
10. Ye J, Huang A, Wang H, Zhang AMY, Huang X,
Lan Q, Sato T, Goyama S, Kurokawa M, Deng C,
Sander M, Schaeffer DF, Li W, Kopp JL, Xie R.
PRDM3 attenuates pancreatitis and pancreatictumorigenesis by regulating inflammatory
response. Cell Death Dis 11, 2020.
11. Shull LC, Sen R, Menzel J, Goyama S,
Kurokawa M, and Artinger KB. The conserved
and divergent roles of Prdm3 and Prdm16 inzebrafish and mouse craniofacial development.
Developmental Biology, S0012-1606(20)30057-9,
2020.
12. Matsuda K and KurokawaM.
Underlying
disease and clinical phenotypes of disseminatedintravascular coagulation. JMA Journal, 15;3(4):357-358, 2020.
13. Kurokawa M. Time trends in disseminatedintravascular coagulation in Japan.
JMA
Journal 15; 3(4): 355-356, 2020.
14. Takaoka K, Koya J, Yoshimi A, Toya T,
Kobayashi T, Nannya Y, Nakazaki K, Arai S,
Ueno H, Usuki K, Yamashita T, Imanishi D, SatoS, Suzuki K, Harada H, Manabe A, Hayashi Y,
Miyazaki Y, and Kurokawa M. Nationwide
epidemiological survey of familial myelodysplastic syndromes/acute myeloid leukemia inJapan: A multicenter retrospective study.
Leukemia and Lymphoma 61(7): 1688-1694,
2020.

163

Department of Allergy andRheumatology
Professor
Keishi Fujio, M.D., Ph.D. (Rheumatology)

Lecturer
Hirofumi Shoda, M.D., Ph.D. (Rheumatology)

Hospital Lecturer
Hiroaki Harada, M.D., Ph.D. (Allergology)

Research Associate
Yukiko Iwasaki, M.D., Ph.D. (Rheumatology)
Haruka Tsuchiya, M.D., Ph.D. (Rheumatology)
Yumi Tsuchida，M.D., Ph.D. (Rheumatology)
Toshihiko Komai, M.D., Ph.D. (Rheumatology)
Norio Hanada, M.D., Ph.D. (Rheumatology)
Toshiaki Shimizu, M.D., Ph.D. (Rheumatology)
Bunki Natsumoto, 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
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, theCentral Ward and the Clinical Research Center A.

Education
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

164

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.

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.
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. 2020
Nov 2:annrheumdis-2020-218189.
Elevation of cytomegalovirus antigenemia
predicts serious infection and death in patients
receiving immunosuppressive therapies for
autoimmune diseases. Yoshihara R, Komai T,
Shoda H, Fujio K. Int J Rheum Dis. 2020 Nov;
23(11):1534-1540.
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.
Integrated bulk and single-cell RNA-sequencing
identified disease-relevant monocytes and a gene
network module underlying systemic sclerosis.
Kobayashi S, Nagafuchi Y, Okubo M, Sugimori
Y, Shirai H, Hatano H, Junko M, Yanaoka H,
Takeshima Y, Ota M, Iwasaki Y, Sumitomo S,

165

Okamura T, Yamamoto K, Shoda H, Fujio K. J
Autoimmun. 2020 Oct 7:102547.
6. Deteriorating anemia in an 86-year-old man was
improved by prednisolone. Kitago M, Kase Y,
Iwata Y, Suwa Y, Tsuchiya H, Hanata N, Kojima
T, Ogawa S, Fujio K, Akishita M. Geriatr
Gerontol Int. 2020 Sep 20.
7. Peptidylarginine Deiminase 4 Promotes the Renal
Infiltration of Neutrophils and Exacerbates the
TLR7 Agonist-Induced Lupus Mice. Hanata N,
Shoda H, Hatano H, Nagafuchi Y, Komai T,
Okamura T, Suzuki A, Gunarta IK, Yoshioka K,
Yamamoto K, Fujio K. Front Immunol. 2020;
11:1095.
8. ReductionofMyeloperoxidase-Antineutrophil
Cytoplasmic Antibody by Mepolizumab in
Eosinophilic Granulomatosis With Polyangiitis.
Komai T, Harada H, Takahashi H, Shoda H,
Fujio K. J Clin Rheumatol. 2020 Jun 18.
9. High incidence of malignancy in SAPHO
syndrome. Yamada S, Nagafuchi Y, Kono M,
Hatano H, Tateishi S, Harada H, Sumitomo S,
Kubo K, Shoda H, Kanda H, Fujio K. Clin Exp
Rheumatol. 2020 Jul-Aug;38(4):805-806
10. Decreased peripheral blood memory B cells areassociated with the presence of interstitial lungdisease in rheumatoid arthritis: a case-control
study. Shimizu T, Nagafuchi Y, Harada H,
Tsuchida Y, Tsuchiya H, Hanata N, Tateishi S,
Kanda H, Sumitomo S, Shoda H, Yamamoto K,
Fujio K. Mod Rheumatol. 2020 Feb 5:1-6.
11. 2019 Diagnostic criteria for mixed connective
tissue disease (MCTD): From the Japan researchcommittee of the ministry of health, labor, andwelfare for systemic autoimmune diseases.
Tanaka Y, Kuwana M, Fujii T, Kameda H, Muro
Y, Fujio K, Itoh Y, Yasuoka H, Fukaya S,
Ashihara K, Hirano D, Ohmura K, Tabuchi Y,
Hasegawa H, Matsumiya R, Shirai Y, Ogura T,
Tsuchida Y, Ogawa-Momohara M, Narazaki H,
Inoue Y, Miyagawa I, Nakano K, Hirata S, Mori
M. Mod Rheumatol. 2020 Jan 7:1-5
12. Response to tocilizumab and work productivity
in patients with rheumatoid arthritis: 2-year
follow-up of FIRST ACT-SC study. Tanaka Y,
Kameda H, Saito K, Kaneko Y, Tanaka E,
Yasuda S, Tamura N, Fujio K, Fujii T, Kojima T,

Anzai T, Hamada C, Fujino Y, Matsuda S,
Kohsaka H. Mod Rheumatol. 2020 Jan 20:1-11.
13. Extremely high levels of multiple cytokines in
the cord blood of neonates born to mothers withsystemic autoimmune diseases. Takahashi N,
Nagamatsu T, Fujii T, Takahashi K, Tsuchida Y,
Fujio K, Fujii T. Cytokine. 2020 Mar;127:
154926.
14. Eosinophilic cholangitis with eosinophilic
granulomatosis with polyangiitis: A case reportand review of the literature. Yoshihara R, Komai
T, Nagafuchi Y, Tsuchida Y, Shoda H, Tanaka M,
Ushiku T, Fujio K. Allergol Int. 2020;69:
154-156.
15. Evaluation of Response Criteria in Rheumatoid
Arthritis Treated With Biologic DiseaseModifying Antirheumatic Drugs. Inoue M,
Kanda H, Tateishi S, Fujio K. Arthritis Care Res(Hoboken). 2020;72:942-949.

166

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

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 11th 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, etc.
Every effort is made to give patients the best care andbest quality of life. Assistant associates and residents
take care of inpatients. The case presentation by
residents is held every day. Weekly clinical conferenceis held to discuss all cases, in particular, those withclinical problems difficult to be solved. Consultations
are very frequent from other departments on the
management of infectious diseases. The generaldiagnostic, therapeutic plans and decisions for eachpatient 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, ourassociates teach them on man-to man basis the basic

167

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”.

(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

Research activities
Both clinical and basic researches 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, such as
Clostridioides difficile infection. Also, various
emerging and re-emerging infectious diseases arecovered. 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.

References
1.

2.

3.

4.

5.

6.

7.

Amano Y, Kage H, Tanaka G, Gonoi W, Nakai Y,
Kurokawa R, et al. Diagnostic prediction of
COVID-19 based on clinical and radiologicalfindings in a relatively low COVID-19
prevalence area. Respir Investig. 2021.
Kitaura S, Okamoto K, Wakabayashi Y, Okada Y,
Okazaki A, Ikeda M, et al. Vibrio fluvialis Liver
Abscess and Bacteremia in a Sashimi Lover: A
Case Report and Review of the Literature. Open
Forum Infect Dis. 2020;7(6):ofaa212.
Usui Y, Ayibieke A, Kamiichi Y, Okugawa S,
Moriya K, Tohda S, et al. Impact of deoxycholate
on Clostridioides difficile growth, toxin
production, and sporulation. Heliyon. 2020;6(4):e03717.
Kitaura S, Wakabayashi Y, Okazaki A, Okada Y,
Okamoto K, Ikeda M, et al. The First Case
Report of Acute Symptomatic HEV Genotype 4
Infection in an HIV-positive Patient in Japan.
Intern Med. 2020;59(13):1655-8.
Okamoto K, Asano S, Yamamoto T, Toyono T,
Yamaguchi R, Okada Y, et al. Poor penetration of
cefcapene into aqueous humor after oral
administration of cefcapene pivoxil to patients
undergoing cataract surgery. J Infect Chemother.
2020;26(2):312-5.
Nakamura M, Tsukada H, Seki G, Satoh N,
Mizuno T, Fujii W, et al. Insulin promotes
sodium transport but suppresses gluconeogenesis
via distinct cellular pathways in human and rat
renal proximal tubules. Kidney Int. 2020;97(2):316-26.
Okada Y, Okugawa S, Ikeda M, Kobayashi T,
Saito R, Higurashi Y, et al. Genetic diversity andepidemiology of accessory gene regulator loci in
Clostridioides difficile. Access Microbiol. 2020;

168

8.

9.

10.

11.

12.

13.

14.

15.

16.

2(7):acmi000134.
Doi K, Ikeda M, Hayase N, Moriya K, Morimura
N, Group C-US. Nafamostat mesylate treatment
in combination with favipiravir for patientscritically ill with Covid-19: a case series. Crit
Care. 2020;24(1):392.
Shinohara T, Otani A, Yamashita M, Wakimoto Y,
Jubishi D, Okamoto K, et al. Acute Pancreatitis
During COVID-19 Pneumonia. Pancreas. 2020;
49(10):e106-e8.
Okada Y, Yagihara Y, Wakabayashi Y, Igawa G,
Saito R, Higurashi Y, et al. Epidemiology andvirulence-associated genes of Clostridioides
difficile isolates and factors associated with toxin
EIA results at a university hospital in Japan.
Access Microbiol. 2020;2(2):acmi000086.
Okushin K, Tsutsumi T, Ikeuchi K, Kado A,
Enooku K, Fujinaga H, et al. Heterozygous
knockout of Bile salt export pump ameliorates
liver steatosis in mice fed a high-fat diet. PLoS
One. 2020;15(8):e0234750.
Enooku K, Tsutsumi T, Kondo M, Fujiwara N,
Sasako T, Shibahara J, et al. Hepatic FATP5
expression is associated with histologicalprogression and loss of hepatic fat in NAFLD
patients. J Gastroenterol. 2020;55(2):227-43.
Mizoguchi M, Matsumoto Y, Saito R, Sato T,
Moriya K. Direct antibiotic susceptibility testingof blood cultures of gram-negative bacilli using
the Drug Susceptibility Testing Microfluidic(DSTM) device. J Infect Chemother. 2020;26(6):554-62.
Shiraya T, Araki F, Ueta T, Fukunaga H, Totsuka
K, Arai T, et al. Ursodeoxycholic Acid Attenuates
theRetinalVascular
Abnormalities
inAnti-PDGFR-beta Antibody-Induced Pericyte
Depletion Mouse Models. Sci Rep. 2020;10(1):977.
Jia F, Diao P, Wang X, Hu X, Kimura T,
Nakamuta M, et al. Dietary Restriction
Suppresses
Steatosis-AssociatedHepatic
Tumorigenesis in Hepatitis C Virus Core Gene
Transgenic Mice. Liver Cancer. 2020;9(5):52948.
Diao P, Wang X, Jia F, Kimura T, Hu X, Shirotori
S, et al. A saturated fatty acid-rich diet enhances
hepatic lipogenesis and tumorigenesis in HCVcore gene transgenic mice. J Nutr Biochem.
2020;85:108460.
17. Ayibieke A, Kobayashi A, Suzuki M, Sato W,
Mahazu S, Prah I, et al. Prevalence andCharacterization of Carbapenem-Hydrolyzing
Class D beta-Lactamase-Producing Acinetobacter
Isolates From Ghana. Front Microbiol. 2020;11:587398.

169

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 associates, one research
associate, and 5 adjunct professors, and othermembers are 4 senior residents, 16 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 2020 April to 2021 March, overall 2,603
patients (99 individuals) were admitted to the ward, allof whom were eating disorder patients. Outpatient
clinic is attended on every morning and afternoon inthree consultation rooms by approximately fifteen

physicians. During 2020 April to 2021 March, thenumbers of the new outpatients and of the overall
outpatients in our department were 144 and 4,119,
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

170

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.
Sixteen 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.

References
1.

Maeda I, Ogawa A, Yoshiuchi K, Akechi T,
Morita T, Oyamada S, Yamaguchi T, Imai K,
Sakashita A, Matsumoto Y, Uemura K, Nakahara
R, Iwase S. Safety and Effectiveness ofAntipsychotic Medication for Delirium inPatients with Advanced Cancer: A Large-scale

8.

Multicenter Prospective Observational Study in
Real-world Palliative Care Settings. Gen Hosp
Psychiatry 67:35-41, 2020
Kurisu K, Miyabe D, Furukawa Y, Shibayama O,
Yoshiuchi K. Association between polypharmacy
and the persistence of delirium: a retrospective
cohort study. BioPsychoSocial Medicine 14:25,
2020
Horie T, Hiraide M, Takakura S, Hata T, Sudo N,
Yoshiuchi K. Development of a new Japaneseversion of the Clinical Impairment Assessment
Questionnaire. BioPsychoSoc Med 14:19, 2020
Kurisu K, Tsurutani Y, Inoue K, Hoshino Y,
Saiki F, Yoshiuchi K. Intra-individual association
between C-reactive protein and insulin
administration in postoperative lumbar spinal
canal stenosis patients: a retrospective cohort
study. Journal of Diabetes Investigation 11(4):980-984, 2020
Kato A, Yoshiuchi K, Fujimaki Y, Fujimori S,
Kobayashi Y, Yamada T, Kobayashi M, Izumida
Y, Suzuki R, Yamauchi T, Kadowaki T.
Understanding the experiences of long-term
maintenance of self-worth in persons with type 2
diabetes in Japan: A qualitative study. BMJ Open
2020;10:e034758.
Yoneda R, Otani M, Hiraide M, Horie T, Mitsui
T, Yoshida T, Komaki G, Yoshiuchi K.
Reliability and validity of the Eating Disorders
Quality of Life (ED-QOL) in Japanese healthy
female adolescents and patients with eating
disorders. BioPsychoSocial Medicine 14:16,
2020
Ohara C, Sekiguchi A, Takakura S, Endo Y,
Tamura N, Kikuchi H, Maruo K, Sugawara N,
Hatano K, Kawanishi H, Funaba M, Sugawara A,
Nohara N, Kawai K, Fukudo S, Sudo N, Cooper
Z, Yoshiuchi K, Ando T. Effectiveness ofenhanced cognitive behavior therapy for bulimia
nervosa in Japan: a randomized controlled trial
protocol. BioPsychoSocial Medicine 14:2, 2020
Kurisu K, Yoshiuchi K, Ogino K, Okada Y, Oda
T. Peak C-reactive protein levels do not predict
30-day mortality for bacteremia: a retrospective
cohort study. Journal of Infection andChemotherapy 26(1):23-27, 2020

171

9.

Matsuda Y, Maeda I, Morita T, Yamauchi T,
Sakashita A, Watanabe H, Kaneishi K, Amano K,
Iwase S, Ogawa A, Yoshiuchi K; Phase-R
Delirium Study Group. Reversibility of delirium
in Ill-hospitalized cancer patients: Does
underlying etiology matter? Cancer Med 9:19-26,
2020
10. Nakao M, Komaki G, Yoshiuchi K, Deter HC,
Fukudo S. Biopsychosocial medicine research
trends: connecting clinical medicine, psychology,
and public health. BioPsychoSocial Med 14:30,
2020
11. Harashima S, Fujimori M. Risk of suicide among
adolescents and young adults with cancer and aneed for targeted interventions. Ann Transl Med
8(7):428, 2020

Internal Medicine
3. Clinical Laboratory Medicine
and Pathology

173

Department of Transfusion
Medicine
Professor
Hitoshi Okazaki, M.D.,Ph.D.

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

1741) 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.

175

References
1.

Tokunaga K, Nakamura K, Inokuchi R, Hayase
N, Terada R, Tomioka Y, Ikeda T, Kobayashi E,
Okazaki H, Sakuma I, Doi K, Morimura N.
Cardiac Variation of Internal Jugular Vein as aMarker of Volume Change in Hemorrhagic Shock.
Shock 54: 717-722, 2020

Reproductive, Developmental andAging Sciences
1. Obstetrics and Gynecology

177

Department of
Reproductive Endocrinology
Professors
Yutaka Osuga

Associate Professors
Takeshi Nagamatsu

Homepage http://www.h.u-tokyo.ac.jp/patient/depts/a_joseika02/index.html#reproduction
Organization
The Department of Reproductive Endocrinology isorganized by Professor Tomoyuki Fujii. All the staff
members are taking part in both clinical and research
activities. For the clinical aspect, we are engaged within-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 200 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 2020
1. Nose-Ogura S, Yoshino O, Dohi M, Kigawa M,
Harada M, Kawahara T, et al. Low Bone Mineral
Density in Elite Female Athletes With a History ofSecondary Amenorrhea in Their Teens. Clin J
Sport Med. 2020;30(3):245-50.
2. Azhary JMK, Harada M, Kunitomi C, Kusamoto
A, Takahashi N, Nose E, et al. Androgens Increase
Accumulation of Advanced Glycation End
Products in Granulosa Cells by Activating ER
Stress in PCOS. Endocrinology. 2020;161(2).
3. Gebril M, Hirota Y, Aikawa S, Fukui Y, Kaku T,
Matsuo M, et al. Uterine Epithelial Progesterone
Receptor Governs Uterine Receptivity ThroughEpithelial Cell Differentiation. Endocrinology.
2020;161(12).

178

4. Matsuo M, Hirota Y, Fukui Y, Fujita H,
Saito-Fujita T, Kaku T, et al. Levonorgestrel
Inhibits Embryo Attachment by Eliminating
Uterine Induction of Leukemia Inhibitory Factor.
Endocrinology. 2020;161(2).
5. Osuga Y, Hayashi K, Kanda S. A multicenter,randomized, placebo-controlled, double-blind,comparative study of dienogest at 1 mg/day inpatients with primary and secondary dysmenorrhea. Fertil Steril. 2020;113(3):627-35 e1.
6. Osuga Y, Hayashi K, Kanda S. Evaluation of theefficacy, safety, and clinically recommended doseof dienogest in the treatment of primarydysmenorrhea: a randomized, double-blind,multicenter, placebo-controlled study. Fertil Steril.
2020;113(1):167-75.
7. 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. 2020.
8. Hirata T, Koga K, Kitade M, Fukuda S, Neriishi K,
Taniguchi F, et al. A National Survey of UmbilicalEndometriosis in Japan. J Minim Invasive
Gynecol. 2020;27(1):80-7.
9. Hirata T, Koga K, Kai K, Katabuchi H, Kitade M,
Kitawaki J, et al. Clinical practice guidelines forthe treatment of extragenital endometriosis inJapan, 2018. J Obstet Gynaecol Res. 2020.
10. Ishizawa C, Hirota Y, Urata Y, Morishima K, Fujii
T, Osuga Y. Prolapse of a pedunculated uterine
leiomyoma through the cervix during GnRH
antagonist treatment: Case report and literature
review. J Obstet Gynaecol Res. 2020.
11. Nose-Ogura S, Yoshino O, Dohi M, Torii S,
Kigawa M, Harada M, et al. Relationship between
tartrate-resistant acid phosphatase 5b and stressfractures in female athletes. J Obstet Gynaecol
Res. 2020;46(8):1436-42.
12. Osuga Y, Hayashi K, Kanda S. Long-term use of
dienogest for the treatment of primary andsecondary dysmenorrhea. J Obstet Gynaecol Res.
2020;46(4):606-17.
13. Takahashi N, Yoshino O, Hayashida E, Nakamura
M, Hori M, Iwahata S, et al. Quantitative analysisof ovarian cysts and tumors by using T2 star
mapping. J Obstet Gynaecol Res. 2020;46(1):140-6.
14. Takamura M, Koga K, Harada M, Hirota Y, Fujii
T, Osuga Y. A case of hemorrhagic shock occurred
during dienogest therapy for uterine adenomyosis.
J Obstet Gynaecol Res. 2020.
15. Takeuchi A, Koga K, Tokita Y, Matsumoto T,
Satake E, Taguchi A, et al. The effects oftokishakuyakusan, a traditional Japanese medicine(kampo), ferulic acid and paeoniflorin, on humanendometriotic stromal cells and peritoneal
macrophages. J Reprod Immunol. 2020;139:103104.
16. Kunitomi C, Harada M, Takahashi N, Azhary
JMK, Kusamoto A, Nose E, et al. Activation of
endoplasmic reticulum stress mediates oxidative
stress-induced apoptosis of granulosa cells in
ovaries affected by endometrioma. Mol Hum
Reprod. 2020;26(1):40-52.
17. Hirata T, Koga K, Osuga Y. Extra-pelvic
endometriosis: A review. Reprod Med Biol. 2020;
19(4):323-33.
18. Arakawa T, Fukuda S, Hirata T, Neriishi K, Wang
Y, Takeuchi A, et al. PAX8: A Highly Sensitive
Marker for the Glands in Extragenital
Endometriosis. Reprod Sci. 2020;27(8):1580-6.
19. Ma S, Hirata T, Arakawa T, Sun H, Neriishi K,
Fukuda S, et al. Expression of ALDH1A Isozymes
in Human Endometrium with and without
Endometriosis and in Ovarian Endometrioma.
Reprod Sci. 2020;27(1):443-52.
20. Sun H, Fukuda S, Hirata T, Arakawa T, Ma S,
Neriishi K, et al. IFITM1 is a Novel, Highly
Sensitive Marker for Endometriotic Stromal Cells
in Ovarian and Extragenital Endometriosis.
Reprod Sci. 2020;27(8):1595-601.
21. Nose-Ogura S, Yoshino O, Kanatani M, Dohi M,
Tabei K, Harada M, et al. Effect of transdermal
estradiol therapy on bone mineral density of
amenorrheic female athletes. Scand J Med Sci
Sports. 2020;30(8):1379-86.
22. Hiraoka T, Hirota Y, Fukui Y, Gebril M, Kaku T,
Aikawa S, et al. Differential roles of uterine
epithelial and stromal STAT3 coordinate uterine
receptivity and embryo attachment. Sci Rep.
2020;10(1):15523.

179

23. Inaba K, Wada-Hiraike O, Harada M, Hirota Y,
Koga K, Fujii T, et al. Dienogest suppresses
cellular proliferation status of endometrial polyps
and acts differently depending on themorphological type. Womens Health (Lond).
2020;16:1745506520952003.
24. Takahashi N, Harada M, Oi N, Izumi G,
Momozawa K, Matsuzawa A, et al. Preclinicalvalidation of the new vitrification device
possessing a feature of absorbing excess
vitrification solution for the cryopreservation ofhuman embryos. J Obstet Gynaecol Res. 2020;
46(2):302-9.
25. Gebril M, Hirota Y, Aikawa S, Fukui Y, Kaku T,
Matsuo M, et al. Uterine Epithelial Progesterone
Receptor Governs Uterine Receptivity ThroughEpithelial Cell Differentiation. Endocrinology.
2020;161(12).

180

Department of
Gynecologic Oncology
Associate Professor
Yasushi Hirota

Homepage https://www.h.u-tokyo.ac.jp/patient/depts/jyoseigeka/
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 patients withgynecological cancer and more than one thousand
patients with benign gynecological diseases are treatedin 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 this field,
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 2020
(1) Maru Y, Kawata A, Taguchi A, Ishii Y, Baba S,
Mori M, Nagamatsu T, Oda K, Kukimoto I, Osuga

181

(2)

(3)

(4)

(5)

(6)

(7)

Y, Fujii T, Hippo Y. Establishment and Molecular
Phenotypingof
Organoids
fromtheSquamocolumnar Junction Region of the Uterine
Cervix. Cancers (Basel). 2020 Mar 15;12(3):694.
Kawata Y, Nagasaka K, Oda K, Makii C,
Takeuchi M, Oki S, Honjo H, Kojima M,
Miyagawa Y, Taguchi A, Tanikawa M, Sone K,
Hiraike H, Matsumoto Y, Wada-Hiraike O, Ayabe
T, Osuga Y, Fujii T. Effect of murine doubleminute 2 inhibitors in preclinical models ofadvanced clear cell carcinomas originating fromovaries and kidneys. Cancer Sci. 2020 Jul 25;111(10):3824-34.
Sone K, Eguchi S, Asada K, Inoue F, Miyamoto
Y, Tanikawa M, Tsuruga T, Mori-Uchino M,
Matsumoto Y, Hiraike-Wada O, Oda K, Osuga Y,
Fujii T. Usefulness of biopsy by officehysteroscopy for endometrial cancer: A casereport. Mol Clin Oncol. 2020 Aug;13(2):141-145.
Toyohara Y, Sone K, Nishida H, Taguchi A,
Miyamoto Y, Tanikawa M, Mori M, Tsuruga T,
Matsumoto Y, Oda K, Osuga Y, Fujii T.
Desensitization strategy for hypersensitivity
reactions to carboplatin in five patients withgynecological cancer. J Obstet Gynaecol Res.
2020 Nov;46(11):2298-2304.
Kojima M, Sone K, Oda K, Hamamoto R, Kaneko
S, Oki S, Kukita A, Kawata A, Honjoh H, Kawata
Y, Kashiyama T, Sato M, Taguchi A, Miyamoto
Y, Tanikawa M, Tsuruga T, Nagasaka K, WadaHiraike O, Osuga Y, Fujii T. Oncol Lett. 2020
Nov;20(5):153. The histone methyltransferase
SMYD2 is a novel therapeutic target for the
induction of apoptosis in ovarian clear cell
carcinoma cells.
Wada M, Kukita A, Sone K, Hamamoto R,
Kaneko S, Komatsu M, Takahashi Y, Inoue F,
Kojima M, Honjoh H, Taguchi A, Kashiyama T,
Miyamoto Y, Tanikawa M, Tsuruga T, MoriUchino M, Wada-Hiraike O, Osuga Y, Fujii T.
Biomolecules. 2020 Dec 16;10(12):1686.
Epigenetic Modifier SETD8 as a Therapeutic
Target for High-Grade Serous Ovarian Cancer
Taguchi A, Hara K, Tomio J, Kawana K, Tanaka
T, Baba S, Kawata A, Eguchi S, Tsuruga T, Mori
M, Adachi K, Nagamatsu T, Oda K, Yasugi T,
Osuga Y, Fujii T. Cancers (Basel). 2020 Jan 22;12(2):270. Multistate Markov Model to Predict
thePrognosisofHigh-Risk
Human
Papillomavirus-Related Cervical Lesions(8) Baba S, Taguchi A, Kawata A, Hara K, Eguchi S,
Mori M, Adachi K, Mori S, Iwata T, Mitsuhashi
A, Maeda D, Komatsu A, Nagamatsu T, Oda K,
Kukimoto I, Osuga Y, Fujii T, Kawana K. Virol J.
2020 Mar 6;17(1):32. Differential expression ofhuman papillomavirus 16-, 18-, 52-, and 58derived transcripts in cervical intraepithelial
neoplasia(9) Sasagawa T, Jinno-Oue A, Nagamatsu T, Morita
K, Tsuruga T, Mori-Uchino M, Fujii T, Shibuya
M. BMC Cancer. 2020 Feb 10;20(1):112.
Production of an anti-angiogenic factor sFLT1 issuppressed via promoter hypermethylation of
FLT1 gene in choriocarcinoma cells(10) Kurokawa R, Nakai Y, Gonoi W, MoriH, Tsuruga
T, Makise N, Ushiku T, Abe O. Eur J Radiol. 2020
Mar;124:108823. Differentiation between ovarian
metastasis from colorectal carcinoma and primaryovarian carcinoma: Evaluation of tumour markers
and "mille-feuille sign" on computed tomography/
magnetic resonance imaging(11) Taguchi A, Nagasaka K, Plessy C, Nakamura H,
Kawata Y, Kato S, Hashimoto K, Nagamatsu T,
Oda K, Kukimoto I, Kawana K, Carninci P, Osuga
Y, Fujii T. Sci Rep. 2020 Oct 22;10(1):17991. Useof Cap Analysis Gene Expression to detect humanpapillomavirus promoter activity patterns at
different disease stages

182

Department of Perinatal Medicine
Associate Professor
Kaori Koga

Homepage https://www.obstetrics-htu.jp/
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 2020
1

Kumasawa K, Iriyama T, Nagamatsu T, Osuga Y,
Fujii T. Pravastatin for preeclampsia: Fromanimal to human. J Obstet Gynaecol Res. 2020

183

2

3

4

5

6

7

8.

Aug;46(8):1255-1262.
Yoshikawa M, Iriyama T, Suzuki K, Sayama S,
Tsuruga T, Kumasawa K, Nagamatsu T, Homma
K, Naguro I, Osuga Y, Ichijo H, Fujii T. ASK1
promotes uterine inflammation leading topathological preterm birth. Sci Rep. 2020 Feb 5;10(1):1887.
Samejima T, Nagamatsu T, Akiba N, Fujii T,
Sayama S, Kawana K, Taguchi A, Kumasawa K,
Iriyama T, Osuga Y, Fujii T. Secretory leukocyte
protease inhibitor and progranulin as possible
regulators of cervical remodeling in pregnancy. J
Reprod Immunol. 2020 Nov 1;143:103241.
Kumasawa K, Kubota K, Takahashi Y, Nakayama
T, Iriyama T, Nagamatsu T, Osuga Y, Fujii T.
Abdominal compartment syndrome complicatedby preeclampsia and partial HELLP syndrome ina 45-year-old woman: A case report. Clin Case
Rep. 2020 Apr 28;8(7):1251-1254.
Samejima T, Nagamatsu T, Iriyama T, Nakayama
T, Seyama T, Sayama S, Kumasawa K, Komatsu
A, Kawana K, Osuga Y, Fujii T. Impact ofadditional risk factors on the incidence of preterm
delivery among pregnant women diagnosed withshort cervix. Taiwan J Obstet Gynecol. 2020 Mar;59(2):195-199.
Takahashi Y, Nagamatsu T, Fujii T, Hashimoto A,
Sayama S, Seyama T, Iriyama T, Kumasawa K,
Osuga Y, Fujii T. Congenital extracardiac venous
system anomaly in two siblings with normal
karyotype and increased nuchal translucency
thickness: a case report. Oxf Med Case Reports.
2020 Jun 13;2020(6)Nabeshima T, Fujii T, Nagamatsu T, Hashimoto
A, Seyama T, Kubota K, Sayama S, Nakayama T,
Kumasawa K, Iriyama T, Osuga Y, Fujii T.
Polyhydramnios is associated with postnatal
dysphagia determining short-term prognosis of thenewborn with 22q11.2 deletion syndrome - A caseseries analysis. Taiwan J Obstet Gynecol. 2020
Sep;59(5):744-747.
Sayama S, Song A, Brown BC, Couturier J, Cai X,
Xu P, Chen C, Zheng Y, Iriyama T, Sibai B,
Longo M, Kellems RE, D'Alessandro A, Xia Y.
Maternal erythrocyte ENT1-mediated AMPK
activation counteracts placental hypoxia andsupports fetal growth. JCI Insight. 2020 May 21;

5(10):e130205.

184

Department of Molecular andCellular Reproductive Medicine
Professor
Yutaka Osuga

Associate Professor
Osamu Hiraike

Homepage http://www.h.u-tokyo.ac.jp/patient/depts/a_joseika02/index.html#reproduction
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 2020
1.

2.

3.

Nose-Ogura S, Yoshino O, Dohi M, Kigawa M,
Harada M, Kawahara T, et al. Low Bone Mineral
Density in Elite Female Athletes With a Historyof Secondary Amenorrhea in Their Teens. Clin J
Sport Med. 2020;30(3):245-50.
Azhary JMK, Harada M, Kunitomi C, Kusamoto
A, Takahashi N, Nose E, et al. Androgens
Increase Accumulation of Advanced Glycation
End Products in Granulosa Cells by Activating
ER Stress in PCOS. Endocrinology. 2020;161(2).
Gebril M, Hirota Y, Aikawa S, Fukui Y, Kaku T,
Matsuo M, et al. Uterine Epithelial Progesterone
Receptor Governs Uterine Receptivity Through185

Epithelial Cell Differentiation. Endocrinology.
2020;161(12).
4. Matsuo M, Hirota Y, Fukui Y, Fujita H,
Saito-Fujita T, Kaku T, et al. Levonorgestrel
Inhibits Embryo Attachment by Eliminating
Uterine Induction of Leukemia Inhibitory Factor.
Endocrinology. 2020;161(2).
5. Osuga Y, Hayashi K, Kanda S. A multicenter,randomized, placebo-controlled, double-blind,comparative study of dienogest at 1 mg/day inpatients with primary and secondary dysmenorrhea. Fertil Steril. 2020;113(3):627-35 e1.
6. Osuga Y, Hayashi K, Kanda S. Evaluation of theefficacy, safety, and clinically recommended doseof dienogest in the treatment of primarydysmenorrhea: a randomized, double-blind,multicenter, placebo-controlled study. Fertil
Steril. 2020;113(1):167-75.
7. 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. 2020.
8. Hirata T, Koga K, Kitade M, Fukuda S, Neriishi
K, Taniguchi F, et al. A National Survey ofUmbilical Endometriosis in Japan. J Minim
Invasive Gynecol. 2020;27(1):80-7.
9. Hirata T, Koga K, Kai K, Katabuchi H, Kitade M,
Kitawaki J, et al. Clinical practice guidelines forthe treatment of extragenital endometriosis inJapan, 2018. J Obstet Gynaecol Res. 2020.
10. Ishizawa C, Hirota Y, Urata Y, Morishima K,
Fujii T, Osuga Y. Prolapse of a pedunculated
uterine leiomyoma through the cervix during
GnRH antagonist treatment: Case report andliterature review. J Obstet Gynaecol Res. 2020.
11. Nose-Ogura S, Yoshino O, Dohi M, Torii S,
Kigawa M, Harada M, et al. Relationshipbetween tartrate-resistant acid phosphatase 5b
and stress fractures in female athletes. J Obstet
Gynaecol Res. 2020;46(8):1436-42.
12. Osuga Y, Hayashi K, Kanda S. Long-term use of
dienogest for the treatment of primary andsecondary dysmenorrhea. J Obstet Gynaecol Res.
2020;46(4):606-17.

13. Takahashi N, Yoshino O, Hayashida E, Nakamura
M, Hori M, Iwahata S, et al. Quantitative analysisof ovarian cysts and tumors by using T2 star
mapping. J Obstet Gynaecol Res. 2020;46(1):140-6.
14. Takamura M, Koga K, Harada M, Hirota Y, Fujii
T, Osuga Y. A case of hemorrhagic shock
occurred during dienogest therapy for uterine
adenomyosis. J Obstet Gynaecol Res. 2020.
15. Takeuchi A, Koga K, Tokita Y, Matsumoto T,
Satake E, Taguchi A, et al. The effects oftokishakuyakusan,a
traditional
Japanese
medicine (kampo), ferulic acid and paeoniflorin,on human endometriotic stromal cells andperitoneal macrophages. J Reprod Immunol.
2020;139:103104.
16. Kunitomi C, Harada M, Takahashi N, Azhary
JMK, Kusamoto A, Nose E, et al. Activation of
endoplasmic reticulum stress mediates oxidative
stress-induced apoptosis of granulosa cells in
ovaries affected by endometrioma. Mol Hum
Reprod. 2020;26(1):40-52.
17. Hirata T, Koga K, Osuga Y. Extra-pelvic
endometriosis: A review. Reprod Med Biol. 2020;
19(4):323-33.
18. Nose-Ogura S, Yoshino O, Kanatani M, Dohi M,
Tabei K, Harada M, et al. Effect of transdermal
estradiol therapy on bone mineral density of
amenorrheic female athletes. Scand J Med Sci
Sports. 2020;30(8):1379-86.
19. Inaba K, Wada-Hiraike O, Harada M, Hirota Y,
Koga K, Fujii T, et al. Dienogest suppresses
cellular proliferation status of endometrial polyps
and acts differently depending on themorphological type. Womens Health (Lond).
2020; 16:1745506520952003.
20. Takahashi N, Harada M, Oi N, Izumi G,
Momozawa K, Matsuzawa A, et al. Preclinicalvalidation of the new vitrification device
possessing a feature of absorbing excess
vitrification solution for the cryopreservation ofhuman embryos. J Obstet Gynaecol Res. 2020;
46(2):302-9.

Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

187

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)

Associate Professor
Yutaka Harita, M.D., Ph.D..

Lecturer
Ryo Inuzuka, M.D., PhD., Satsuki Kakiuchi, M.D.,Ph.D.(Department of Maternal, Fetal andNeonatal Medicine), Mitsuteru Hiwatari, M.D., Ph.D. (Department of Cell Therapy andTransplantation Medicine), Hikoro Matsui M.D., Ph. D., Shoichiro Kanda, M.D.,Ph.D

Associate
Riki Nishimura, M.D.,Ph.D., Atsushi Sato, M.D.,Ph.D., Kohei Kashima, M.D.,Ph.D., Yuko
Kajiho, M.D.,Ph.D., Akiko Kinumaki, M.D.,Ph.D., Takako Matsuoka, M.D.,Ph.D., Konomi
Shimoda, M.D., Shunpei Uchino, M.D.,Ph.D., Keihou Owada, M.D.,Ph.D., Yoshihiko
Shitara, , M.D., Takeo Mukai, 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., Hiroki Takehara , M.D., Kaname Uchida, M.D., Go Kimoto, M.D., Moe Hidaka,
M.D., Akiharu Omori, M.D., Yosuke Ogawa, M.D., Kazuhiro Shiraga, M.D., Shota Kato,
M.D., Yuriko Katayama, M.D., Susumu Urata, M.D., Nao Takasugi, M.D., Chie Takahashi,
M.D., Mami Kobayashi, M.D., Kaname Sato, M.D.
(As of March 31, 2021)

Homepage

http://square.umin.ac.jp/ped/

Introduction and Organization
The former Department of Pediatrics developed
into 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
professor, 4 lecturers, 1 project lecturers, 23 associate
professors, 3 project research associates, 5 seniorresidents, and graduate students on March 31, 2020.

188

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. Offices are on the second and third
floors of the East Research Building.
Our laboratories are located on the seventh floor of
the Clinical Research Building Center and on thesecond 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. In addition, patients regarding
genetics, pulmonology, and allergology / immunology
are followed 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 have specialized clinics covering 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). There are 21 beds in the
NICU and 36 beds in the growing care unit (GCU).
There are 12 beds in the PICU and our institution isgoing to fulfill the designation as children’s hospital
affiliated to the university hospital. In the NICU, we
are taking care of small premature babies weighingfrom 400g to 4,000g often associated with congenital
disorders requiring invasive interventions.
PICU is one of tertiary centers of pediatricemergency covering the east part of Tokyo. The PICU
provides advanced monitoring and comprehensive
care for children facing critical illness or injury as
well as those with complex medical needs. Our highly
skilled team has specialized training and equipment toquickly assess and treat children with serious or
life-threatening medical issues. Our PICUs provide
critical care for any child who needs it. We care forchildren facing a full range of severe and complex
medical conditions, including: Severe infections, suchas sepsis and pneumonia, 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.
In general ward of the Pediatric Medical Center, wetreat 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 in the wards.
Cardiology; We use the most comprehensive hearttests and treatments to deliver the highest quality carefrom admission, to discharge, to follow-up, and ourservices range from fetal cardiology to cardiac disease
prevention to pediatric interventional cardiology toheart transplantation.
Neurology; We are part of several multidisciplinary
teams, including those that treat: childhood stroke,
hypoxic ischemic encephalopathy and otherneuro-logical disease.
Hematology/Oncology; A multidisciplinary team ofexperienced healthcare providers will care for children.
Approximately 10 patients received hematopoietic
stem cell transplantation every year. There are patientswith severe combined immunodeficiency, aplastic
anemia-syndrome, relapse/refractory acute lymphoblastic leukemia, acute myeloid leukemia and highrisk neuroblastoma. Genomic medicine is also
provided. Our team includes: Pediatric hematologist/
oncologists, Stem cell transplant physicians, Nurse
specialists, Nurses, Social workers
Kidney disease, Endocrinology; Our team has many
years of experience and a great depth of knowledge
about kidney diseases affecting children andadolescents. Furthermore, the Division of Endocrinology at The University of Tokyo Hospital treats
more children with hormone (endocrine) disorders
At Department of Pediatrics, we pay for all
treatment; McDonald House housing for families with

189

options for bigger accommodations with low pricestaying. Our onsite 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
as a first language, Niko-niko Volunteer and much
more.
Many patients need to stay long in the hospital. We
provide an official in-hospital school ”Kodama
Gakkyu” where patients receive education and havechances to communicate with other patients as well as
their family members. “Niko-niko Volunteer”
members, 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 hospitalsuch as a Tanabata festival, a Christmas party andmusic concerts. All the residents, fellows and nurses
participate in these activities. We have two child carespecialists in the pediatric ward.

Teaching activities
The second grade students are provided with lectures by the staff members and the visiting lecturers
about general pediatrics. The third grade students
attend clinical clerkship in the inpatient ward for 2
weeks. During this bedside learning,small-group
lessons on various pediatric fields are held every day,some of which are switched to online seminars dueto the SARS-CoV2 epidemic. We also offer an elective clinical clerkship course for those who are especially interested in pediatrics in their fourth grade.
Observing the outpatient clinic and learning thenormal development of children are another goal forthe fourth grade students. On the last day of eachclerkship, the professor evaluates the students’achievements. We also provide a variety of online
contents for students.

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 subjects of research during
the last year are listed as follows.
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 reveal novel mechanism of pediatrictumors 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
analyzed pathogenic mechanism of nail-patella
syndrome.
Endocrinology and Metabolism group:
We are analyzing genes and mechanisms involved in
endocrinology and bone diseases. We analyzed thefunction of the novel gene identified in a rarecongenital disease using model animals and iPS cells.
We also analyzed the responsible gene for hereditary
rickets and found novel mutations and etiology.
Cardiology group:
To reveal the molecular mechanism of cardiomyopathy, we perform genome-wide association
studies and generating animal model for cardiomyopathy. Also we perform hemodynamic analysis
for patients with congenital heart disease using
clinical imaging modalities.
Neurology Group:
The pathogenetic mechanism of acute encephalopathy is investigated. Using mouse models of tuberous
sclerosis, the pathogenetic mechanism of neurodevelopmental disorders is investigated. Based onearlier research, a clinical trial of valganciclovir, anantiviral drug for cytomegalovirus infection has been
conducted for infants with congenital cytomegalovirus

190

infection.
Neonatology group:
Epigenetic changes in cord blood and postnatal
peripheral blood of preterm and SGA infants areinvestigated using epigenome-wide methylation
analysis. Influence of microbiome on neonatal
immune function is also investigated. Neonatal brain
function has been investigated using near infra-red
spectro-scopy (NIRS) with researchers of Departmentof Education. Cytokine profiles have been
investigated in order to elucidate pathophysiology ofseveral diseases in perinatal period.
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.

4.

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Yamada T, Yamamoto K, Miyasaka Y, Furuyama
M, Takemura T, Gotoh Y, Takizawa H, Tamagaki
K, Ozawa A, Ashida A, Hattori M, Oka A,
Kitanaka S：Clinical and genetic characterizationof nephropathy in patients with nail-patella
syndrome. Eur J Hum Genet. 2020; 28：14141421.
Hirono K, Hata Y, Miyao N, Okabe M, Takarada
S, Nakaoka H, Ibuki K, Ozawa S, Origasa H,
Nishida N, Ichida F; LVNC study collaborates:
Inuzuka R et al：Increased Burden of Ion Channel
Gene Variants Is Related to Distinct Phenotypes
in Pediatric Patients With Left Ventricular
Noncompaction. Circ Genom Precis Med. 2020;
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Kanda S, Ohmuraya M, Akagawa H, Horita S,
Yoshida Y, Kaneko N, Sugawara N, Ishizuka K,
Miura K, Harita Y, Yamamoto T, Oka A, Araki K,
Furukawa T, Hattori M ： Deletion in the
Cobalamin Synthetase W Domain-Containing
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Anomalies of the Kidney and Urinary Tract. J
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Kimura S, Seki M, Kawai T, Goto H, Yoshida K,
Isobe T, Sekiguchi M, Watanabe K, Kubota Y,
Nannya Y, Ueno H, Shiozawa Y, Suzuki H,
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Department of Pediatric Surgery
Professor
Jun Fujishiro, M.D., Ph.D.

Lecturer
Kan Suzuki, M.D., Ph.D.

Mariko Yoshida, M.D., Ph.D.

Research Associate
Eiichiro Watanabe, M.D., Ph.D.

Homepage

Kotaro Tomonaga, M.D.

Kanako Omata, M.D.

pedsurg.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, three research associates and nine graduate
students. More than 20 members of our department
shoulder the clinical work as pediatric surgeons.

Clinical activities
Staff members higher than the level of research
associate take charge of the outpatient clinic from
Monday through Friday. The pediatric surgical194

outpatient 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 400 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.

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Mansbach JM, Teach SJ, Freishtat RJ, Hasegawa
K. Serum soluble receptor for advanced glycation
end-products (sRAGE) in infants withbronchiolitis: Associations with acute severity
and recurrent wheeze. Clin Infect Dis. 2020.
Epub ahead of print(29) Fujiogi M, Camargo CA Jr, Raita Y, Bochkov
YA, Gern JE, Mansbach JM, Piedra PA,
Hasegawa K. Respiratory viruses are associatedwith serum metabolome among infants
hospitalized for bronchiolitis: A multicenter
study. Pediatr Allergy Immunol. 31: 755-766.
2020.
(30) 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. 2020. Epub ahead of print(31) Fujiogi M, Camargo CA Jr, Raita Y, Bochkov
YA, Gern JE, Mansbach JM, Piedra PA,
Hasegawa K. Association of rhinovirus species
with nasopharyngeal metabolome in bronchiolitis
infants: A multicenter study. Allergy. 75: 23792383. 2020.
(32) Fujiogi M, Camargo CA Jr, Bernot JP, Freishtat
RJ, Harmon B, Mansbach JM, Castro-Nallar E,
Perez-Losada M, Hasegawa K. In infants withseverebronchiolitis:
dual-transcriptomic
profiling of nasopharyngeal microbiome and host
response. Pediatr Res. 88: 144-146. 2020.
(33) Fujiogi M, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Fujishiro J. Clinical features,practice patterns and outcomes of omphalocele: adescriptive study using a nationwide inpatient
database in Japan. Ann Clin Epidemiol. 2: 61-68.

2020.
(34) Sakamoto T, Fujiogi M, Matsui H, Fushimi K,
Yasunaga H. ASO Author Reflections:
Anastomotic complications are more prevalent inlaparoscopic total gastrectomy than in open total
gastrectomy. Ann Surg Oncol. 27: 527-528. 2020.
(35) Sakamoto T, Fujiogi M, Yasunaga H. Response to"Comment On the Effect of minimally invasive
esophagectomy versus open esophagectomy foresophageal cancer". Ann Surg. 2020. Epub aheadof print(36) Konishi K, Mizuochi T, Takeuchi I, Arai K,
Yamamoto K. Congenital chloride diarrhea in a
Japanese neonate with a novel SLC26A3
mutation. Pediatr Int. 62: 1294-1296. 2020.
(37) Mizuochi T, Arai K, Kudo T, Nambu R, Tajiri H,
Aomatsu T, Abe N, Kakiuchi T, Hashimoto K,
Sogo T, Takahashi M, Etani Y, Takaki Y, Konishi
KI, Ishihara J, Obara H, Kakuma T, Kurei S,
Yamashita Y, Mitsuyama K. Diagnostic accuracyof serum proteinase 3 antineutrophil cytoplasmic
antibodies in children with ulcerative colitis. J
Gastroenterol Hepatol. 2020. in press(38) Konishi KI, Mizuochi T, Honma H, Etani Y,
Morikawa K, Wada K, Yamamoto K. A novel denovo SLC26A3 mutation causing congenitalchloride diarrhea in a Japanese neonate. Mol
Genet Genomic Med. 8: e1505. 2020.
(39) Mizuochi T, Arai K, Kudo T, Nambu R, Tajiri H,
Aomatsu T, Abe N, Kakiuchi T, Hashimoto K,
Sogo T, Takahashi M, Etani Y, Takaki Y, Konishi
KI, Ishihara J, Obara H, Kakuma T, Kurei S,
Yamashita Y, Mitsuyama K. Antibodies toCrohn’s disease peptide 353 as a diagnostic
marker for pediatric Crohn’s disease: aprospective multicenter study in Japan. J
Gastroenterol. 55: 515-522. 2020.

Reproductive, Developmental andAging Sciences
3. Aging Sciences

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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.

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 elderly patients tend to have multiple organ
disorders, these patients should be taken cared as awhole from multiple points of view. In addition,
symptoms, signs and responses to the treatment in theelderly patients could be quite different from theyounger counterparts. Specific knowledge on thephysiological and metabolic changes with aging isnecessary when these elderly 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, two 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 elderly patients fromviewpoints of basic aging science using molecularbiology technique and clinical aspects using the recent
advancement of technology and geriatric 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 andsarcopenia, osteoporosis, chronic obstructive
pulmonary disease (COPD), and sleep apnea. As a‘second opinion outpatient clinic’, we accept
consultation on polypharmacy. Since 2003, we
provide ‘women’s general outpatient clinic’ by female
physicians for treatment of gender sensitive

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conditions. In the inpatient setting, we have our properwards in the 13th floor of our hospital, and generally
accept approximately 10 patients who are treated byjunior, senior, and chief residents of our staff. Olderpatients often suffer from a variety of diseases andclinical problems. To deal with them, our department
forms multi-disciplinary teams composed ofgeriatricians and related specialists such as
psychologists
andpharmacists
toprovidecomprehensive 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 disorderin the elderly
6) Clinical study on metabolic syndrome in theelderly7) Biomarkers of dementia, caregiver’s stress andgeriatric syndromes8) Research on appropriate healthcare for theelderly 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) Role of nuclear receptors in senescence andcarcinogenesis14) Molecular mechanism of vitamin K function
and its roles in aging
15) Diagnosis and prevention of aspiration pneumonia
16) Novel roles of antimicrobial peptide, defensin17) Adrenomedullin and airway hyperresponsiveness18) Klotho protein and vitamin D in lung19) Clinical investigation of sleep-related breathing
disorderPublications (Original Articles)
1.

2.

3.

Shibasaki K, Asahi T, Kuribayashi M, Tajima
Y, Marubayashi M, Iwama R, Akishita M,
Ogawa S. Potential prescribing omissions ofanti-osteoporosis drugs is associated withrehabilitation outcomes after fragility fracture:
Retrospective cohort study. Geriatr Gerontol Int.
2021 Feb 28. doi: 10.1111/ggi.14145. Online
ahead of print.
Umeda-Kameyama Y, Kameyama M, Tanaka T,
Son BK, Kojima T, Fukasawa M, Iizuka T,
Ogawa S, Iijima K, Akishita M. Screening of
Alzheimer's disease by facial complexion using
artificial intelligence. Aging (Albany NY). 2021;
13(2):1765-1772. doi: 10.18632/aging.202545.
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. 2021;16:e0246276. doi: 10.
1371/journal.pone.0246276. PMID: 33529213.

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4.

Suzuki Y, Sakakibara M, Shiraishi N, Komiya H,
Akishita M, Kuzuya M. Use of Anti-Dementia
Drugs Reduces the Risk of Potentially
Inappropriate Medications: A Secondary
Analysis of a Nationwide Survey of Prescribing
Pharmacies. Dement Geriatr Cogn Disord. 2020
Dec 4:1-7. doi: 10.1159/000512043. Online
ahead of print.
5. Nomura K, Eto M, Ogawa S, Kojima T, Iijima K,
Nakamura T, Araki A, Ouchi Y, Akishita M.
Association between low muscle mass andmetabolic syndrome in elderly Japanese women.
PLoS One. 2020;15:e0243242. doi: 10.1371/
journal.pone.0243242.
6. Okumura K, Akao M, Yoshida T, Kawata M,
Okazaki O, Akashi S, Eshima K, Tanizawa K,
Fukuzawa M, Hayashi T, Akishita M, Lip GYH,
Yamashita T. ELDERCARE-AF Committees andInvestigators. Low-Dose Edoxaban in Very
Elderly Patients with Atrial Fibrillation. N Engl
J Med. 2020;383:1735-1745. doi: 10.1056/
NEJMoa2012883.
7. Hattori Y, Abe T, Kojima T, Hamada S, Ogawa
S, Ura N, Akishita M. Potential prescribing
omissions may have no influence on cause ofdeath in care-dependent older adults withpercutaneous endoscopic gastrostomy tube.
Geriatr Gerontol Int. 2020; 20: 961-966. doi:
10.1111/ggi.14009.
8. Umeda-Kameyama Y, Kameyama M, Kojima T,
Ishii M, Kidana K, Yakabe M, Ishii S, Urano T,
Ogawa S, Akishita M. Cognitive function has astronger correlation with perceived age than withchronological age. Geriatr Gerontol Int. 2020;
20:779-784. doi: 10.1111/ggi.13972.
9. Wada-Isoe K, Kikuchi T, Umeda-Kameyama Y,
Mori T, Akishita M, Nakamura Y. Validation of
the Neuropsychiatric Inventory Based on Item
Response Theory. J Alzheimers Dis Rep. 2020;4:
151-159. doi: 10.3233/ADR-200172.
10. Hosoi T, Yamana H, Tamiya H, Matsui H,
Fushimi K, Akishita M, Yasunaga H, Ogawa S.
Association between comprehensive geriatricassessment and short-term outcomes amongolder adult patients with stroke:A nationwide retrospective cohort study using
propensity score and instrumental variable

11.

12.

13.

14.

15.

16.

17.

methods. EClinicalMedicine. 2020;23:100411.
doi: 10.1016/j.eclinm.2020.100411.
Ishizaki T, Mitsutake S, Hamada S, Teramoto C,
Shimizu S, Akishita M, Ito H. Drug prescription
patterns and factors associated with polypharmacy in >1 million older adults in Tokyo.
Geriatr Gerontol Int. 2020;20:304-311. doi:
10.1111/ggi.13880.
Hamada S, Kojima T, Maruoka H, Ishii S, Hattori
Y, Okochi J, Akishita M. Utilization of drugs forthe management of cardiovascular diseases atintermediate care facilities for older adults inJapan. Arch Gerontol Geriatr. 2020;88:104016.
doi: 10.1016/j.archger.2020.104016.
Nomura K, Eto M, Ogawa S, Kojima T, Iijima K,
Nakamura T, Araki A, Ouchi Y, Akishita M. The
association between low muscle mass andcardiovascular risk actors in elderly women.
PLoS One. 2020 Dec 3;15(12):e0243242. doi:10.
1371/journal.pone.0243242. eCollection 2020
Kameyama M, Ishibashi K, Toyohara J,
Wagatsuma K, Umeda-Kameyama Y, Shimoji K,
Kamemaru K, Murayama S, Ogawa S, Tokumaru
A, Ishii K. Voxel-Based morphometry focusing
on medial temporal lobe structures has limited
capability to detect amyloid β. Aging. 2020 Oct
5; 12(19): 19701-19710. doi: 10.18632/aging.
104012. Online ahead of print.
Hattori Y, Abe T, Kojima T, Hamada S, Ogawa
S, Ura N, Akishita M. Potential prescribing
omissions (PPO) may have no influence on causeof death in care-dependent older adults withpercutaneous endoscopic gastrostomy (PEG)
tube. Geriatr Gerontol Int. 2020;20(10):961-966
Nakatoh S, Fujimori K, Tamaki J, Okimoto N,
Ogawa S, Iki M. Insufficient increase in bonemineral density testing rates and pharmacotherapy after hip fracture in Japan. J Bone Miner
Metab. 2020;385:589-596
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. 2021;21(1):14-19

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18. Nakatoh S, Fujimori K, Tamaki J, Okimoto N,
Ogawa S, Iki M. Insufcient persistence of andadherence to osteoporosis pharmacotherapy inJapan. J Bone Miner Metab. 2021 Jan 5. doi:
10.1007/s00774-020-01188-w. Online ahead ofprint.
19. 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. 2021;36(1):33-40
20. 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 Geniohyoid Muscle Is Associated with
MaximumTongue Pressure and Tongue Area inPatients with Sarcopenic Dysphagia. J Nutr
Health Aging. 2021;25(3):356-360
21. Tanaka T, Hirano H, Ohara Y, Nishimoto M,
Iijima K. Oral Frailty Index-8 in the risk
assessment of new onset oral frailty andfunctional disability among community-dwellingolder adults. Arch Geront Geriatr. May-Jun 2021;
94: 104340. doi: 10.1016/j.archger.2021.104340.
Epub 2021 Jan 19.
22. Nishimoto M, Tanaka T, Iijima K. Is oral frailty
related to meal satisfaction? J Aging Science.
2021;9(1):245
23. Tanaka T, Kawahara T, Aono, H, Yamada, S,
Ishizuka S, Takahashi K, Iijima K. A comparisonof sarcopenia prevalence between former Tokyo
1964 Olympic athletes and general communitydwelling older adults. J Cachexia Sarcopenia
Muscle. 2021; 12(2): 339-349. doi: 10.1002/jcsm.
12663.
24. Cherbuin N, Iijima K, Kalula S, Malothra R,
Rasmussen LJ, Chan A, Lafortune L, Harper S,
Zheng X, Lindeman D. Societal need forinterdisciplinary ageing research. An International Association of Research Universities“Ageing, Longevity, and Health” Stream (IARUALH) position statement. Biomed Hub. 2021;
6(1):42–47. Published online 2021 Feb 25. doi:
10.1159/000513513.
25. Makizako H, Nishita Y, Jeong S, Otsuka R,
Shimada H, Iijima K, Obuchi S, Kim H,

Kitamura A, Ohara Y, Awata S, Yoshimura N,
Yamada M, Toba K, Suzuki T. Trends inprevalence of frailty in Japan: A meta-analysis
from the ILSA-J. J Frailty Aging. 2020 (in press).
Published online December 22, 2020, http://dx.
doi.org/10.14283/jfa.2020.68.
26. Lim WS, Liang CK, Assantachai P, Auyeung TW,
Kang L, Lee WJ, Lim JY, Sugimoto K, Akishita
M, Chia SL, Chou MY, Ding YY, Iijima K, Jang
HC, Kawashima S, Kim M, Kojima T, Kuzuya M,
Lee J, Lee SY, Lee Y, Peng LN, Wang NY, Wang
YW, Won CW, Woo J, Chen LK, Arai H.
COVID-19 and Older People in Asia: AWGS
Calls to Actions. Geriatr Gerontol Int. 2020 May
4; 547-558. doi: 10.1111/ggi.13939.
27. Suzuki M, Okochi J, Iijima K, Murata T, Kume
H. Nationwide survey of continence statusamong elderly residents living in long-term carefacilities in Japan: the prevalence and associatedrisk factors of incontinence and effect ofcomprehensive care on continence status. Geriatr
Gerontol Int. 2020;20(4):285-290. doi: 10.1111/
ggi.13872. Epub 2020 Jan 28.
28. Takahashi K, Murayama H, Tanaka T, Takase M,
Suthutvoravut U, Iijima K. A qualitative study on
the reasons for solitary eating habits of older
adults living with family. PLoS One. 2020;15(6):e0234379. Published online 2020 Jun 8; doi:
10.1371/journal.pone.0234379.
29. Murakami M, Iijima K, Watanabe Y, Tanaka T,
Iwasa Y, Edahiro A, Ohara Y, Motokawa K,
Shirobe M, Hirano H. Development of a simple
method to measure masseter muscle mass.
Gerodontology. 2020; 37(4): 383-388. doi:10.
1111/ger.12487.
30. 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, and Makizako
H. Are Japanese Older Adults Rejuvenating?
Changes in Health-Related Measures Among
Older Community Dwellers in the Last Decade.
Rejuvenation Research 2021 Feb;24(1):37-48.
doi: 10.1089/rej.2019.2291. Epub 2020 Jul 8.
31. Shimada K, Hamada S, Sawano M, Yamamoto H,
Yoshie S, Iijima K, Miyata H. Implementation ofguidelines-based medications after the discharge

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32.

33.

34.

35.

36.

37.

38.

of older adults undergoing percutaneous
coronary intervention in a city of Japan: A cohort
study using claims data. Tohoku J Exp Med.
2020;252(2):143-152. doi: 10.1620/tjem.252.143.
Tsuchiya-Ito R, Ishizaki T, Mitsutake S, Hamada
S, Yoshie S, Iijima K, Tamiya N. Association ofhouseholdincomewithhome-based
rehabilitation and home help service utilization
among long-term home care service users. BMC
Geriatrics. 2020; 20:314. Published online 2020
Aug 28. doi: 10.1186/s12877-020-01704-7
Fujisaki-Sueda-Sakai
M,
Takahashi
K,
Yoshizawa Y, Iijima K. Frailty checkup
Supporters’ intentions to participate in humanresource development and training activities. J
Frailty Aging. 2020;9(4):238-243. http://dx.doi.
org/10.14283/jfa.2020.6.
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
Affairs. 2021;40(3):478-486.
Tsuchiya-Ito R, Kusumoto N, MaruyamaSakurai K, Tamai A, Yokoyama H, Watanabe A,
Fujiwara T, Yamanaka T. Determinants of the
Implementation of Home Evaluations among
Patients with Fall-Related Fractures at a
Convalescent Rehabilitation Ward in Tokyo: A
Cross-Sectional Study. Journal of Aging andEnvironment 2020 doi:10.1080/26892618.2020.
1859036.
Hirakawa Y, Hirahara S, Yamaguchi Y,
Yamanaka T, Arai H, Miura H. Improving thequality of community primary palliative care in
COPD: A qualitative study of health-careproviders. Home Health Care Services. Quarterly2020 doi: 10.1080/01621424.2020.1845272.
Pazan F, Gercke Y, Weiss C, Wehling M,
Akazawa H, Kojima T, Kumaki R, Akishita M,
Takeya Y, Ohno Y, Yamanaka T, Kozaki K,
Suzuki, Mizukami K, Mizokami F, Ikeda Y,
Shimizu A. The JAPAN-FORTA (Fit fOR The
Aged) list: Consensus validation of a clinical tool
to improve drug therapy in older adults. Arch
Gerontol Geriatr. 2020;91:104217.
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. 2021
Mar;21(3):291-298. doi: 10.1111/ggi.14128.
39. Kase Y, Okano H. Expression of ACE2 and aviral virulence-regulating factor CCN family
member 1 in human iPSC-derived neural cells:
implications for COVID-19-related CNS
disorders. Inflamm Regen. 2020;40:32.
40. Pazan F, Gercke Y, Weiss C, Kojima T, Wehling
M; FORTA raters:. The JAPAN-FORTA (FitfOR The Aged) list: Consensus validation of aclinical tool to improve drug therapy in older
adults. Arch Gerontol Geriatr. 2020,91:104251
41. Hamada S, Kojima T, Maruoka H, Ishii S, Hattori
Y, Okochi J, Akishita M. Utilization of drugs tomanage cardiovascular diseases at intermediatecare facilities for older adults in Japan. Arch
Gerontol Geriatr. 2020;88:104016

Surgical Sciences
1. Surgery

205

Department of Thoracic Surgery
Professor
Nakajima, Jun

Assistant Professor
Sato, Masaaki
Kitano, Kentaro
Konoeda, Chihiro
Nagano, Masaaki
Yanagiya, Masahiro

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 1997.
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,
postgraduates, and the surgical residents in our
university.

206

Clinical activities
Six staffs (Nakajima J, Sato M, Kitano K, Konoeda
C, Nagano M, and Yanagiya M), who are certificatedas members of the Japanese Board of General
Thoracic Surgery, are in charge of the Department ofThoracic 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 2019, Ministry of Health, Labour andWelfare documented that number of deaths frommalignant neoplasms was approximately 380 thousandout of 1.38 million total deaths in Japan. Of them, 75
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 78 lung transplants(including 17 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

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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

4.

5.

6.

Selected publications (2020)
1. Ando T, Matsumoto Y, Zokumasu K, Yotsumoto T,
Maemura K, Amano Y, Watanabe K, Nakajima J,
Nagase T, Takai D. Integrin α11 in non-small celllung cancer is associated with tumor progression
and postoperative recurrence. Cancer Sci 2020;
111(1): 200-208
2. Aoki S, Yamashita H, Takahashi W, Nawa K, Ota
T, Imae T, Ozaki S, Nozawa Y, Nakajima J, Sato
M, Anraku M, Nitadori J, Karasaki T, Abe O,
Nakagawa K. Salvage stereotactic bodyradiotherapy for post-operative oligo-recurrenceof non-small cell lung cancer: A single-institution
analysis of 59 patients. Oncol Lett., 2020; 19(4):2695-2704
3. Edwards JG, Chansky K, Van Schil P, Nicholson
AG, Boubia S, Brambilla E, Donington J,
Galateau-Sallé F, Hoffmann H, Infante M, Marino
M, Marom EM, Nakajima J, Ostrowski M, Travis
WD, Tsao MS, Yatabe Y, Giroux DJ, Shemanski L,
Crowley J, Krasnik M, Asamura H, Rami-Porta R;
International Association for the Study of Lung
Cancer Staging and Prognostic Factors Committee,
Advisory Board Members, and Participating
Institutions.The IASLC Lung Cancer Staging

7.

8.

9.

Project: Analysis of Resection Margin Status andProposals for Residual Tumor Descriptors for
Non-Small Cell Lung Cancer. J Thorac Oncol
2020; 15(3): 344-359
Hirata T, Koga K, Kitade M, Fukuda S, Neriishi K,
Taniguchi F, Honda R, Takazawa N, Tanaka T,
Kurihara M, Nakajima J, Horie S, Nakai H,
Enomoto T, Mandai M, Narahara H, Kitawaki J,
Harada T, Katabuchi H, Yoshimura K, Osuga Y. A
National Survey of Umbilical Endometriosis inJapan. J Minim Invasive Gynecol. 2020; 27(1):80-87Matsumura M, Yamashita S, Ishizawa T,
Akamatsu N, Kaneko J, Arita J, Nakajima J,
Kokudo N, Hasegawa K. Oncological benefit ofcomplete metastasectomy for simultaneouscolorectal liver and lung metastases. Am J Surg
2020; 219(1): 80-87
Agzarian J, Litle V, Linkins LA, Brunelli A,
Schneider L, Kestenholz P, Li H, Rocco G, Girard
P, Nakajima J, Samama CM, Scarci M, Anraku M,
Falcoz PE, Bertolaccini L, Lin J, Murthy S,
Hofstetter W, Okumura M, Solli P, Minervini F,
Kirk A, Douketis J, Shargall Y. International
Association for the Study of Lung Cancer Staging
and Prognostic Factors Committee, Advisory
Board Members, and Participating Institutions.
The IASLC Lung Cancer Staging Project:
Analysis of Resection Margin Status andProposals for Residual Tumor Descriptors for
Non-Small Cell Lung Cancer. J Thorac Oncol
2020;15(3):344-359.
Makise N, Mori T, Kobayashi H, Nakagawa K,
Ryo E, Nakajima J, Kohsaka S, Mano H,
Aburatani H, Yoshida A, Ushiku T. Mesenchymal
Tumors with RREB1-MRTFB Fusion Involving
the Mediastinum: Extra-Glossal Ectomesenchymal Chondromyxoid Tumors? Histopathology 2020;76(7):1023-1031.
Aizawa H, Karasaki T, Nagayama K, ShinozakiUshiku A, Aburatani H, Mano H, Nakajima J.
Clinical Application of Next-generation Sequencing for the Diagnosis of Lung Squamous Cell
Carcinoma: Is It Primary or Secondary? Intern
Med 2020; 59(10):1299-1302.
Yanagiya M, Hamaya H, Matsuzaki H, Ikemura M,
Nakajima J. Atypical type A thymoma variant

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manifesting polymyalgia rheumatic. Ann Thorac
Surg 2020;110(4): e253-e255.
10. Tian D, Shiiya H, Sato M, Nakajima J. Rat lungtransplantation model: modifications of the cuff
technique. Ann Transl Med 2020;8(6):407
11. Jheon S, Ahmed AD, Fang VW, Jung W, Khan AZ,
Lee JM, Nakajima J, Sihoe AD, Thongcharoen P,
Tsuboi M, Turna A. General thoracic surgery
services across Asia during the 2020 COVID-19
pandemic. Asian Cardiovasc Thorac Ann. 2020;28(5):243-249.
12. Kawashima S, Yoshioka T, Hino H, Kitano K,
Nagayama K, Sato M, Kojima R, Kamiya M,
Urano Y, Nakajima J. ɤ-glutamyl hydroxymethyl
rhodamine green fluorescence as a prognostic
indicator for lung cancer. Gen Thorac Cardiovasc
Surg. 2020;68(12):1418-1424.
13. Matsumoto K, Sato S, Okumura M, Niwa H, Hida
Y, Kaga K, Date H, Nakajima J, Usuda J, Suzuki
M, Souma T, Tsuchida M, Miyata Y, Takeshi N;
Committee
forPatient
SafetyQuality
Management of Japanese Association for Chest
Surgery. Left upper lobectomy is a risk factor for
cerebral infarction after pulmonary resection: amulticentre, retrospective, case-control study inJapan. Surg Today 2020;50(11):1383-1392.
14. Shinozaki-Ushiku A, Kohsaka S, Kage H, Oda K,
Miyagawa K, Nakajima J, Aburatani H, Mano H,
Ushiku T. Genomic profiling of multiple primarycancers including synchronous lung adenocarcinoma and bilateral malignant mesotheliomas:
Identification of a novel BAP1 germline variant.
Pathol Int. 2020;70(10):775-780.
15. Jheon S, Ahmed AD, Fang VW, Jung W, Khan AZ,
Lee JM, Sihoe AD, Thongcharoen P, Tsuboi M,
Turna A, Nakajima J. Thoracic cancer surgery
during the COVID-19 pandemic: a consensus
statement from the Thoracic Domain of the AsianSociety for Cardiovascular and Thoracic Surgery.
Asian Cardiovasc Thorac Ann. 2020;28(6):322329.
16. Ikeda N, Endo S, Fukuchi E, Nakajima J, Yokoi K,
Chida M, Date H, Iwasaki A, Yokomise H, Sato M,
Okumura M, Yamamoto H, Miyata H, Kondo T.
Current status of surgery for clinical stage IA lungcancer in Japan: analysis of the national clinicaldatabase. Surg Today 2020;50(12):1644-1651.

17. Sun C, Anraku M, Kawahara T, Karasaki T,
Kitano K, Nagayama K, Sato M, Nakajima J.
Prognostic significance of low pectoralis muscle
mass on preoperative chest computed tomography
in localized non-small cell lung cancer after
curative-intent surgery. Lung Cancer 2020; 147:
71-76.
18. Kakimi K, Matsushita H, Masuzawa K, Karasaki
T, Kobayashi Y, Nagaoka K, Hosoi A, Ikemura S,
Kitano K, Kawada I, Manabe T, Takehara T,
Ebisudani T, Nagayama K, Nakamura Y, Suzuki R,
Yasuda H, Sato M, Soejima K, Nakajima J.
Adoptive transfer of zoledronate-expanded
autologous Vγ9Vδ2 T-cells in patients withtreatment-refractory non-small-cell lung cancer: amulticenter, open-label, single-arm, phase 2 study.
J Immunother Cancer 2020;8(2): e001185.
19. Yotsumoto T, Maemura K, Watanabe K, Amano Y,
Matsumoto Y, Zokumasu K, Ando T, Kawakami
M, Kage H, Nakajima J, Yatomi Y, Nagase T,
Takai D. NRXN1 as a novel potential target of
antibody-drug conjugates for small cell lungcancer. Oncotarget 2020;11(39):3590-3600.
20. Miyake H, Murono K, Kawai K, Nozawa H, Maki
H, Hasegawa K, Nakajima J, Ishihara S. Impact ofSurgical Resection on Metachronous Metastasesof Colorectal Cancer According to Tumor
Doubling Time. In Vivo 2020;34(6):3367-3374.
21. Endoh M, Shiono S, Yamauchi Y, Mun M, Ikeda
N, Hashimoto H, Horio H, Asamura H, Yoshino I,
Matsuguma H, Nakajima J, Oyama T, Shintani Y,
Nakayama M, Matsutani N, Kawamura M.
Pulmonary metastasectomy for pulmonary metastasis of breast cancer has a limited prognostic
impact: a multi-institutional retrospective analysis.
J Thorac Dis 2020;12(11):6552-6562.
22. 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-oilin-water Emulsion In Vivo. In Vivo 2021;35(1):239-248.

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23. 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
24. Yanagiya M, Sato M, Ueda K, Nagayama K,
Kawahara T, Kawashima S, Yotsumoto T,
Yoshioka T, Fukumoto KJ, Nakajima J.
Preoperative lung surface localization for
pulmonary wedge resection: a single-center
experience. J Thorac Dis. 2020;12(5):2129-2136.
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
26. Tian D, Wang Y, Shiiya H, Sun CB, Uemura Y,
Sato M, Nakajima J. Outcomes of marginal
donors for lung transplantation after ex vivo lungperfusion: A systematic review and meta-analysis.
J Thorac Cardiovasc Surg. 2020;159(2):720-730.

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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. Healso started implantation of alcohol-preserved aortic
homograft for abdominal aortic aneurysm in 1952, andclosed commissurotomy for mitral valve stenosis in
1954. The first open heart surgery (atrial septal defectclosure) was performed in 1955, using selective brain
perfusion cooling method that was developed in the
Department.
Establishment of Department of Thoracic Surgery in
the University of Tokyo Hospital was approved by thegovernment first in Japan December 15, 1964. Under
the leadership of Professor Kimoto excellent researchworks were created especially on pacemaker andartificial 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 to the
Department. Dr. Kenichi Asano, the third Professor,

started posterior-leaflet preserving mitral valve
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 tothe 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 of patients who
require ventricular assist device and hearttransplantation treatment. Present staffs are one Chief
Professor, one Associate Professor and three Lecturer
and seven Associates.

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Clinical Activities
Clinical conference starts at 7:15 am in weekdays.
Regular surgery is scheduled on Monday, Wednesday
and Friday. Patient round is on Tuesday. Adult patientsare hospitalized in the South Wing of 5th floor, andpediatric patients in the South Wing of 2nd floor. Clinics
are open Monday through Friday for the follow-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
11 Board-certified surgeons, each of whom has his own
subspecialty among adult cardiac, thoracic aortic orcongenital heart disease. We are famous for off- pumpcoronary artery bypass surgery, mitral valve plasty,
heart transplantation, ventricular assist device
implantation, aortic valve sparing root replacement,arch replacement, treatment of extended thoracic aortic
aneurysm and repair of complex congenital heartdiseases, such as Jatene, Fontan and Norwood
operations. Transcatheter aortic valve replacement was
initiated in 2015. Many high-risk very old patients withaortic valve stenosis were successfully 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 2021, 155 cases ofheart transplantation including 14 pediatric patientsand 382 cases of ventricular assist device (VAD)
implantation including 249 implantable continuousflow VADs were performed in The University Hospitalwith 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 daily clinicalworks as well as research works during the course of“Free Quarter” and “Research Lab Visit”, which arescheduled in the summer and spring vacations at 1st and2nd grade. Joint lectures with the Cardiology
Department are scheduled 3rd through 4th grades. Eachstudent is assigned one or two cardiovascular surgicalcases in the Regular Clinical Clerkship, in which he/she
is required to learn preoperative patient evaluation andmanagement, surgical treatment and postoperative care,based on participatory 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 protocolsof left ventricular assist device, 2) basic and clinicalresearch on cryopreserved allograft, 3) application ofregenerative medicine to end-stage heart failure, 4)analysis of cardiomyocytes matured and differentiatedfrom iPS cells, 5) mechanism analysis of right heart
failure and development of effective pharmacologicaland mechanical therapy, 6) development of versatile

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suture device, 7) clinical research to test the safety andefficacy of artificial pancreas during open heart surgery.

References
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Shiraishi Y, Amiya E, Hatano M, Katsuki T, Bujo
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Endo M, Kimura M, Ando M, Shimada S,
Kinoshita O, Ono M, Komuro I.: Impact of
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Fukushima S, Asakura K, Hamasaki T, Onda K,
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Panthee N, Ono M, Yamamoto T, Ikemura M,
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K, Nagata M, Nonaka Y, Furuya Y, Hisa T,
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with autologous hematopoietic stem celltransplantation despite transient heart failure
associated with engraftment syndrome. Ann
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Tsuji M, Narita K, Fujita K, Ishida J, Ono M,
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Rejection Due to Atopic Dermatitis Exacerbation
3 Years After Heart Transplantation. Front
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Thoracoabdominal aorta replacement for a patientwith Marfan syndrome with poor left ventricularfunction. JTCVS Tech. 2021 Jan 28;7:45-48.
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Miyata H, Motomura N, Natsugoe S, Ozawa S,
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Tanemoto K, Tatsuishi W, Toh Y, Tsukihara H,
Watanabe M, Yamamoto H, Yokoi K, Okita Y.
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Cardiovasc Surg. 2020 Apr;68(4):414-449.
PMID: 32140991.
24. Hirata Y, Shimizu H, Kumamaru H, Takamoto S,
Motomura N, Miyata H, Okita Y. Congenital
Heart Disease After the Fukushima Nuclear
Accident: The Japan Cardiovascular Surgery
Database Study. J Am Heart Assoc. 2020 Jul 7;
9(13):e014787. PMID: 32613886.

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25. Shiraga K, Hirata Y, Saito A, Ozcelik N, Asakai
H, Inuzuka R, Soma K, Sato M, Hirata Y, Oka A.
Successful angioplasties using high pressure large
balloons in a patient with severe anastomotic
pulmonary artery stenosis soon after single-lungtransplantation. J Cardiol Cases. 2020 May 10;22(1):22-25. PMID: 32636964
26. Protopapas EM, Rito ML, Vida VL, Sarris GE,
Tchervenkov CI, Maruszewski BJ, Tobota Z,
Zheleva B, Zhang H, Jacobs JP, Dearani JA,
Stephens EH, Tweddell JS, Sandoval NF, Bacha
EA, Austin EH, Sakamoto K, Talwar S, Kurosawa
H, Halees ZYA, Jatene MB, Iyer KS, Lee C,
Sharma R, Hirata Y, Edwin F, Cervantes JL,
O'Brien J, St Louis J, Kirklin JK; COVID-19
International Congenital Heart Surgery Taskforce.
Early Impact of the COVID-19 Pandemic onCongenital Heart Surgery Programs Across theWorld: Assessment by a Global Multi-Societal
Consortium. World J Pediatr Congenit Heart Surg.
2020 Nov;11(6):689-696. PMID: 32844725
27. Saito A, Soma K, Masuzawa A, Hatsuse S,
Nakayama Y, Amiya E, Yao A, Hirata Y, Komuro
I. Symptomatic Right Ventricular Outflow Tract
Obstruction Due to Sinus of Valsalva Aneurysm.
Circ J. 2020 Nov 25;84(12):2324. PMID:
33041292.
28. Committee for Scientific Affairs, The Japanese
Association for Thoracic Surgery, Shimizu H,
Okada M, Toh Y, Doki Y, Endo S, Fukuda H,
Hirata Y, Iwata H, Kobayashi J, Kumamaru H,
Miyata H, Motomura N, Natsugoe S, Ozawa S,
Saiki Y, Saito A, Saji H, Sato Y, Taketani T,
Tanemoto K, Tangoku A, Tatsuishi W, Tsukihara
H, Watanabe M, Yamamoto H, Minatoya K,
Yokoi K, Okita Y, Tsuchida M, Sawa Y. Thoracic
and cardiovascular surgeries in Japan during
2018 : Annual report by the Japanese Association
for Thoracic Surgery. Gen Thorac Cardiovasc
Surg. 2021 Jan;69(1):179-212. PMID: 33090365

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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.
Kousuke Hirano M.D. Ph.D
Haruki Ogawa M.D.

Homepage

Yasuhiro Okumura M.D., Ph.D.
Motonari Ri M.D., Ph.D.
Ryohei Iwata 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, and216

ligation, etc., are performed. They can attend theoperations as an assistant.
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 100
gastric and 60 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.

Sugawara K, Yoshimura S, Yagi K, Nishida M,
Aikou S, Yamagata Y, et al. Long-term healthrelated quality of life following robot-assisted

217

2.

3.

4.

5.

6.

7.

8.

9.

radical transmediastinal esophagectomy. Surg
Endosc 2020 Apr;34(4):1602-1611.
Sugawara K, Yamashita H, Okumura Y, Yagi K,
Yoshimura S, Kawasaki K, et al. Relationships
among body composition, muscle strength, andsarcopenia in esophageal squamous cell
carcinoma patients. Support Care Cancer 2020
Jun;28(6):2797-2803.
Sugawara K, Yagi K, Okumura Y, Nishida M,
Aikou S, Yamashita H, et al. Long-term
outcomes of multimodal therapy combining
definitive chemoradiotherapy and salvage
surgery for T4 esophageal squamous cell
carcinoma. Int J Clin Oncol 2020 Apr;25(4):552-560.
Sugawara K, Yamashita H, Seto Y. Optimal
Definition of Nodal Skip Metastasis in Patients
With Esophageal Squamous Cell Carcinoma.
Ann Thorac Surg 2020 Aug;110(2):754.
Sugawara K, Mori K, Okumura Y, Yagi K,
Aikou S, Uemura Y, et al. Preoperative Low
Vital Capacity Influences Survival After
Esophagectomy for Patients with Esophageal
Carcinoma. World J Surg 2020 Jul;44(7):23052313.
Sugawara K, Yamashita H, Yajima S, Uemura Y,
Okumura Y, Nishida M, et al. Preoperative
restrictive pulmonary dysfunction influences thesurvival after gastrectomy for elderly patientswith gastric carcinoma. Surg Today 2020 Sep;
50(9):1065-1073.
Sugawara K, Aikou S, Yajima S, Uemura Y,
Okumura Y, Nishida M, et al. Pre- andpost-operative low prognostic nutritional index
influences survival in older patients with gastriccarcinoma. J Geriatr Oncol 2020 Jul;11(6):989996.
Sugawara K, Yagi K, Uemura Y, Okumura Y,
Nishida M, Aikou S, et al. Associations of
Systemic Inflammation and Sarcopenia With
Survival of Esophageal Carcinoma Patients. Ann
Thorac Surg 2020 Aug;110(2):374-382.
Toriumi T, Yamashita H, Kawasaki K, Okumura
Y, Wakamatsu K, Yagi K, et al. Preoperative
Exercise Habits are Associated with Postgastrectomy Complications. World J Surg 2020
Aug;44(8):2736-2742.

10. Sugawara K, Iwai M, Yajima S, Tanaka M,
Yanagihara K, Seto Y, et al. Efficacy of a
Third-Generation Oncolytic Herpes Virus G47Δ
in Advanced Stage Models of Human Gastric
Cancer. Mol Ther Oncolytics 2020 Apr 8;17:205-215.
11. Sugawara K, Yamashita H, Urabe M, Okumura Y,
Yagi K, Aikou S, et al. Poor nutritional status andsarcopenia influences survival outcomes ingastric carcinoma patients undergoing radical
surgery. Eur J Surg Oncol 2020 Oct;46(10 Pt A):
1963-1970.
12. Seto Y. Essential Updates 2018/2019: Essential
Updates for esophageal cancer surgery. Ann
Gastroenterol Surg 2020 Feb 18;4(3):190-194.
13. Sugawara K, Yamashita H, Okumura Y, Yagi K,
Aikou S, Seto Y. Age-dependent survival impact
of body mass index in patients with oesophageal
squamous cell carcinoma. Eur J Surg Oncol 2020
Oct;46(10 Pt A):1948-1955.
14. Yoshimura S, Takahashi M, Aikou S, Okumura
Y, Jinbo K, Onoyama H, et al. One-by-One
Comparison of Lymph Nodes Between 18F-FDG
Uptake and Pathological Diagnosis in Esophageal
Cancer. Clin Nucl Med 2020 Oct;45(10):741746.
15. Atsumi S, Katoh H, Komura D, Hashimoto I,
Furuya G, Koda H, et al. Focal adhesion
ribonucleoprotein complex proteins are major
humoral cancer antigens and targets in
autoimmune diseases. Commun Biol 2020 Oct
16;3(1):588-5.

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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.

Takeaki Ishizawa, 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.

219

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 (2020)
1. Matsumura M, Yamashita S, Ishizawa T,
Akamatsu N, Kaneko J, Arita J, Nakajima J,
Kokudo N, Hasegawa K. Oncological benefit ofcomplete metastasectomy for simultaneouscolorectal liver and lung metastases. American
journal of surgery 2020;219(1): 80-87.
2. Oyama H, Tada M, Takagi K, Tateishi K, Hamada
T, Nakai Y, Hakuta R, Ijichi H, Ishigaki K, Kanai
S, Kogure H, Mizuno S, Saito K, Saito T, Sato T,
Suzuki T, Takahara N, Morishita Y, Arita J,
Hasegawa K, Tanaka M, Fukayama M, Koike K.
Long-term Risk of Malignancy in Branch-Duct
Intraductal Papillary Mucinous Neoplasms.
Gastroenterology 2020;158(1): 226-237.e225.
3. Miyata A, Arita J, Shirata C, Abe S, Akamatsu N,
Kaneko J, Kokudo N, Hasegawa K. Quantitative
Assessment of the Accuracy of Real-Time Virtual
Sonography for Liver Surgery. Surgicalinnovation 2020;27(1): 60-67.
4. Kawaguchi Y, Hasegawa K, Tzeng CD, Mizuno T,
Arita J, Sakamoto Y, Chun YS, Aloia TA, Kokudo
N, Vauthey JN. Performance of a modified
three-level classification in stratifying open liverresection procedures in terms of complexity andpostoperative morbidity. The British journal ofsurgery 2020;107(3): 258-267.

5. Kiritani S, Arita J, Matsumura M, Nishioka Y,
Kudo H, Ichida A, Ishizawa T, Akamatsu N,
Kaneko J, Hasegawa K. Repeat hepatectomy forpatients with recurrent neuroendocrine liver
metastasis: Comparison with first hepatectomy.
Surgery 2020;167(2): 404-409.
6. Nakazawa A, Akamatsu N, Miyata Y, Komagome
M, Maki A, Arita J, Ishizawa T, Kaneko J, Beck Y,
Hasegawa K. Usefulness of preoperative drip
infusioncholangiography
withcomputed
tomography for predicting surgical difficulty
during laparoscopic cholecystectomy. Journal ofhepato-biliary-pancreatic sciences 2020;27(6):315-323.
7. Ito D, Ishizawa T, Hasegawa K. Laparoscopic
positive staining of hepatic segments using
indocyanine green-fluorescence imaging. Journalof hepato-biliary-pancreatic sciences 2020;27(7):441-443.
8. Matsubara S, Isayama H, Nakai Y, Kawakubo K,
Yamamoto N, Saito K, Saito T, Takahara N,
Mizuno S, Kogure H, Ishizawa T, Arita J,
Hasegawa K, Koike K. Endoscopic ultrasoundguided gallbladder drainage with a combinedinternal and external drainage tubes for acutecholecystitis. Journal of gastroenterology andhepatology 2020;35(10): 1821-1827.
9. Ichida A, Kono Y, Sato M, Akamatsu N, Kaneko J,
Arita J, Sakamoto Y, Kokudo N, Hasegawa K.
Timing for removing prophylactic drains after
liver resection: an evaluation of drain removal on
the third and first postoperative days. Annals oftranslational medicine 2020;8(7): 454.
10. Allard MA, Akamatsu N, Kokudo T, Kobayashi K,
Kaneko J, Ishizawa T, Arita J, Hasegawa K.
ClinicalSignificanceof
Spontaneous
Portosystemic Shunts in Living Donor Liver
Transplantation. Liver transplantation : official
publication of the American Association for the
Study of Liver Diseases and the International
Liver Transplantation Society 2021;27(1): 77-87.
11. Nagata R, Akamatsu N, Nakazawa A, Kaneko J,
Ishizawa T, Arita J, Hasegawa K. Sex differencesin postsurgical skeletal muscle depletion after
donation of living-donor liver transplantation,although minimal, should not be ignored. BMC
surgery 2020;20(1): 119.

220

12. Kobayashi Y, Shindoh J, Nishioka Y, Inagaki Y,
Mitsui J, Arita J, Hasegawa K. Germline MICA
Polymorphism Is Associated with the Long-Term
Outcomes in Patients Undergoing Hepatectomy
for Colorectal Liver Metastases. Journal ofgastrointestinal surgery: official journal of theSociety for Surgery of the Alimentary Tract 2020;24(9): 2137-2139.
13. Shirata C, Nishioka Y, Sato J, Watadani T, Arita J,
Akamatsu N, Kaneko J, Sakamoto Y, Abe O,
Hasegawa K. Therapeutic effect of portal veinstenting for portal vein stenosis after upperabdominal surgery. HPB: the official journal of
the International Hepato Pancreato Biliary
Association 2021;23(2): 238-244.
14. Kobayashi K, Kawaguchi Y, Kobayashi Y,
Matsumura M, Ishizawa T, Akamatsu N, Kaneko J,
Arita J, Sakamoto Y, Kokudo N, Hasegawa K.
Identification of liver lesions using fluorescenceimaging: comparison of methods for administering indocyanine green. HPB: the official journalof the International Hepato Pancreato Biliary
Association 2021;23(2): 262-269.
15. Goto R, Kosai-Fujimoto Y, Yagi S, Kobayashi T,
Akamatsu N, Shimamura T, Imura S, Ogiso S,
Mizuno S, Takatsuki M, Fukuhara T, Kanto T,
Eguchi S, Yanaga K, Ogura Y, Fukumoto T,
Shimada M, Hasegawa K, Ohdan H, Uemoto S,
Soejima Y, Ikegami T, Yoshizumi T, Taketomi A,
Maehara Y. De novo hepatocellular carcinoma inliving donor liver grafts: A Japanese multicenter
experience. Hepatology research: the official
journal of the Japan Society of Hepatology 2020;50(12): 1365-1374.
16. Kono Y, Ishizawa T, Kokudo N, Kuriki Y, Iwatate
RJ, Kamiya M, Urano Y, Kumagai A, Kurokawa
H, Miyawaki A, Hasegawa K. On-Site Monitoringof Postoperative Bile Leakage Using BilirubinInducible Fluorescent Protein. World J Surg 2020;
44(12): 4245-4253.
17. Kono Y, Ishizawa T, Kokudo N, Kuriki Y, Iwatate
RJ, Kamiya M, Urano Y, Kumagai A, Kurokawa
H, Miyawaki A, Hasegawa K, Ito D, Ishizawa T,
Hasegawa K. On-Site Monitoring of Postoperative Bile Leakage Using Bilirubin-Inducible
Fluorescent Protein Laparoscopic positive
staining of hepatic segments using indocyanine

green-fluorescence imaging. World J Surg 2020;
44(12): 4245-4253.
18. Yamashita S, Roh S, Hattori Y, Maki H, Akamatsu
N, Kaneko J, Hasegawa K, Okazaki M.
Microvascular Hepatic Artery Anastomosis in
Living Donor Liver Transplantation for
Erythropoietic Protoporphyria. Plastic andreconstructive surgery Global open 2020;8(8):e3066.
19. Yamamoto M, Doi K, Hayase N, Asada T,
Akamatsu N, Kaneko J, Hasegawa K, Morimura
N. Pulse oximetry-based capillary refilling
evaluation predicts postoperative outcomes inliver transplantation: a prospective observational
cohort study. BMC Anesthesiol 2020;20(1): 251.
20. Yamamoto M, Doi K, Hayase N, Asada T,
Akamatsu N, Kaneko J, Hasegawa K, Morimura
N, Yamashita S, Roh S, Hattori Y, Maki H,
Akamatsu N, Kaneko J, Hasegawa K, Okazaki M,
Goto R, Kosai-Fujimoto Y, Yagi S, Kobayashi T,
Akamatsu N, Shimamura T, Imura S, Ogiso S,
Mizuno S, Takatsuki M, Fukuhara T, Kanto T,
Eguchi S, Yanaga K, Ogura Y, Fukumoto T,
Shimada M, Hasegawa K, Ohdan H, Uemoto S,
Soejima Y, Ikegami T, Yoshizumi T, Taketomi A,
Maehara Y. Pulse oximetry-based capillary
refilling evaluation predicts postoperative
outcomes in liver transplantation: a prospective
observational cohort study Microvascular Hepatic
Artery Anastomosis in Living Donor Liver
Transplantation for Erythropoietic Protoporphyria
De novo hepatocellular carcinoma in living donorliver grafts: A Japanese multicenter experience.
BMC Anesthesiol 2020;20(1): 251.
21. Nakai Y, Gonoi W, Kurokawa R, Nishioka Y, Abe
H, Arita J, Ushiku T, Hasegawa K, Abe O. MRI
Findings of Liver Parenchyma Peripheral toColorectal Liver Metastasis: A Potential Predictorof Long-term Prognosis. Radiology 2020;297(3):584-594.
22. Matsumura M, Kawaguchi Y, Kobayashi Y,
Kobayashi K, Ishizawa T, Akamatsu N, Kaneko J,
Arita J, Kokudo N, Hasegawa K. Indocyanine
green administration a day before surgery may
increase bile duct detectability on fluorescencecholangiography during laparoscopic cholecyst-

221ectomy. Journal of hepato-biliary-pancreaticsciences 2021;28(2): 202-210.
23. Fujiwara H, Takahara N, Tateishi K, Tanaka M,
Kanai S, Kato H, Nakatsuka T, Yamamoto K,
Kogure H, Arita J, Nakai Y, Kasuga M, Ushiku T,
Hasegawa K, Koike K. 5-Aminolevulinic acidmediated photodynamic activity in patient-derived
cholangiocarcinoma organoids. Surgical oncology
2020;35: 484-490.
24. 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. Bioscience trends 2021;14(6): 443-449.
25. Kiritani S, Kaneko J, Ito D, Morito M, Ishizawa
T, Akamatsu N, Tanaka M, Iida T, Tanaka T,
Tanaka R, Asakura T, Arita J, Hasegawa K. Silk
fibroin vascular graft: a promising tissueengineered scaffold material for abdominal
venous system replacement. Scientific reports
2020;10(1): 21041.
26. Miyata A, Arita J, Kawaguchi Y, Hasegawa K,
Kokudo N. Simulation and navigation liver
surgery: an update after 2,000 virtual
hepatectomies. Global health & medicine 2020;2(5): 298-305.

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Department of Urology
Professor
Haruki Kume, M.D., Ph.D.

Assistant Professor
Daisuke Yamada, M.D., Ph.D., Taketo Kawai, M.D., Ph.D.,
Yusuke Sato, M.D., Ph.D., Yuta Yamada, M.D., Ph.D., Yoshiyuki Akiyama, M.D., Ph.D.

Associate
Jimpei Miyakawa, M.D., Ph.D., Kanae Yoshida, M.D., Kenichi Sasaki, M.D., Takahiro
Oshina, M.D., Akira Hanashi, M.D., Kenichi Hashimoto, Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/urology/

Introduction and Organization

Clinical activities

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
prostatectomy substituting open procedures.

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 Tuesday, Wednesday, Thursday and Friday. 1621
operations were performed in 2020. The numbers of
main operations are adrenalectomy 19, nephrectomy
25, partial nephrectomy 59, nephroureterectomy 28,
radical cystectomy 21, radical prostatectomy 120,transurethral resection of the bladder tumor (TUR-Bt)
251, transurethral resection of the prostate (TUR-P) 11,
and Robot assisted surgery 193(radical prostatectomy
151, partial nephrectomy 40, radical cystectomy 9,pyeloplasty 2).
At the weekly professor’s round on Wednesday, dataof all in patients are presented and appropriate
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

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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 21,567 patientdays from January 2020 to December 2020.

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.

Research activities
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

References
1.

Tanaka M, Irie S, Nakagawa K, Nishimatsu H,
Inokuchi J, Eto M. Nonischemic or Ischemic
Laparoscopic Partial Nephrectomy Using a
Newly Developed Hybrid Energy Device in a
Porcine Model.
J Endourol, 34(1), 82-87,
2020.1.

2.

Zaitsu M, Lee HE, Lee S, Takeuchi T, Kobayashi
Y, Kawachi I. Occupational disparities in bladdercancer survival: A population-based cancer
registry study in Japan. Cancer Med, 9(3) 894901,2020.2.
3. Zaitsu M, Takeuchi T, Kobayashi Y, Kawachi I.
Light to moderate amount of lifetime alcohol
consumption and risk of cancer in Japan. Cancer,
126(5), 1031-1040,2020.3.
4. Kim Y, Zaitsu M, Tsuno K, Li X, Lee S, Jang SN,
Kawachi I. Occupational Differences in
C-Reactive Protein Among Working-age Adults
in South Korea. J Occup Environ Med, 62(3),194-201,2020.3.
5. Yamada Y, Kimura N, Takayama KI, Sato Y,
Suzuki T, Azuma K, Fujimura T, Ikeda K, Kume
H, Inoue S. TRIM44 promotes cell proliferationand migration by inhibiting FRK in renal cell
carcinoma. Cancer Sci, 111(3), 881-890,2020.3.
6. Yoshida A, Arai J, Fukuhara H, et al. Expanding
the clinicopathologic and molecular apectrum of
BCOR-associatedsarcomasinadults.
Histopathology, 76(4), 509-520,2020.3.
7. Fukumoto S, Soen S, Taguchi T, Ishikawa T,
Matsushima H, Terauchi M, Horie S, Yoneda T,
Sugimoto T, Matsumoto T, Subcommittee for
CTIBL in the JSBMR. Management manual forcancer treatment-induced bone loss (CTIBL):
position statement of the JSBMR. J Bone Miner
Metab, 38(2), 141-144,2020.3.
8. Akiyama Y. Update on the pathophysiology ofinterstitial cystitis/bladder pain syndrome.
Current Bladder Dysfunction Reports, 15, 1-8,
2020.3.
9. Masuda K, Aizawa N, Watanabe D, Okegawa T.
Pathophysiological changes of the lower urinary
tract
behindvoidingdysfunction
instreptozotocin-induced long-term diabetic rats.
Scientific Reports, 10, 4182,2020.3.
10. Enomoto Y, Namba Y, Hoshika Y, Komemushi Y,
Mitani K, Kume H, Kobayashi E, Miyama Y,
Homma Y, Ushiku T, Seyama K. A case of
Birt-Hogg-Dubé syndrome implying reduced or
no wild-type folliculin without mutated protein ispathogenic. Eur J Med Genet, 63(4), 103820,
2020.4.

224

11. Suzuki M, Okochi J, Iijima K, Murata T, Kume H.
Nationwide survey of continence status amongolder adult residents living in long-term carefacilities in Japan: The prevalence and associatedrisk factors of incontinence and effect ofcomprehensive care on continence status. Geriatr
Gerontol Int, 20(4), 285-290,2020.4.
12. Kobayashi Y, Yamada D, Kawai T, Sato Y,
Teshima T, Yamada Y, Nakamura M, Suzuki M,
Matsumoto A, Nakagawa T, Hosoi A, Nagaoka K,
Karasaki T, Matsushita H , Kume H, Kakimi K.
Different immunological effects of the moleculartargeted agents sunitinib, everolimus andtemsirolimus in patients with renal cell
carcinoma. Int J Oncol, 56(4), 999-1013,2020.4.
13. Kakutani S, Asamoto M, Araki F, Chen YN,
Shinokawa M, Okagami Y, Ohata T, Taguchi S,
Yamada Y, Takeshima Y, Kume H, Yamada Y,
Aihara M, Ito N, Fukuhara H. Prospective
evaluation of visual function in patients withocular diseases after robot-assisted laparoscopic
prostatectomy. Int J Urol, 27(4), 307-312,2020.4.
14. Yamazaki M, Takayama T, Fujisaki A, Kamimura
T, Mashiko T, Fujimura T. Robot-assisted partial
nephrectomy of initial cases using a 3D
square-block type kidney model. Transl Androl
Urol, 9(2), 494-500,2020.4.
15. Taguchi S, Uemura Y, Fujimura T, Morikawa T,
Naito A, Kawai T, Suzuki M, Kume H, Fukuhara
H. Quantification of the individual risk of each
Gleason pattern, including tertiary Gleason
pattern 5, after radical prostatectomy: development of the modified Gleason grade grouping(mGGG) model. BMC Cancer, 20(1), 371,2020.
5.
16. Kobayashi K, Yamamoto S, Takahashi S,
Ishikawa K, Yasuda M, Wada K, Hamasuna R,
Hayami H, Minamitani S, Matsumoto T, Kiyota
H, Tateda K, Sato J, Hanaki H, Masumori N,
Hiyama Y, Yamada H, Egawa S, Kimura T,
Nishiyama H, Miyazaki J, Matsumoto K, Homma
Y, Kamei J, Fujimoto K, Torimoto K, Tanaka K,
Togo Y, Uehara S, Matsubara A, Shoji K, Goto H,
Komeda H, Ito T, Mori K, Mita K, Kato M,
Fujimoto Y, Masue T, Inatomi H, Takahashi Y,
Ishihara S, Nishimura K, Mitsumori K, Ito N,
Kanamaru S, Yamada D, Hiroshi M, Yamashita

17.

18.

19.

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22.

M, Tsugawa M, Takenaka T, Takahashi K, Oka Y,
Yasufuku T, Watanabe S, Chihara Y, Okumura K,
Kawanishi H, Matsukawa M, Shigeta M, Koda S.
The third national Japanese antimicrobial
susceptibility pattern surveillance program:
Bacterial isolates from complicated urinary tract
infection patients. J Infect Chemother, 26(5),418-428,2020.5.
Matsuzawa Y, Kitamura T, Suzuki M, Koyama Y,
Shigehara K. Prevalence, Genotype distribution
and Predictors against HPV infections targeted by
2-, 4-, 9-valent HPV vaccines among Japanesemale. Vaccines (Basel), 8(2),221,2020.5.
Ikeda A, Kojima T, Kawai K, Hinotsu S, Keino N,
Shiga K, Miyake H, Miyata Y, Enomoto Y,
Shimizu F, Anai S, Matsuyama H, Suzuki C,
Kanimoto Y, Shigeta K, Naito S, Akaza H,
Nishiyama H. Risk for intravesical recurrence of
bladder cancer stratified by the results on two
consecutive UroVysion fluorescence in situ
hybridization tests: a prospective follow-up study
in Japan. Int J Clin Oncol, 25(6), 1163-1169,
2020.6.
Akiyama Y, Luo Yi, Hanno PM, Maeda D,
Homma Y. Interstitial cystitis/bladder pain
syndrome: The Evolving Landscape, Animal
Models, and Future Perspectives. Int J Urol,
27(6), 491-503,2020.6.
Yamada Y, Teshima T, Fujimura T, Sato Y,
Nakamura M, Niimi A, Kimura N, Kakutani S,
Kawai T, Yamada D, Suzuki M, Kume H.
Comparison of Perioperative Outcomes inElderly (Age ≧ 75 Years) vs. Younger Men
Undergoing
Robot-Assisted
RadicalProstatectomy. PLoS One, 15(6), e0234113,
2020.7.
Akiyama Y, Maeda D, Katoh H, Kume H.
Comparative transcriptome analysis of interstitial
cystitis/bladder pain syndrome with Hunnerlesions and Bacillus Calmette-Guerin related
cystitis by next-generation RNA-sequencing:
Discovery of disease-specific genes andassociated biological pathways. European
Urology Open Science, 19, e485-e486,2020.7.
Takayama KI, Fujimura T, Suzuki Y, Inoue S.
Identification of long non-coding RNAs in
advanced prostate cancer associated with

225

23.

24.

25.

26.

27.

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30.

androgen receptor splicing factors. Communications Biology,3, Article no. 393,2020.7.
Homma Y, Akiyama Y, Tomoe H, Furuta A, Ueda
T, Maeda D, Lin AT, Kuo HC, Lee MH, Oh SJ,
Kim JC, Lee KS. Clinical guidelines forinterstitial cystitis/bladder pain syndrome. Int J
Urol, 27(7), 578-589,2020.7.
Fujisaki A, Kinjo M, Shimoinaba M, Honda S,
Yoshimura Y. An evaluation of the impact of
post-hysterectomy vesicovaginal fistula repair on
the mental health of patients in a developed
country. Int Urogynecol J, 31(7), 1371-1375,
2020.7.
Kameda T, Takayama T, Sugihara T, Takeshima S,
Yamazaki M, Komatsubara M, Kamei J, Fujisaki
A, Ando S, Kurokawa S, Fujimura T. The
efficacy of axitinib as a first‐line treatment formetastatic renal cell carcinoma. Asia-Pac J Clin
Oncol, 16(4), 241-246,2020.8.
Omura S, Taguchi S, Miyagawa S, Matsumoto R,
Samejima M, Ninomiya N, Masuda K, Nakamura
Y, Yamaguchi T, Kinjo M, Tambo M, Okegawa T,
Higashihara E, Fukuhara H. Prognostic
significance of the albumin-to-globulin ratio forupper tract urothelial carcinoma. BMC Urology,
in press,2020.8.
Yamamoto S, Kageyama Y, Fujii Y, Aizawa T,
Urakami S, Fukui I. Randomized Study of
Postoperative Single Intravesical Instillation With
Pirarubicin and Mitomycin C for Low-risk
Bladder Cancer. Anticancer Res, 40(9), 52955299,2020.9.
Akiyama Y and Homma Y. Immunomodulating
therapies for interstitial cystitis/bladder pain
syndrome. Current Bladder Dysfunction Reports,
15, 186-191,2020.9.
Naito A, Taguchi S, Suzuki M, Kawai T, UchidaK, Fujimura T, Fukuhara H, Kume H. Transientacute kidney injury observed immediately after
robot-assisted radical prostatectomy but not after
open radical prostatectomy. Mol Clin Oncol,
13(3), 18,2020.9.
Taguchi S, Shiraishi K, Fukuhara H. Updated
evidence on oncological outcomes of surgery
versus external beam radiotherapy for localized
prostate cancer. Japanese Journal of ClinicalOncology, 50(9), 963–969,2020.9.

31. Takeuchi T, Maki K, Okuno Y, Hattori-Kato M,
Mikami K. Selection of AVP-shortage patients ascandidates for low-dose oral desmopressin
administration. medRxiv, in press,2020.9.
32. Kamei J, Aizawa N, Nakagawa T, Kaneko S,
Fujimura T, Homma Y, Kume H, Igawa Y.
Lacking transient receptor potential melastatin 2
attenuates lipopolysaccharide‐induced bladderinflammation and its associated hypersensitivity
in mice. Int J Urol, in press, Online ahead of print,
2020.10.
33. 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.
Clinical and Experimental Nephrology, in press,
Online ahead of print,2020.10.
34. Taguchi S, Tambo M, Watanabe M, Machida H,
Kariyasu T, Fukushima K, Shimizu Y, Okegawa T,
Yokoyama K, Fukuhara H. Prospective validationof Vesical Imaging-Reporting and Data System(VI-RADS) using a next-generation magnetic
resonance imaging scanner: Is denoising deeplearning reconstruction useful? J Urol, Online
ahead of print,2020.10.
35. Takeshima Y, Suzuki M, Ikegaya H, Idota N, Sato
Y, Kawai T, Kume H. A cross-sectional cadaveric
study of the correlation between genital organ
measurements, serum testosterone, and serum
prostate-specific antigen levels in Japanese malesubjects. Int J Physiol Pathophysiol Pharmacol,in press,2020.11.
36. Imuta H, Fujita D, Oba S, Kiyosue A, Nishimatsu
H, Yudo K, Suzuki E. Histone methylation anddemethylation are implicated in the transient andsustained activation of the interleukin-1β gene inmurine macrophages. Heart Vessels, 35(12),1746-1754,2020.11.
37. Kinoshita Y, Yagisawa T, Sugihara T, Hara K,
Takeshima S, Kubo T, Shinzato T, Shimizu T,
Suzuki M, Maeshima A, Kamei J, Fujisaki A,
Ando S Suzuki M, Kume H, Fujimura T.
Clinical outcomes in donors and recipients ofkidney transplantations involving medicallycomplex living donors – a retrospective study.
Transpl Int, 33(11), 1417-1423,2020.11.

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38. Kurokawa S, Kamei J, Sakata K, Sugihara T,
Fujisaki A, Ando S, Takayama T, Morita T,
Fujimura T. Questionnaire survey assessing
seasonal changes in lower urinary tract symptoms
in men with benign prostate hyperplasia. Turk J
Urol, 46(6), 468-473,2020.11.
39. Takeshima Y, Tanaka Y, Takemura K, Nakazono
S, Yamashita E, Kume H. Evaluating the efficacy
of a low-cost cognitive MRI-targeted prostatebiopsy protocol: is there still a role for lower
volume centers in the Prostate Imaging Reportingand Data System(PI-RADS)version 2 era? Int
Urol Nephrol, 52(11), 2043-2050,2020.11.
40. Uemura H, Matsushima H, Kobayashi K,
Mizusawa H, Nishimatsu H, Fizazi K, Smith M,
Shore N, Tammela T, Tabata K, Matsubara N,
Iinuma M, Uemura H, Oya M, Momma T,
Kawakita M, Fukasawa S, Kobayashi T, Kuss I,
Le Berre MA, 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, 25(11), 0nline first,2020.11.
41. Takemura K, Kawai T, Sato Y, Miyakawa J,
Taguchi S, Akiyama Y, Yamada Y, Nakamura M,
Yamada D, Suzuki M, Nakagawa T, Kume H.
Impact of initial computed tomography findings
on management of atypical urinary cytology of
the upper urinary tract. Urol Int, 105(7-8), 619623,2020.11.
42. Azuma T, Sato Y, Ohno T, Azuma M, Kume H.
Serum soluble B7-H3 is a prognostic marker forpatients with non-muscle-invasive bladder cancer.
PLoS One, 15(12), e0243379,2020.12.
43. 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. American Journal of PhysiologyRenal Physiology, in press, 320(2), F174-F182,
2020.12.
44. Fujisaki A, Takayama T, Yamazaki M, Kamimura
T, Katano S, Komatsubara M, Kamei J, Sugihara

45.

46.

47.

48.

49.

50.

T, Ando S, Fujimura T. Utilization of athree-dimensional printed kidney model forfavorable TRIFECTA achievement in earlyexperience of robot-assisted partial nephrectomy.
Transl Androl Urol, in press, Online ahead ofprint,2020.12.
Taguchi S, Nakagawa T, Uemura Y, Akamatsu N,
Gonoi W, Naito A, Kawai T, Kume H, Fukuhara
H. Comparison of Major Definitions ofSarcopenia Based on the Skeletal Muscle Index
in Patients with Urothelial Carcinoma. Future
Oncol, Online ahead of print,2020.12.
Tsuru I, Niimi F, Honda S, Azuma T. Safety ofsame-day administration of a gemcitabine plus
cisplatin chemotherapy regimen in urothelial
carcinoma. Molecular and Clinical Oncology,
14(3),57,2020.12
Ando S, Tsunoda H, Suzuki T, Matsubara S,
Fujimura T. Current status of sperm cr yopreser
vation for fer tility preser vation prior to cancer
treatment at Jichi Medical University Hospital.
Jichi Medical University Journal, 43, in press,
2020.
Yoshimura N, Homma Y, Tomoe H, Otsuka A,
Kitta T, Masumori N, Akiyama Y, Niimi A,
Mitsui T, Nanri M, Namima T, Takei M,
Yamaguchi A, Sekiguchi Y, Kajiwara M,
Kobayashi S, Ameda K, Ohashi Y, Sakamoto S,
Muraki O, Shishido T, Kageyama S, Kokura K,
Okazoe H, Yamanishi T, Watanabe T, Uno T,
Oohinata A, Ueda T. Dimethyl sulfoxide, an old
drug but still new: Amulticenter, randomised,double-blind, placebo-controlled, clinical study
on the efficacy and safety of intravesicalinstillation of KRP-116D ( 50% dimethyl
sulfoxide solution) for interstitial cystitis/bladderpain syndrome in Japanese patients. Int J Urol,
28(5), 545-553,2020.12.
Kitamura T, Suzuki M, Koyama Y, Kawata Y,
Sumita M, Shigehara K. Reactivation of HPV in
the glans of penis persists for a long time inJapanese male cases. Asian J Epidemiol, 13(2),47-53,2020.12.
Miyakawa J, Kawai T,Makino K, Akiyama Y,
Yamada Y, Nakamura M, Sato Y, Yamada D,
Suzuki M, Kume H. Impact of age, body massindex, and renal function for severe hypotension

227

caused by oral 5-aminolevulinic acid administration in patients undergoing transurethral resectionof bladder tumor. Photodiagnosis and Photodynamic Therapy,2020.

228

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., Hiroaki Ishii, M.D., Ph.D.,
Junko Kishikawa, 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 ten 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 408
surgically treated inpatients in the year of 2020. 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229

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

230

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K, Hata K, Tanaka T, Nishikawa T, Sasaki K,
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H, Abe O, Ishihara S: Utility of computed
tomography and (18) F-fluorodeoxyglucose withpositronemission
tomography/computed
tomography for distinguishing appendiceal
mucocele caused by mucinous adenocarcinoma
from other pathologies. Colorectal Dis 22(12):1984-1990, 2020
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Fujii M, Togasaki K, Ebisudani T, Shimokawa M,
Takano A, Takahashi S, Ohta Y, Nanki K,
Igarashi R, Ishimaru K, Ishida H, Sukawa Y,
Sugimoto S, Saito Y, Maejima K, Sasagawa S,
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K, Maekawa A, Tanabe M, Ishihara S, Hamamoto
Y, Yasuda H, Sekine S, Kudo A, Kitagawa Y,
Kanai T, Nakagawa H, Sato T: An Organoid
Biobank of Neuroendocrine Neoplasms Enables
Genotype-Phenotype Mapping. Cell 183(5):14201435.e1421, 2020
Miyake H, Murono K, Kawai K, Nozawa H,
Maki H, Hasegawa K, Nakajima J, Ishihara S:
Impact of Surgical Resection on Metachronous
Metastases of Colorectal Cancer According toTumor Doubling Time. In Vivo 34(6):3367-3374,
2020
Murono K, Miyake H, Hojo D, Nozawa H,
Kawai K, Hata K, Tanaka T, Nishikawa T, Shuno
Y, Sasaki K, Kaneko M, Emoto S, Ishii H,
Sonoda H, Ishihara S: Vascular anatomy of thesplenic flexure, focusing on the accessory middle
colic artery and vein. Colorectal Dis 22(4):392-398, 2020
Murono K, Nozawa H, Nagata H, Ishimaru K,
Sonoda H, Emoto S, Kaneko M, Sasaki K, Otani
K, Kawai K, Muro K, Ishihara S: Efficacy of
intraperitoneally administered paclitaxel forcolorectal cancer with peritoneal metastases. Int J
Colorectal Dis 2020
Nagata H, Kawai K, Hata K, Tanaka T, Nozawa
H, Ishihara S: Laparoscopic surgery for T4 coloncancer: a risk factor for peritoneal recurrences?
Surgery 2020
Nanki K, Fujii M, Shimokawa M, Matano M,

231

14.

15.

16.

17.

18.

19.

Nishikori S, Date S, Takano A, Toshimitsu K,
Ohta Y, Takahashi S, Sugimoto S, Ishimaru K,
Kawasaki K, Nagai Y, Ishii R, Yoshida K, Sasaki
N, Hibi T, Ishihara S, Kanai T, Sato T: Somatic
inflammatory gene mutations in human ulcerative
colitis epithelium. Nature 577(7789):254-259,
2020
Nishikawa T, Ushiku T, Emoto S, Murono K,
Kaneko M, Sonoda H, Sasaki K, Shuno Y,
Tanaka T, Hata K, Kawai K, Nozawa H, Ishihara
S: Anal canal adenocarcinoma with pagetoidspread and inguinal lymph node metastasis
treated with preoperative chemoradiotherapy: A
case report. Mol Clin Oncol 12(6):529-532, 2020
Noguchi T, Emoto S, Kawai K, Nishikawa T,
Shuno Y, Sasaki K, Kaneko M, Murono K, Ishii
H, Sonoda H, Tanaka T, Hata K, Nozawa H,
Ishihara S: Anastomotic bleeding following
ileocolic end-to-side anastomosis using a circular
stapler: incidence and risk factors. Surg Today
2020
Nozawa H, Emoto S, Murono K, Shuno Y, Kawai
K, Sasaki K, Sonoda H, Ishii H, Iida Y,
Yokoyama Y, Anzai H, Ishihara S: Change inskeletal muscle index and its prognostic
significance in patients who underwent successful conversion therapy for initially unresectable
colorectal cancer: observational study. Therap
Adv Gastroenterol 13:1756284820971197, 2020
Nozawa H, Ishii H, Sonoda H, Emoto S, Murono
K, Kaneko M, Sasaki K, Nishikawa T, Shuno Y,
Tanaka T, Kawai K, Hata K, Ishihara S: Effectsofprecedingendoscopic
treatmentonlaparoscopic surgery for early rectal cancer.
Colorectal Dis 2020
Nozawa H, Shinagawa T, Kawai K, Hata K,
Tanaka T, Nishikawa T, Sasaki K, Kaneko M,
Murono K, Emoto S, Sonoda H, Ishihara S:
Laparoscopic surgery in rectal cancer patientstaking anti-thrombotic therapy. Minim Invasive
Ther Allied Technol 29(4):202-209, 2020
Nozawa H, Sonoda H, Ishii H, Emoto S, Murono
K, Kaneko M, Sasaki K, Nishikawa T, Shuno Y,
Tanaka T, Kawai K, Hata K, Ishihara S:
Postoperative chemotherapy is associated withprognosis of stage IV colorectal cancer treatedwithpreoperative
chemotherapy/

20.

21.

22.

23.

24.

25.

26.

27.

chemoradiotherapy and curative resection. Int J
Colorectal Dis 35(1):177-180, 2020
Ochiai K, Kaneko M, Nozawa H, Kawai K, Hata
K, Tanaka T, Nishikawa T, Shuno Y, Sasaki K,
Hiyoshi M, Emoto S, Murono K, Sonoda H,
Ishihara S: Incidence of and risk factors for
lymphocele formation after lateral pelvic lymph
node dissection for rectal cancer: a retrospective
study. Colorectal Dis 22(2):161-169, 2020
Ozaki K, Sasaki K, Nozawa H, Kawai K, Hata K,
Tanaka T, Ikemura M, Ishihara S: A case of
mucosal prolapse syndrome combined with an
adenoma. ANZ J Surg 90(7-8):1502-1504, 2020
Ozawa T, Ishihara S, Fujishiro M, Kumagai Y,
Shichijo S, Tada T: Automated endoscopic
detection and classification of colorectal polyps
using convolutional neural networks. Therap Adv
Gastroenterol 13:1756284820910659, 2020
Saito H, Tanimoto T, Ozawa T, Ishihara S,
Fujishiro M, Shichijo S, Hirasawa D, Matsuda T,
Endo Y, Tada T: Automatic anatomicalclassification of colonoscopic images using deep
convolutional neural networks. Gastroenterology
Report 2020
Sasaki K, Fukui R, Hata K, Nozawa H, Ushiku T,
Aburatani H, Mano H, Ishihara S: Clinicaldiagnosis of a double primary sigmoid coloncancer and metastatic tumour using a genetargeted panel test: a case report. ANZ J Surg
2020
Sasaki K, Nozawa H, Kawai K, Hata K, Tanaka T,
Nishikawa T, Shuno Y, Kaneko M, Murono K,
Emoto S, Sonoda H, Ishihara S: Management ofisolated para-aortic lymph node recurrence ofcolorectal cancer. Surg Today 50(9):947-954,
2020
Shinagawa T, Hata K, Ikeuchi H, Fukushima K,
Futami K, Sugita A, Uchino M, Watanabe K,
Higashi D, Kimura H, Araki T, Mizushima T,
Itabashi M, Ueda T, Koganei K, Oba K, Ishihara
S, Suzuki Y: Rate of Reoperation Decreased
Significantly After Year 2002 in Patients With
Crohn's Disease. Clin Gastroenterol Hepatol
18(4):898-907 e895, 2020
Shinagawa T, Hata K, Morikawa T, Matsunaga K,
Emoto S, Murono K, Kaneko M, Sasaki K,
Nishikawa T, Tanaka T, Kawai K, Nozawa H,

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28.

29.

30.

31.

32.

Fukayama M, Ishihara S: Loss of RUNX3
Immunoreactivity in Non-Neoplastic Rectal
Mucosa May Predict the Occurrence of
Ulcerative Colitis-Associated Colorectal Cancer.
Digestion 101(2):156-164, 2020
Shiratori H, Kawai K, Okada M, Nozawa H, Hata
K, Tanaka T, Nishikawa T, Shuno Y, Sasaki K,
Kaneko M, Murono K, Emoto S, Ishii H, Sonoda
H, Ushiku T, Ishihara S: Metastatic role ofmammalian target of rapamycin signaling
activation by chemoradiotherapy in advanced
rectal cancer. Cancer Sci 111(4):1291-1302, 2020
Shiratori H, Nozawa H, Kawai K, Hata K,
Tanaka T, Kaneko M, Emoto S, Sonoda H,
Ishihara S: Risk factors and therapeuticsignificance of inguinal lymph node metastasis inadvanced lower rectal cancer. Int J Colorectal Dis
35(4):655-664, 2020
Taira T, Nozawa H, Kawai K, Sasaki K, Murono
K, Kaneko M, Emoto S, Iida Y, Ishii H,
Yokoyama Y, Anzai H, Sonoda H, Ishihara S:
Oncological Outcomes of Pathological T1 Lower
Rectal Cancer Patients With or Without
Preoperative Chemoradiotherapy. In Vivo 34(6):3559-3564, 2020
Tanaka T, Kobunai T, Yamamoto Y, Murono K,
Emoto S, Hiyoshi M, Kaneko M, Sasaki K,
Shuno Y, Nishikawa T, Hata K, Kawai K,
Nozawa H, Ishihara S: Assessment of the
Changes in Mitochondrial Gene Polymorphism inUlcerative Colitis and the Etiology of Ulcerative
Colitis-associated Colorectal Cancer. Anticancer
Res 40(1):101-107, 2020
Toyoshima O, Nishizawa T, Sakitani K,
Yamakawa T, Yoshida S, Fukagawa K, Hata K,
Ishihara S, Suzuki H: Colonoscopy using backbrace support belt: A randomized, prospective
trial. JGH Open 4(3):441-445, 2020

233

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
Mitsuru Matsukura M.D., Ph.D., Ryosuke Taniguchi, 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.

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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.

23520) 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.

References
1. Nakayama A, Morita H, Hoshina K, Komuro I.
Quantification of abdominal aortic aneurysm
calcification using the agastson method can predict
accelerated expansion rate. Circ J 83;689,2019
2. Makino Y, Miyahara T, Nitta J, Miyahara K, Seo A,
Kimura M, Suhara M, Akai A, Akagi D, Yamamoto
K, Hoshina K. Proresolving lipid mediators
Resolvin D1 and Protectin D1 isomer attenuate
neointimal hyperplasia in the rat carotid arteryballoon injury model. J Surg Res 233;104-110,2019
3. Nitta J, Akai T, Miyahara K, Hanada K, Hoshina K.
Original homebuilt off-the-job training system for
vascular surgeons: assessment and analysis of thesystem. Ann Vasc Dis 11;525-530,2018
4. Nitta J, Hoshina K, Isaji T. Changes in blood flow
distribution after hypogastric artery embolizationand the ischaemic tolerance of the pelvic circulation.
Medicine(Baltimore) 98;e14214,2019
5. Hanada K, Yamamoto K, Akai T, Taniguchi R,
Takayama T, Hoshina K. Phlegmasia cerulea dolens
as an initial manifestation of a fistula between aruptured iliac artery aneurysm and the iliac vein. J
Vasc Surg Cases Innov Tech 28;41-44,2019
6. Hashimoto T, Isaji T, Hu H, Yamamoto K, Bai H,
Santana JM, Kuo A, Kuwahara G, Foster TR,
Hanisch JJ, Yatsula BA, Sessa WC, Hoshina K,
Dardik A. Stimulation of Caveolin-1 Signaling
Improves
Arteriovenous
FistulaPatency.
Arterioscler Thromb Vasc Biol 39;754-64,2019
7. Miyahara K, Hoshina K, Nitta J, Kimura M,
Yamamoto S, Ohshima M. Hemodynamic
SimulationofPancreaticoduodenal
ArteryAneurysm Formation Using an Electronic Circuit
Model and a Case Series Analysis. Ann Vasc Dis
12;176-181,2019
8. Sano M, Yamamoto K, Seo A, Akai A, Akagi D,
Takayama T, Hoshina K. Wound healing afterrevascularization for critical limb ischemia. Int

Angiol 38;225-229,2019
9. Yuhn C, Hoshina K, Miyahara K, Oshima M.
Computational simulation of flow-induced arterial
remodeling of the pancreaticoduodenal arcade
associated with celiac artery stenosis. J Biomech
92;146-154,2019
10. Nakayama A, Amiya E, Morita H, Hyodo K,
Takayama N, Konishi Y, Taya M, Fujiwara T,
Hosoya Y, Hoshina K, Komuro I. The potential of
cardiac rehabilitation as a method of suppressing
abdominal aortic aneurysm expansion: a pilot study.
Heart Vessels 34;2031-2039,2019
11. Nakayama A, Amiya E, Morita H, Hyodo K,
Takayama N, Konishi Y, Taya M, Fujiwara T,
Hosoya Y, Hoshina K, Komuro I. Correction to: The
potential of cardiac rehabilitation as a method of
suppressing abdominal aortic aneurysm expansion: apilot study. Heart Vessels 34;2030,2019
12. Hanada K, Takayama T, Sasaki T, Taniguchi R,
Hoshina K. A hybrid procedure for middle colicartery aneurysm complicated by chronic juxtarenal
segmental aortic occlusion. J Vasc Surg Cases Innov
Tech 5;327-331,2019
13. Isaji T, Ono S, Hashimoto T, Yamamoto K,
Taniguchi R, Hu H, Wang T, Koizumi J, Nishibe T,
Hoshina K, Dardik A. Murine Model of Central
Venous Stenosis using Aortocaval Fistula with an
Outflow Stenosis. J Vis Exp 149,2019
14. Haga M, Hoshina K, Koyama H, Miyata T, Ikegami
Y, Murai A, Nakamura Y. Bicycle exercise training
improves ambulation in patients with peripheralartery disease. J Vasc Surg 2019, Epub ahead ofprint
15. Hojo D, Nishikawa T, Takayama T, Hiyoshi M,
Emoto S, Nozawa H, Kawai K, Hata K, Tanaka T,
Shuno Y, Kaneko M, Sasaki K, Murono K, Ishii H,
Sonoda H, Hoshina K, Ishihara S. 3D printed
model-based simulation of laparoscopic surgery fordescending colon cancer with a concomitant
abdominal aortic aneurysm. Tech Coloproctol 23;
793-7,2019
16. Sano M, Hoshina K, Kawahara T, Kimura M, Akai T,
Isaji T, Yamamoto K, Takayama T. Egg-shell like
Calcification as a Protective Factor for Splenic
Artery Aneurysm Dilatation. Ann Vasc Surg 2019
Epub ahead of print
17. Matsuura S, Yamamoto K, Akai T, Isaji T, Takayama

236

T, Hoshina K. Effect of drug-coated balloons intreatment of stenosis of the femoral artery and vein
bypass graft not responding to plain old balloon
angioplasty: a case report. Surg Case Rep 5;204,2019
18. Ouchi H, Nishi H, Nakamura M, Hirakawa Y,
Tanaka T, Takeda N, Akai T, Ohashi Y, Hoshina K,
Takayama T, Nangaku M. Vascular Ehlers-Danlos
syndrome diagnosed in a patient initiating
hemodialysis. Kidney Int Rep 4;1646-1648,2019

237

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.

Takako Wakeda M.D., Ph.D.

Mayumi Harada M.D., Ph.D.

Arisa Morizono M.D., Ph.D.

Ayaka Sato M.D., Ph.D.

Homepage
Organization
Our section is staffed by one professor, one
associate professor, one lecturer, and five associates.
Official activities of our sections are run on the sameschedule of the Department of Gastrointestinal
Surgery.

Clinical Activities
Endocrine Surgery had not been so familiar withJapanese; however, it has been a long time to bestudied this area by top level surgeons in westerncountries. We have started our activities for this area
since 1987 and our department has been establishedwith reconstruction of our hospital structure in 1997.
This is a result of the growth of demand nationally andinternationally and it is caused by not only treatment
for malignant disease but also functional one or giving
more attention to quality of life.
Professional skill and wider knowledge of
endocrine system are required for this area. Diseases
we treat at our department are breast, thyroid, andparathyroid. In additional to treatment for malignant
cases of these diseases, we perform surgical proce-dures as well as systemic treatment. We co-work withthe department of endocrine internal medicine andhave about 250 surgical procedures annually in total.
In breast surgery, more than a half of the mammary
cancer patients undergo the breast-preserving surgery.
In addition, sentinel node navigation surgery has been
adopted, resulting in better quality of postoperative
life. Reconstruction surgery for the breast cancer islikely to provide much better QOL. In this field, we
have started collaboration with the Department of
Plastic Surgery. Chemotherapy, hormone therapy andmolecular- targeting therapy play important roles intreatment of the breast cancer. We have accumulated a
lot of experience and 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 wide areas related to breast cancer,

238

thyroid disease, and parathyroid disease. Most of ourstudies are performed with other good institutions.
1) Hereditary Breast and Ovarian Cancer syndrome2) 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 cancer and thyroid cancer.
5) Studies in the area of sentinel node biopsy inbreast cancer.
6) Studies about management of the toxic effects ofchemotherapies.
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.

Konishi T, Fujiogi M, Michihata N, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Impact of Body Mass Index on
Outcomes After Breast Cancer Surgery:
Nationwide Inpatient Database Study in Japan.
Clin Breast Cancer. 2020 Dec;20(6): e663-e674.
Konishi T, Fujiogi M, Michihata N, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Treatments and outcomes of
encapsulating peritoneal sclerosis in patients
undergoing peritoneal dialysis: 295 cases from anationwide inpatient database in Japan. Perit Dial
Int. 2020 Nov;40(6):593-599.
Konishi T, Fujiogi M, Niwa T, Morita K, Matsui
H, Fushimi K, Tanabe M, Seto Y, Yasunaga H.

4.

5.

6.

7.

Comparison of outcomes after differentiatedthyroid cancer surgery performed with andwithout energy devices: A population-based
cohort study using a nationwide database inJapan. Int J Surg. 2020 May; 77:198-204.
Sasahara A, Tanabe M, Hayashi K, Konishi T,
Oya M, Sakiyama K, Morizono A, Harada M,
Otsuji K, Ishibashi Y, Sato A, Kikuchi Y, Niwa T,
Hinata M, Nishioka K, Seto Y. A case of primarybreast angiosarcoma with multiple discontinuous
small lesions. Surg Case Rep. 2019 Oct 25;5(1):157.
Sato A, Sakai T, Iwase T, Kano F, Kimura K,
Ogiya A, Koizumi M, Tanabe M, Horii R,
Akiyama F, Ueno T, Ohno S. Altered lymphaticdrainage patterns in re-operative sentinel lymph
node biopsy for ipsilateral breast tumor
recurrence. Radiat Oncol. 2019 Sep 2;14(1):159.
Tominaga K, Minato H, Murayama T, Sasahara A,
Nishimura T, Kiyokawa E, Kanauchi H, Shimizu
S, Sato A, Nishioka K, Tsuji EI, Yano M, Ogawa
T, Ishii H, Mori M, Akashi K, Okamoto K,
Tanabe M, Tada KI, Tojo A, Gotoh N.
Semaphorin signaling via MICAL3 induces
symmetric cell division to expand breast cancer
stem-like cells. Proc Natl Acad Sci U S A. 2019
Jan 8;116(2):625-630.
Harada M, Morikawa M, Ozawa T, Kobayashi M,
Tamura Y, Takahashi K, Tanabe M, Tada K, Seto
Y, Miyazono K, Koinuma D. Palbociclib
enhances activin-SMAD-induced cytostasis in
estrogen receptor-positive breast cancer. Cancer
Sci. 2019 Jan;110(1):209-220.

Surgical Sciences
2. Sensory and Motor System Medicine

240

Department of Dermatology
Professor
Shinichi Sato, M.D., Ph.D.

Associate Professor
Yoshihide Asano, M.D., Ph.D.

Lecturer
Sayaka shibata,M.D.,PhD.

Hayakazu Sumida, M.D., Ph.D.

Ayumi Yoshizaki, M.D., Ph.D.

Hiraku Suga, M.D., Ph.D.

Hospital Lecturer
Takuya Miyagawa, M.D., Ph.D.

Takashi Yamashita, M.D., Ph.D.

Associate
Miki Miyazaki, M.D., Ph.D.

Tomomi Miyake,M.D.

Hiroaki Kamijo M.D., Ph.D.

Satoshi Ebata, M.D., Ph.D.

Takemichi Fukazawa, M.D., Ph.D.

Yuki Fukui, 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, one associate professors, four
lecturers, two 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.

241

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.

Fukui Y, Miyagawa T, Toyama S, Omatsu J,
Hirabayashi M, Nakamura K, Yoshizaki A, Sato
S, Asano Y. Serum delta-like 4 levels: a possible
association with interstitial lung disease insystemic sclerosis. Journal of Dermatology.
2020;47(4):e136-e137.
Miura S, Asano Y, Saigusa R, Yamashita T,
Taniguchi T, Takahashi T, Ichimura Y, Toyama
T, Yoshizaki A, Sato S, Kadono T. Regulation ofSkin Fibrosis by RALDH1-producing Dermal
Dendritic Cells via Retinoic Acid-mediatedRegulatory T cell Induction: a Role in
Scleroderma. Journal of Dermatological Science.
2020;97(2):125-134.
Kazuki M Matsuda, Ayumi Yoshizaki, Ai
Kuzumi, Takemichi Fukasawa, Satoshi Ebata,
Asako
Yoshizaki-Ogawa,Shinichi
Sato.
Combined immunosuppressive therapy provides
favorable prognosis and increased risk ofcytomegalovirus reactivation in anti-melanoma
differentiation-associated gene 5 antibody
positivedermatomyositis.
Journalof
Dermatology. 2020;47(5):483-489.

4.

Sumida H. Recent advances in roles of G-protein
coupled receptors in intestinal intraepithelial
lymphocytes Bioscience of Microbiota. Food and
Health. 2020;39(3):77-82.
5. Yuki Isami, Yuriko Kawase, Akari Kondo,
Wataru Akita, Koji Yasuda, Takeshi Matsutani,
Hiroshi
Mitsui.
Pyoderma
gangrenosum
associated with ulcerative colitis: a recalcitrant
case responded to adalimumab with granulocyte
and monocyte adsorption apheresis. Journal of
Dermatology. 2020;47(5):e213-e215.
6. Naohiko Aozasa, Masaru Hatano, Ryosuke
Saigusa, Kouki Nakamura, TakehiroTakahashi,
Tetsuo Toyama, Hayakazu Sumida, Zenshiro
Tamaki, Hisataka Maki, Shun Minatsuki, Issei
Komuro, Shinichi Sato, Yoshihide Asano.
Clinical significance of endothelial vasodilatory
function evaluated by EndoPAT in patients withsystemic sclerosis. Journal of Dermatology.
2020;47(6):609-614.
7. Kouki Nakamura, Yohei Ichimura, Zenshiro
Tamaki, Ayumi Yoshizaki, Shinichi Sato,
Yoshihide Asano. Acute exacerbation ofinterstitial lung disease with onset of myositis insystemic sclerosis patients: a report of two cases.
Scandinavian Journal of Rheumatology. 2020;
49(3):247-248.
8. Kazuki M Matsuda, Hiroko Tanaka-Mizutsugu,
Yuriko Kishi, Haruko Hino, Shinji Kagami. A
case of trigeminal trophic syndrome responded tomirogabalin. The European Journal of
Dermatology. 2020;3(2)：206-207.
9. Mariko Takaoka, Tomonori Takekoshi, Rina
Nakajima, Asuka Furukawa, Yuichi Tamura,
Yuichiro Shirai, Yoshiaki Furuya, Seisuke
Nagase, Aeru Hayashi. An anti-RNA polymerase
III antibody-positive systemic sclerosis patientwith thymic carcinoma whose digital ulcers
healed during treatment with macitentan andsildenafil for pulmonary arterial hypertension.
The European Journal of Dermatology. 2020;30(2):207-209.
10. Toyama S, Sato S, Asano Y. Localized
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242

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chemotherapy. Clinical and Experimental
Dermatology. 2020;45(5):632-634.
Naohiko Aozasa, Miki Miyazaki, Jun Hayakawa,Takeshi Tamaki, Yasuhito Hamaguchi, Shinichi
Sato, Yoshihide Aasano. A case of systemicsclerosis with multiple primary malignancies inwhom anti-RNA polymerase III antibody was
detected by immunoprecipitation. Journal of
Dermatology. 2020;47(7):e269-e270.
Satoshi Ebata, Ayumi Yoshizaki, Takemichi
Fukasawa, Yoshihide Asano, Koji Oba, Shinichi
Sato. The rapid decrease of serum surfactant
protein-D levels predicts the reactivity ofrituximab therapy in systemic sclerosisassociated interstitial lung disease. Journal of
Dermatology. 2020;47(7):796-800.
Toyama S, Yamashita T, Saigusa R, Miura S,
Nakamura K, Hirabayashi M, Miyagawa T,
Fukui Y, Omatsu J, Yoshizaki A, Sato S, Asano
Y. Decreased serum cathepsin S levels in patientswith systemic sclerosis-associated interstitiallung disease. Journal of Dermatology. 2020;
47(9):1027-1032.
Momoko Nakao, Tomomitsu Miyagaki*, Makoto
Sugaya, Shinichi Sato. Exacerbated imiquimodinduced psoriasis-like skin inflammation in
IRF5-deficient mice. International Journal of
Molecular Science. 2020;21(10):3681.
Asano Y. The pathogenesis of systemic sclerosis:
an understanding based on a common pathologic
cascade across multiple organs and additionalorgan-specific pathologies. Journal of Clinical
Medicine. 2020;9(9):E2687.
Asano Y, Sato S. Localized scleroderma-likelesions induced by Köbner phenomenon in apatient with systemic sclerosis positive for
anticentromere antibody. The European Journalof Dermatology. 2020;30(4):431-432.
Nakamura K, Taniguchi T, Hirabayashi M,
Yamashita T, Saigusa R, Miura S, Takahashi T,
Toyama T, Ichimura Y, Yoshizaki A,
Trojanowska M, Fujiu K, Nagai R, Sato S, Asano
Y. Altered properties of endothelial cells andmesenchymal stem cells underlying thedevelopment of scleroderma-like vasculopathy in
Klf5+/-;Fli1+/- mice. Arthritis Rheumatol. 2020;72(12):2136-2146.

18. Otobe S, Hisamoto T, Miygaki T, Morimura S,
Suga H, Sugaya M and Sato Shinichi SATO .
CX3CR1 Deficiency Attenuates DNFB-induced
Contact Hypersensitivity Through Skewed
Polarization Towards M2 Phenotype inMacrophages. International Journal of Molecular
Science. 2020;21(19):7401.
19. Fukayama M, Asano Y, Omatsu J, Kawashima H,
Shirai A, Sato S. Generalized Argyria
Successfully
TreatedWith
Q-switched
Alexandrite Laser: A Case Report. Acta Derm
Venereol. 2020;100(19):adv00348.
20. Momoko Nakao, Makoto Sugaya, Hideki Fujita,
Tomomitsu Miyagaki, Sohshi Morimura, Sayaka
Shibata, Yoshihide Asano and Shinichi Sato.
TLR2 Deficiency Exacerbates ImiquimodInduced Psoriasis-Like Skin Inflammation
through Decrease in Regulatory T Cells andImpaired IL-10 Production. International Journalof Molecular Science. 2020;21(22):8560.
21. Kouki Nakamura, Masahiro Kamata, Shinichi
Sato, Yoshihide Asano. Subacute thyroiditis in
psoriasis patients treated with biologics targeting
tumor necrosis factor‐α and interleukin‐17A, areport of two cases. Journal of Cutaneous
Immunology and Allergy. 2020;49(3):247-248.

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Department of Plastic andReconstructive Surgery
Professor
Mutsumi Okazaki, M.D.

Associate Professor
Takuya Iida, M.D.

Lecturer
Shimpei Miyamoto, M.D.

Project Lecturer
Shuji Yamashita, M.D., Masakazu Kurita, M.D.

Associate
Yoko Tomioka, M.D.,

Koji Kanayama, M.D.,

Yong Rui M.D.,

Yuta Moriwaki, 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, 1 lecturer, 2 project lecturers, 5associates, 5 physicians, and 4 residents. There areabout 100 doctors in the department, but most areserving in rotation at affiliated hospitals.
The outpatient clinic is located on the 3rd floor of
the outpatients building, while there are wards with
about 20 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. 1088 newpatients visited our department, including 808 patientsin emergency. 1461 surgeries were performed. Eachweek, the professor goes the round of inpatients on
Friday morning. 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 and244

trauma, 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, microsurgicaltraining 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.

4.

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Hattori Y, Harima M, Yamashita S, Iida T, Niu A.
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Yoshida S, Koshima I, Imai H, Uchiki T, Sasaki
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A, Hori Y, Matsuoka K, Mori H, Yamamoto Y,
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Japanese Clinical Practice Guidelines for Vascular Anomalies 2017. J Dermatol. 2020;47(5):e138-e183.
Fujisawa K, Suzuki A, Yamakawa T, Onishi F,
Minabe T. Pediatric-Specific Midfacial Fracture
Patterns and Management: Pediatric Versus Adult
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Kiyama M, Kanayama K, Roh S, Hattori Y, Oba J,
Iida T, Ushiku T, Okazaki M. Multiple symmetriclipomatosis with vulvar involvement: a rare casereport associated with walking difficulty andurination disorder. Eur J Plast Surg. 2020;43(3):347-352.
Kobayashi K, Matsumoto F, Miyakita Y, Arikawa
M, Omura G, Matsumura S, Ikeda A, Sakai A,
Eguchi K, Narita Y, Akazawa S, Miyamoto S,
Yoshimoto S. Risk Factors for Delayed Surgical
Recovery and Massive Bleeding in Skull Base
Surgery. Biomed Hub. 2020;5(2):87-100.
Yoshida S, Hamada Y, Koshima I, Imai H, UchikiT, Sasaki A, Fujioka Y, Nagamatsu S, Yokota K,
Harima M, Yamashita S. Role of lymphatico
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fortreatmentoflymphorrhea in lower limbs. J Plast Reconstr
Aesthet Surg. 2020;73(7):1357-1404.
Gu J, Tomioka Y, Kida K, Xiao Y, Saito I,
Okazaki M, Someya T, Sekino M. Measurementof optical reflection and temperature changes
after blood occlusion using a wearable device.
Sci Rep. 2020;10(1):11491.
Kato H, Doi K, Kanayama K, Araki J,
Nakatsukasa S, Chi D, Mori M, Fuse Y, Sakae Y,
Uozumi T. Combination of Dual Wavelength
Picosecond and Nanosecond Pulse Width
Neodymium-Doped Yttrium-Aluminum-Garnet
Lasers for Tattoo Removal. Lasers Surg Med.
2020;52(6):515-522.
Kato H, Kinoshita K, Saito N, Kanayama K,
Mori M, Asahi N, Sunaga A, Yoshizato K, Itami
S, Yoshimura K. The Effects of Ischemia andHyperoxygenation on Hair Growth and Cycle.
Organogenesis. 2020;16(3):83-94.
Yamashita S, Hattori Y, Tomioka Y, Kurita M,
Miyamoto S, Iida T, Okazaki M. Superficial
Circumflex Iliac Perforator-Osteocutaneous Flap
for Reconstruction of Extensive Composite
Defects in the Forefoot. Plast Reconstr Surg Glob
Open. 2020;8(8):e3076.
Yamashita S, Roh S, Hattori Y, Maki H,
Akamatsu N, Kaneko J, Hasegawa K, Okazaki M.
Microvascular Hepatic Artery Anastomosis in
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Surg Glob Open. 2020;8(8):e3066.
Hidaka T, Kurita M, Ogawa K, Tomioka Y,
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Reconstr Surg. 2020;146(2):243e-245e.
Yoshimura K, Sato K, Aoi N, Kurita M, Hirohi T,
Harii K. Cell-Assisted Lipotransfer for Cosmetic
Breast Augmentation: Supportive Use of
Adipose-Derived Stem/Stromal Cells. Aesthetic
Plast Surg. 2020;44(4):1258-1265.
Hidaka T, Kurita M, Miyamoto S, Watanabe M,
Kitamura Y, Okada K, Fujiwara S, Okazaki M.
Reconstruction for Severe Extracorporeal
Membrane Oxygenation-induced Ischemic Lower
Limb Injury Complicated by Osteomyelitis. Plast
Reconstr Surg Glob Open. 2020;8(8):e3074.
Kitamura Y, Oki M, Kurita M, Okazaki M.
Combined Use of an Innervated Radial Forearm
Flap and Labia Minora Peripheral Skin Graft for
Total Upper Lip Reconstruction. J Craniofac Surg.
2020;31(6):1678-1680.
Kobayashi E, Yamashita S. A training tool for
lymphatic vessel anastomosis in supermicrosurgery: An ultrafine polyvinyl alcohol tube.
Microsurgery. 2020;40(8):930-931.
Kanayama K, Takada H, Saito N, Kato H,
Kinoshita K, Shirado T, Mashiko T, Asahi R,
Mori M, Tashiro K, Sunaga A, Kurisaki A,
Yoshizato K, Yoshimura K. Hair regeneration
potential of human dermal sheath cells cultured
under physiological oxygen. Tissue Eng Part A.
2020;26(21-22):1147-1157.
Iida T, Yoshimatsu H, Seto Y, Mori K, Okazaki M.
Two-stage Reconstruction Using a Free
Jejunum/Ileum Flap After Total Esophagectomy.
Ann Plast Surg. 2020;85(6):638-644.
Tomioka YK, Narushima M, Yamashita S, Ito A,
Okazaki M. Foot Web Space Transfer forCongenital Syndactyly. Plast Reconstr Surg Glob
Open. 2020;8(12):e3292.
Tomioka Y, Kondo K, Numahata T, Moriwaki Y,
Okazaki M. Endoscopic open rhinoplasty enables
a cosmetic approach for a rare case of
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bone. Auris Nasus Larynx. 2020;47(6):10641069.
Kagaya Y, Arikawa M, Higashino T, Miyamoto S.

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anterolateral thigh and iliotibial tract flap after
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50 consecutive cases''. J Plast Reconstr Aesthet
Surg. 2021;74(1):223-243.
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;32(2):730-733.
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;41(2):175-180.
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;30(1):28-35.
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;9(2):e3369.
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;55(1):21-24.
Matsutani H, Kamochi H, Ishikawa Y. Use of
Surgical Tape Strips to Eliminate Hair Fragmentsfrom Split-thickness Skin Grafts from the
Scalp:A Simple and Quick Technique.
International Journal of Surgical Wound Care.
2021; 2(1): 32-5.
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;10(3):560.

247

Department of Oral-Maxillofacial
Surgery
Professor
Kazuto Hoshi, M.D., Ph.D.

Associate Professor
Hideto Saijo, D.D.S., Ph.D.

Lecturer
Toru Ogasawara, D.D.S., Ph.D.

Kazumi Ohkubo, D.D.S., Ph.D.

Hideyuki Suenaga, D.D.S., Ph.D.

Takahiro Abe, D.D.S., Ph.D. (until June)

Masanobu Abe, D.D.S., Ph.D.

Fujihara Yuko, D.D.S., Ph.D. (from November)

AssociateFujihara Yuko, D.D.S., Ph.D. (until October)Mari Okayasu, D.D.S., Ph.D.

Keigo Kubota, 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.

Yoko Uchida, D.D.S., Ph.D.
Kenichi Kumagai, D.D.S., Ph.D. (from January, 2021)

Homepage http://plaza.umin.ac.jp/%7Eoralsurg/
Introduction and Organization
Department of Oral and Maxillofacial Surgery,commenced by Dr. Hisashi Ishihara in 1900, is one ofthe 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 and inflammation. In
particular, we have established and practiced medical
system for cleft lip and palate since around 2000. In
November 2016, we established the Cleft Lip andPalate Center, which we become the center for oral
surgeons, orthodontists, and others. Specialists suchasprosthodontists,
otolaryngologists,
anesthesiologists,obstetricians,
pediatricians,
pediatric surgeons, speech therapists, nurses, dental
hygienists, and dental technicians form a team to deal
with illnesses from all directions and provide
multidisciplinary treatment. Dental care for thepatients who have systemic disorders or under
medical control is another field of our department.
Multidisciplinary treatment teamed by these
specialists is characteristic and has performed
excellent results in clinical works. In research fields,
all staffs participate in the clinical and basic researchto support the treatment scientifically and to develop
new treatment protocols, and we have mainly performed the experimental studies on the regenerative
abilities of tissues such as bone, periosteum, cartilage,

248

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, andat present Professor Kazuto Hoshi of our department
is concurrently serving as its director. The Departmentof Oral and Maxillofacial Surgery has Cartilage andBone Regenerative Medicine and a Tissue
Engineering Department, where assistant professors,and graduate students are conducting basic researchon regenerative medicine in the maxillofacial region.

combined with reconstruction surgery.
Peculiarity of our treatment strategy is team approachthat consists of oral and maxillofacial surgeons,orthodontists and prosthodontists. In our department,
patients with congenital dento-facial deformity aretreated by utilizing several techniques such as distraction technique, autologous bone graft technique, andthe original artificial bone graft technique in addition
to orthognatic surgery. The original bone graft is madefrom patient’s three dimensional images of CT data
and this technique is now applied for patients.

Education
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 patients withcongenital orofacial anomalies such as cleft lip andpalate, jaw deformities and other congenital
deformities. Speech therapy for the patients with cleft
lip and palate is also performed by speech therapists
in our department.
Special section for patients of congenital deformities
is on Monday afternoon examined by plastic surgeon,oral and maxillofacial surgeons, orthodontists. We
also have special sections for patients 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, fixationof orofacial fractures, resection of malignant tumors

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 and branchialarch syndromes, dentofacial deformities caused bydevelopmental and acquired problems, surgicalresection and functional reconstruction of benign andmalignant tumors, temporomandibular joint disorders,
inflammation and maxillofacial trauma. Minimum
dental knowledge concerning jaw movement, toothpain, 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 forthem in outpatient clinic. Dental caries treatments,
periodontal cares and applications of dentures are
instructed. Tooth extractions and orthodontic
treatment are instructed by oral surgeons andorthodontists. Medical cares in the ward are taught 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.

249

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 the jaw
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. Soutome S, Hasegawa T, Yamguchi T, Aoki K,
Kanamura N, Mukai T, Yamazoe J, Nishikawa M,
Isomura E, Hoshi K, Umeda M; Joint ResearchCommittee of Japanese Society of Oral Care.
Prevention of postoperative pneumonia by
perioperative oral care in patients with esophageal
cancer undergoing surgery: a multicenter
retrospective study of 775 patients. Support Care
Cancer. 2020 Jan 2. doi: 10.1007/s00520-01905242-w.
2. Moriguchi K, Iffah-Rasyiqah F, Abe M,
Kiyokawa K, Yamamoto S, Suzuki K. Targeting
Antibiotic Resistance Genes Is a Better Approachto Block Acquisition of Antibiotic ResistanceThan Blocking Conjugal Transfer by Recipient
Cells: A Genome-Wide Screening in Escherichia
coli. Frontiers in Microbiology. 2019; 10:2939,
Published online 2020 Jan 8, doi: 10.3389/fmicb.
2019.02939.
3. Kokubu S, Inaki R, Hoshi K, Hikita A. Adiposederived stem cells improve tendon repair andprevent ectopic ossification in tendinopathy byinhibiting
inflammation
andinducing
neovascularization in the early stage of tendon
healing. Regen Ther. 2020 Jan 17;14:103-110.
4. Wang X, Xu Y, Guo S, Zhang J, Abe M, Tan H,
Wang S, Chen P, Zong L. T1-2N1M0 triplenegative breast cancer patients from the SEER
database showed potential benefit from postmastectomy radiotherapy. Oncology Letters. 2020
Jan; 19(1), 735-744, Published online 2019 Nov
21, doi: 10.3892/ol.2019.11139,
5. Komura M, Komura H, Ishimaru T, Konishi K,
Komuro H, Hoshi K, Takato T. Tracheal cartilage
growth promotion by intra-tracheal administration of basic FGF. Pediatr Surg Int. 2020
Jan;36(1):33-41. Doi: 10.3892/ol.2019. 11139,
6. Fujihara Y, Abe T, Asawa Y, Nishizawa S, Saijo H,
Hikita A, Hoshi K. Influence of Damage-250

AssociatedMolecular
Patterns
fromChondrocytes in Tissue-Engineered Cartilage.
Tissue Eng Part A. 2020 Feb 19. doi: 10.1089/
ten.TEA.2019.0185.
7. Nishizawa S, Kanazawa S, Fujihara Y, Asawa Y,
Nagata S, Harai M, Hikita A, Takato T, Hoshi K.
Glial Fibrillary Acidic Protein as Biomarker
Indicates Purity and Property of Auricular
Chondrocytes. Biores Open Access. 2020 Mar 3;9(1):51-63. doi: 10.1089/biores.2019.0058.
8. Komatsu N, Komatsu M, Ohashi R, Horii A,
Hoshi K, Takato T, Abe T, Hamakubo T. Saponin
Facilitates Anti-Robo1 Immunotoxin Cytotoxic
Effects on Maxillary Sinus Squamous Cell
Carcinoma. J Oncol. 2020 Mar 11;2020:9593516.
doi: 10.1155/2020/ 9593516.
9. Ishikawa S, Iijima K, Matsukuma D, Asawa Y,
Hoshi K, Osawa S, Otsuka H. Interpenetrating
polymer network hydrogels via a one-pot and insitu gelation system based on peptide selfassembly and orthogonal cross-linking for tissue
regeneration. Chem Mater. 2020 Mar 24;
32(6):2353-2364. doi: 10.1021/acs. chemmater.
9b04725
10. Aoki E, Asawa Y, Hikita A, Hoshi K.
Establishment of a new technique for the
fabrication of regenerative cartilage with amicroslicer device to prepare three dimensional
diced cartilage. Biomed Res. 2020 Apr 1; 41(2):67-80. doi: 10.2220/ biomedres.41.67.
11. Fujihara Y, Abe T, Hoshi K. Controlling the
Phenotype of Macrophages Promotes Maturationof Tissue-Engineered Cartilage. Tissue Eng Part
A. 2020 Apr 13. doi: 10.1089/ten.TEA.2019.0190.
12. Ma Q, Kobayashi E, Suenaga H, Hara K, Wang J,
Nakagawa K, Sakuma I, Masamune K.
Autonomous surgical robot with camera-based
markerless navigation for oral and maxillofacial
surgery. IEEE/ASME Trans Mechatron. 2020
April;25(2):1084-1094. doi: 10.1109/TMECH.
2020.2971618.
13. Tsujimura T, Takase O, Yoshikawa M, Sano E,
Hayashi M, Hoshi K, Takato T, Toyoda A, Okano
H, Hishikawa K: Controlling gene activation byenhancers through a drug-inducible topologicalinsulator. Elife, 2020 May 5:9. pii: e47980 doi:
10.7554/eLife.47980

14. Umeyama R, Yamawaki T, Liu D, Kanazawa S,
Takato T, Hoshi K, Hikita A. Optimization ofculture duration of bone marrow cells before
transplantation with a β-tricalcium phosphate/recombinant collagen peptide hybrid scaffold.
Regen Ther. 2020 May 19; 14:284-295. doi:
10.1016/j.reth.2020.04. 005.
15. Kitano VJ, Ohyama Y, Hayashida C, Ito J,
Okayasu M, Sato T, Ogasawara T, Tsujita M,
Kakino A, Shimada J, Sawamura T, Hakeda Y.
LDL uptake-dependent phosphatidylethano－lamine translocation to the cell surface promotes
fusion of osteoclast-like cells. J Cell Sci. 2020
May 27; 133(10):jcs243840. doi: 10.1242/jcs.
243840.
16. Kawakami H, Yonenaga K, Sunega H, Masanobu
A, Takato T, Hoshi K. A difficult-to-diagnose
case of extranodal NK/T‐cell lymphoma, nasal
type, primary to maxillary gingival ulcers thatdeveloped after living‐donor liver transplantation.
Oral Sci Int. 2020 May; 17(2);97-102. First
Published 2019 Nov. 26. doi: 10.1002/osi2. 040.
17. Keigo Kubota, Shinsaku Arai, Takeshi Mitsuyasu,
Kaori Matsumura, Hideto Saijo, Kazuto Hoshi,
Seiji Nakamura. Prader-Willi syndrome with acleft palate: A case report. J Oral Maxillofac Surg
Med Pathol. 2019 Dec 13. doi.; org/ 10.1016/
j.ajoms.2019.11.006.
18. Ma Q, Kobayashi E, Fan B, Nakagawa K, Sakuma
I, Masamune K, Suenaga H. Automatic 3D
landmarking model using patch-based deepneural networks for CT image of oral andmaxillofacial surgery. Int J Med Robot. 2020 Jun;
16(3):e2093. doi: 10.1002/rcs.2093.
19. Abe M, Mitani A, Yao A, Takeshima H, Zong L,
Hoshi K, Yanagimoto S. Close association of
gum bleeding with systemnic diseases in lateadolescence. Int J Environ Res Public Health.
2020 Jun 16; 17(12):4290. doi: 10.3390/ijerph
17124290.
20. Abe M, Mitani A, Hoshi K, Yanagimoto S. Large
gender gap in oral hygiene behavior and its impact
on gingival health in late adolescence. Int J
Environ Res Public Health. 2020 Jun 18;
17(12):4394. doi: 10.3390/ ijerph17124394.
21. Abe M, Mitani A, Yao A, Zong L, Hoshi K,
Yanagimoto S. Awareness of Malocclusion Is

251

Closely Associated with Allergic Rhinitis,
Asthma, and Arrhythmia in Late Adolescents.
Healthcare. 2020 July 12, 8(3):209; doi:10.3390/
healthcare8030209.
22. Komatsu N, Komatsu M, Ohashi R, Horii A,
Hoshi K, Takato T, Abe, Hamakubo T.
Photosensitizer with illumination enhances invivo
antitumor
effectofanti-ROBO1
immunotoxin on maxillary sinus squamous cell
carcinoma, Anticancer Research, 2020 July;
40(7),3793-9.
23. Zhang C, Wei HT, Hu W, Sun Y, Zhang Q, Abe M,
Du Z, Xu Y, Zong L, Hu X. The feasibility oflaparoscopic TSME preserving the left colicartery and superior rectal artery for upper rectal
cancer. World Journal of Surgical Oncology, 2020
Aug 18; 18(1):212. doi: 10.1186/s12957-02001986-6, PMID: 32811501,
24. Uchino N, Hoshi K, Takato T, Okayasu M, Saijo
Hideto, Nakatsuka T, Ohkubo K, Follow-up studyof nasal deformity in cleft lip and palate patients:
morphological changes and image analysis withgrowth. Oral Science International. 2020 Aug;18(1):62-72 https://doi.org/10.1002/ osi2.1081
25. Ning FL, Pei JP, Zhang NN, Wang J, Quan HG,
Mei ZB, Zeng XT, Abe M, Zhang CD. Harvest of
at least eighteen lymph nodes is associated withimproved survival in patients with pN0 coloncancer: Aretrospective cohort study. Journal ofCancer Research and Clinical Oncology. 2020
Aug; 146(8):2117-2133. Epb 2020 Apr 13, doi:
10.1007/s00432-020-03212.
26. Xu Y, Duan Z, Hu W, Zhu K, You J, Abe M, Chen
P, Zhang, Q, Zong L. Huge MesentericFibromatosis
Presenting
withIntestinal
Perforation and Acute Diffuse Peritonitis: A Case
Report. Translational Cancer Research. 2020 Sep;
9(9):5674-5678, doi: 10.21037/tcr-19-1151.
27. Fujihara Y, Abe T, Hoshi K. Controlling the
Phenotype of Macrophages Promotes Maturationof Tissue-Engineered Cartilage. Tissue Eng Part
A. 2020 Sep; 26(17-18):1005-1013. doi:
10.1089/ten.TEA.2019.0190. Epub 2020 Apr 13.
28. Takeshima H, Niwa T, Yamashita S, TakamuraEnya T, Iida N, Wakabayashi M, Nanjo S, Abe M,
Sugiyama T, Kim Y, Ushijima T. TET repression
and increased DNMT activity synergisticallyinduce aberrant DNA methylation. Journal of
Clinical Investigation, 2020 Oct 1, 130(10):53705379; doi: 10.1172/ JCI124070,
29. Zhang C, Mei Z, Pei J, Abe M, Zeng X, Huang Q,
Nishiyama K, Akimoto N, Haruki K, Nan H,
Meyerhardt JA, Zhang R, Li X, Ogino S, Ugai T.
A Modified TNM Classification for Primary
Operable Colorectal Cancer. JNCI Cancer
Spectrum.
2020
Oct.16;5(1):pkaa093,
eCollection 2021 Feb, doi: 10.1093/jncics/
pkaa093,
30. Zhang N, Ning, F, Guo R, Pei J, Qiao Y, Fan J,
Jiang B, Liu Y, Chi Z, Mei Z, Abe M, Zhu J,
Zhang R, Zhang C.
Prognostic values ofpreoperative inflammatory and nutritional
markers for colorectal cancer. Frontiers in
Oncology, 2020 Nov 3; 10:585083, doi: 10.3389/
fonc.2020.585083,
31. Yamakawa D, Kawase-Koga Y, Fujii Y, Kanno Y,
Sato M, Ohba S, Kitaura Y, Kashiwagi M,
Chikazu D. Effects of Helioxanthin DerivativeTreated Human Dental Pulp Stem Cells on
Fracture Healing. Int J Mol Sci. 2020 Dec 1;
21(23):9158. doi:10.3390/ijms21239158.
32. Watanabe T, Asawa Y, Watanabe M, Okubo R, Nio
M, Takato T, Hoshi K, Hikita A. The usefulness ofthe decellularized matrix from three-dimensional
regenerativwe cartilage as a scaffold material.
Regen Ther. 2020 Dec 10;15:312-322. doi:
10.1016/j.reth.2020.11. 005. eCollection 2020
Dec.
(Review articles)
1. Ogasawara T, EC Ko, J Yu. Application of StemCells in the Oral and Maxillofacial Region. StemCells Int. 2020 Apr 13; 2020:2421453. doi:
10.1155/2020/2421453.
(Patents)
1. Ma Q, Suenaga H, Masamune K, Kobayashi E:
Automatic surgical planning system, surgicalplanning method, and program (PCT/JP2020/042491)

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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

253

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.

254

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.

255

References
1. Shibayama K, Sugaya H, Matsuki K, Takahashi N,
Tokai M, Onishi K, Tanaka S: Repair Integrity
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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,
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14. Kobayashi H, Ikegami M, Ushiku T, Anraku M,
Ohki T, Shinoda Y, Tanaka S, Kawano H:
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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
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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
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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257

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,

258

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,259

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

260

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

261

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., Hiroshi Murata, M.D., Takashi Fujishiro, M.D.,
Tetsuya Toyono, M.D., Ph.D., Kiyohito Totsuka, M.D., Ph.D., Keiko Azuma, M.D.,
Fumiyuki Araki, M.D., Ph.D., Taku Toyama, M.D., Kohei Ueta, M.D., Ph.D.,
Takahiro Minami, M.D., Ph.D., Kohdai Kitamoto, M.D., Ph.D.

Homepage

http://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 2200 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 7860
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262

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.
1.
2.
3.
4.
5.
6.
7.
8.

9.
10.
11.
12.
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14.
15.
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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

2.

3.

4.

5.

6.

7.

8.

Aihara M, Lu F, Kawata H, Iwata A,
Odani-Kawabata N, Shams NK. Omidenepag
Isopropyl Versus Latanoprost in Primary
Open-Angle Glaucoma and Ocular Hypertension:
The Phase 3 AYAME Study. Am J Ophthalmol.
2020;10;220:53-63.
Azuma K, Inoue T, Fujino R, Igarashi N, Asano
S, Nomura Y, Hashimoto Y, Azuma K, Asaoka R,
Kadonosono K, Obata R. Comparison between
blue-on-yellow and white-on-white perimetry inpatients with branch retinal vein occlusion. Sci
Rep.2020; 17;10(1):20009.
Fujino R, Asaoka R, Aoki S, Sugiura A,
Kusakabe M, Asano-Shimizu K, Nomura Y, Aoki
A, Hashimoto Y, Azuma K, Inoue T, Obata R.
The usefulness of the retinal sensitivity
measurement with a microperimetry forpredicting the visual prognosis of branch retinal
vein occlusion with macular edema.Graefes Arch
Clin Exp Ophthalmol.2020 ;258(9):1949-1958.
Fujishiro T, Honjo M, Kawasaki H, Asaoka R,
Yamagishi R, Aihara M. Structural Changes andAstrocyte Response of the Lateral Geniculate
Nucleus in a Ferret Model of Ocular
Hypertension. Int J Mol Sci. 2020;17;21(4):1339.
Hashimoto Y, Kitamoto K, Aihara M, Usui T.
Toxicity profiles of fixed-combination eye drops
for glaucoma therapy using cultivated humancorneal epithelial sheets. Jpn J Ophthalmol. 2020;
64(3):304-311.
Igarashi N, Honjo M, Kaburaki T, Aihara M.
Effects of ROCK Inhibitors on Apoptosis ofCorneal Endothelial Cells in CMV-Positive
Posner-Schlossman Syndrome Patients. Invest
Ophthalmol Vis Sci. 2020;3;61(10):5.
Kitamoto K, Taketani Y, Fujii W, Inamochi A,
Toyono T, Miyai Takashi, Yamagami S, Kuroda
M, Usui T, Ouchi Y.Generation of mouse modelof TGFBI-R124C corneal dystrophy using
CRISPR/Cas9-mediatedhomology-directed
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263

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Nakahara H, Komae K, Kawashima H, Aihara M.
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Department ofOtorhinolaryngology and Head& Neck Surgery
Professor
Tatsuya Yamasoba, M.D., Ph.D.

Associate Professor
Kenji Kondo, M.D., Ph.D.

Lecturer
Akinori Kashio, M.D., Ph.D.

Shu Kikuta, M.D., Ph.D.

Yu Matsumoto, M.D., Ph.D.

Yuki Saito, M.D., Ph.D.

Research Associate
Chisato Fujimoto, M.D., Ph.D.

Rumi Ueha, M.D., Ph.D.

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.

Taku Sato, M.D.

Toshihiko Sakai, M.D.

Shintaro Yoshihara, M.D., Ph.D.

Teru Kamogashira, M.D., Ph.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 in Japan.
Our department covers all otorhinolaryngologicaldiseases and associated systemic diseases, and has
specialized clinics in middle ear and inner ear diseases,
hearing impaired infant and children, adult and elderly
patients, facial paresis, vertigo and balance disorders,olfactory disorders and paranasal diseases, voice andspeech disorders, taste and swallowing respiratory
disorders, aphasia, central auditory disorders and head& neck cancers.

A professor, associate professors, lecturers (assistantprofessors) and associates participate in surgery, outpatient and in-patient care as well as research andeducational 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 clubis held to introduce current research papers.

Clinical activities
In the out-patient clinic, general and special services

265

are provided to approximately 150 out-patients on adaily basis in all areas of otorhinolaryngology andrelated specialties, and approximately 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 bronchoesophagological surgery, and paranasal surgery andother minor surgery. Preoperative and postoperative
problems are checked and discussed by each group, theprofessor’s and associate 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 withneighboring tissues and reconstruct upper respiratory
and swallowing functions at one stage operationcooperating with plastic surgeons. Reconstructive
surgery of microtia and atresia to reconstruct external
ear is routinely performed with plastic 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 the professor
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, bronchoesophagology andrhinology and is related to case research, clinical statistics and clinical electrophysiology. Basic research isalso encouraged to solve essence of clinical problems
and to elucidate basic phenomena or anatomical andcellular 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 control
in patients with vestibulopathy using mathematicalmodels12) Hair cell physiology and pathology andintroduction of hair cell regeneration in theauditory and vestibular end organ
13) Clinical neurophysiology of the facial nerves
focusing on degeneration and regeneration inpatients

26614) 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. Ueha R, Ueha S, Kenji K, Nishijima H, Yamasoba
T.Effects of Cigarette Smoke on the Nasal
Respiratory and Olfactory Mucosa in Allergic
Rhinitis Mice. Frontia in neuroscience. 14: 126,2020
2. Ueha R, Maeda E, Ino K, Shimizu T, Sato T, GotoT, Nito T, Yamasoba T. Sleep-Induced Glottis
Closure in Multiple System Atrophy Evaluated by
Four-Dimensional
Computed
Tomographycomputed tomography. Frontia in medicine 7: 132,2020
3. Ueha R, Sato T, Goto T, Yamauchi A, Zelter NN,
Mitsui J, Belafsky CP, Yamasoba T. Esophageal
dysmotility is common in patients with multiple
system atrophy. Laryngoscope 131(4):832-838,
2020
4. Tsuchiya K, Ueha R, Suzuki S, Goto T, Sato T, Nito
T, Yamasoba T. Heightened risk of early vocal foldmotion impairment onset and dysphagia in theparkinsonian variant of multiple system atrophy: acomparative study. Clinical Parkinsonism &Related Disorders 3: Online open access, 2020
5. Koizumi M, Suzuki S, Matsui H, Fushimi
K,Yamasoba T, Yasunaga H. Trends incomplications after functional endoscopic sinus
surgery in Japan: A comparison with a previous
study (2007-2013vs. 2013-2017). Auris Nasus
Larynx 47(5): 814-819, 2020
6. Kamogashira T, Fujimoto C, Kinoshita M,
Kikkawa Y, Yamasoba T, Iwasaki S. Prediction of
Vestibular Dysfunction by Applying Machine
Learning Algorithms to Postural Instability. Front.
Neurol. 11: 7, 2020
7. Kondo K, Kikuta S, Ueha R, Suzukawa K,
Yamasoba T. Age-Related Olfactory Dysfunction:
Epidemiology, Pathophysiology, and ClinicalManagement. Front Aging Neurosci 12: 208, 2020
8. Saito Y, Hayashi R, Iida Y, Mizumachi T, Fujii T,
Matsumoto F, Beppu T, Yoshida M, Shinomiya H,
Kamiyama R, Kitano M, Yokoshima K, Fujimoto
Y, Hama T, Yamashita T, Okami K, Miura K,
Fujisawa T, Sano D, Kato H, Minami S, Sugasawa
M, Masuda M, Ota I, Iwae S, Kawata R, Monden
N, Imai T, Asakage T, Okada M, Yoshikawa T,
Tanioka K, Kitayama M, Doi M, Fujii S, Fujii M,
Oridate N, Nakamizo M, Yoshimoto S, Homma A,
Nibu KI, Yane K. Optimization of therapeuticstrategy for p16-positive oropharyngeal squamouscell carcinoma: Multi-institutional observational
study based on the national Head and Neck Cancer
Registry of Japan. Cancer 126: 4177-4187, 2020
9. Saito Y, Favorov AV, Forman M, Ren S, Sakai A,
Fukusumi T, Liu C, Sadat S, Ando M, Xu G, Khan
Z, Pang J, Valsamakis A, Fisch KM, Califano JA.
Rational genomic optimization of DNA detection
for human papillomavirus type 16 in head and necksquamous cell carcinoma. Head & Neck 42: 688697, 2020
10. Kobayashi K, Matsumoto F, Yasuji Miyakita,
Arikawa M, Omura G, Matsumura S, Ikeda A,
Sakai A, Egushi K, Narita Y, Akazawa S,
Miyamoto S, Yoshimoto S. Risk Factors for
Delayed Surgical Recovery and Massive Bleeding
in Skull Base Surgery Biomed Hub. 7: 87-100,
2020
11. Fujimoto C, Kamogashira T, Takenouchi S,

267

Kinoshita M, Sugasawa K, Kawahara T, Yamasoba
T, Iwasaki S. Utriculo-ocular pathway dysfunction
is more frequent in vestibular migraine thanprobable vestibular migraine. J Neurol 267(8):2340-2346, 2020
12. Fujimoto C, Kawahara T, Yagi M, Murofushi T.
Association between vestibular dysfunction andfindings of horizontal head-shaking and vibrationinduced nystagmus. J Vestib Res. 30(5):319-327,
2020
13. Hayashi K, Suzuki Y, Fujimoto C, Kanzaki S.
Molecular Mechanisms and Biological Functionsof Autophagy for Genetics of Hearing Impairment.
Genes (Basel) 11(11): E1331, 2020
14. Ichijo K, Kinoshita M, Fujimoto C, Uranaka T,
Kikkawa YS, Sugasawa K, Yamasoba T, Iwasaki S.
Acute bilateral vestibulopathy with simultaneous
involvement of both superior and inferior
vestibular nerves. Auris Nasus Larynx 47(5): 905908, 2020
15. Saegusa C Hosoya M, Nishiyama T, Saeki T,
Fujimoto C, Okano H, Fujioka M, Ogawa K. Lowdose rapamycin-induced autophagy in cochlear
outer sulcus cells. Laryngoscope Investig
Otolaryngol 5(3): 520-528, 2020
16. Koda K, Kashio A, Uranaka T, Hoshi Y,
Takenouchi S, Matsumoto Y, Iwasaki S, Yamasoba
T. Cochlear implant magnet dislocation caused by
1.5T MRI: Case-series study. Archives of Clinicaland Medical Case Reports 4: 883-889, 2020
17. Mori A, Kashio A, Akamatsu Y, Ogata E, Hoshi Y,
Matsumoto Y, Iwasaki S, Yamasoba T. Long-Term
Outcomes of Cochlear Implantation in Children
with Cochlear Nerve Deficiency. Archives ofClinical and Medical Case Reports 4: 990-1002,
2020
18. Buchman CA, Gifford RH, Haynes DS, Lenarz T,
O'Donoghue G, Adunka O, Biever A, Briggs RJ,
Carlson ML, Dai P, Driscoll CL, Francis HW,
Gantz BJ, Gurgel RK, Hansen MR, Holcomb M,
Karltorp E, Kirtane M, Larky J, Mylanus EAM,
Roland JT Jr, Saeed SR, Skarzynski H, Skarzynski
PH, Syms M, Teagle H, Van de Heyning PH,
Vincent C, Wu H, Yamasoba T, Zwolan T.
Unilateral Cochlear Implants for Severe, Profound,or Moderate Sloping to Profound Bilateral
Sensorineural Hearing Loss: A Systematic Review

and Consensus Statements. JAMA Otolaryngol
Head Neck Surg. 146(10):942-953, 2020
19. Yoshihara S, Suzuki S, Yamasoba T, Kondo K.
Recurrent facial palsy: The prognostic value ofelectrophysiological tests according to recurrence
interval. Auris Nasus Larynx. 47(1): 105-110, 2020
20. Goto T, Ueha R, Sato T, Fujimaki Y, Nito T,
Yamasoba T. Single, high-dose local injection ofbFGF improves thyroarytenoid muscle atrophy
after paralysis. Laryngoscope. 130(1): 159-165,
2020
21. Ueha R, Nativ-Zeltzer N, Sato T, Goto T, Yamauchi
A, Belafsky PC, Yamasoba T. The effects of barium
concentrationlevelsonthepulmonary
inflammatory response in a rat model of aspiration.
Eur Arch Otorhinolaryngol. 277(1): 189-196, 2020
22. Tao A, Huang GL, Igarashi K, Hong T, Liao S,
Stellacci F, Matsumoto Y, Yamasoba T, Kataoka K,
Cabral H. Polymeric Micelles Loading Proteinsthrough Concurrent Ion Complexation and pHCleavable Covalent Bonding for In Vivo Delivery.
Macromol Biosci. 20(1): e1900161, 2020
23. Kinoh H, Quader S, Shibasaki H, Liu X, Maity A,
Yamasoba T, Cabral H, Kataoka K. Translational
Nanomedicine Boosts Anti-PD1 Therapy to
Eradicate Orthotopic PTEN-Negative Glioblastoma. ACS Nano. 14(8): 10127-10140, 2020
24. Kinoh H, Shibasaki H, Liu X, Yamasoba T, Cabral
H, Kataoka K. Nanomedicines blocking adaptive
signals in cancer cells overcome tumor TKI
resistance. J Control Release. 321: 132-144, 2020
25. Kakigi A, Egami N, Uehara N, Fujita T, Nibu KI,
Yamashita S, Yamasoba T. Live imaging andfunctional changes of the inner ear in an animalmodel of Meniere's disease. Sci Rep. 10(1): 12271,
2020
26. 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 intoatypical Ly6G+ SiglecF+ immune cells withneurosupportive potential in olfactory neuroepithelium. J Leukoc Biol. 109:481-496, 2020
27. Tuerdi A, Kikuta S, Kinoshita M, Kamogashira T,
Kondo K, Yamasoba T. Zone-specific damage ofthe olfactory epithelium under protein restriction.
Sci Rep. 10(1): 22175, 2020

268

Department of
Rehabilitation Medicine
Professor
Nobuhiko Haga, 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269

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

References
1. Goto M, Haga N, Takedani H: Physical activity andits related factors in Japanese people withhaemophilia. Haemophilia 25: e267-e273, 2019

2. Mano H, Fujiwara S, Haga N: Body knowledge inchildren with congenital lower limb deficiency.
Pediatr Int 61(2): 158-165, 2019
3. 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
4. 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
5. 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): 232234, 2019.9
6. 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 and molecular studies in
split hand/foot malformation: identification of twoplausible candidate genes (LRP6 and UBA2). Eur J
Hum Genet 27: 1845-1857, 2019
7. 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
8. 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
9. 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,
Homma Y, Kume H: Longitudinal change of270comprehensive lower urinary tract symptoms andvarious types of urinary incontinence during
robot-assisted radical prostatectomy. Neurourol
Urodyn 38(4): 1067-1075, 201910. 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, 201911. 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, 201912. 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, 201913. Morita K, Miura K, Kasai K, Hashimoto R: Eyemovement characteristics in schizophrenia: A
recent update with clinical implications. Neuropsychopharmacol Rep. Epub ahead of print, 201914. 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

272

Department of Anesthesiology
Professor
Kanji Uchida, M.D., Ph.D.

Associate Professor
Masahiko Sumitani, M.D., Ph.D.

Lecturer
Nobuko Ito, M.D., Ph.D.,

Masahiko Bougaki, M.D., Ph.D.,

Mitsuaki Muroya, M.D., Ph.D.,

Yoshiteru Mori, M.D.,

Gaku Kawamura, M.D., Ph.D.,

Taro Kariya, M.D., Ph.D.

Associate
Masaaki Asamoto, M.D.,

Yosuke Imai, M.D., Ph.D.,

Ken Kuwajima, M.D., Ph.D.,
Michiko Ushio, M.D.,

Yuho Tamai, M.D.,

Ayako Hirai, M.D.,

Kazuhito Mietani, M.D., Ph.D.,

Atsuko Kato, M.D.,

Takuma Hiraiwa, M.D.,

Mizuho Sato, M.D.,

Masaki Iwakiri, M.D., Ph.D.,

Miki Shinokawa, M.D.,
Yuko Araki, M.D.,

Reo Inoue, M.D., Ph.D.,
Seiichiro Kawashima, M.D.,

Ai Furuta, M.D., Emi Morinushi, M.D., Inhee Jeong, M.D.,
Yuji Ueda, M.D.,

Miyako Nagaya, M.D.,

Tomoaki Nakamura, M.D.,

Hayato Narita, M.D.,

Kanae Tsutsumi, M.D.,

Satoshi Kasahara, M.D., Ph.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, 2021, the Department ofAnesthesiology consists of Professor Kanji Uchida;
Associate Professor Masahiko Sumitani; Lecturers
Nobuko Ito, Masahiko Bougaki, Yoshiteru Mori,
Mitsuaki Muroya, Gaku Kawamura, Taro Kariya; 24
Associates, 18 anesthesiology residents, and 8 graduate
students. The outpatient clinic is located on the 2nd
floor of Outpatient Clinic Building and the 3rd floor ofCentral Clinical Service Building 2, the inpatient units
are located on the 6th floor north of Inpatient Building
A, and the offices and laboratories are located on
Clinical Research Building East, Central Building
South, and the 4th floor of Clinical Research Building

A. The current activities of our department in clinic,
education, and research are described 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 Universityof Tokyo Hospital. The number of surgeries at the
University of Tokyo Hospital increased as a result of
the doubling of the number of operating rooms to 23
when the Central Clinical Service Building 2 became
operational in January 2007, and the annual number ofsurgical cases reached 11,323 (8,831 managed by theanesthesiologists) in FY2019 (Apr 2019 – Mar 2020).
In FY2020 (Apr 2020 – Mar 2021), however, the273

number of surgeries decreased due to the SARS-CoV-2
infectious disease (COVID-19) pandemic, and the total
number of surgeries was 9,954, of which theanesthesiologists managed 7,927 cases. The number ofsurgeries for patients with many complications andelderly patients has been increasing every year, and in
addition, heart, liver, and lung transplants from braindead donors have been performed.
Because many patients with severe and complicatedconditions, both surgically and medically, are treated at
the University of Tokyo Hospital, we routinely provide
anesthesia for patients with many preoperative
comorbidities, including transplant recipients with endstage organ failure. We contribute to a good
postoperative recovery by performing a carefulpreoperative assessment, optimizing the patient's
condition preoperatively, and performing appropriate
intraoperative anesthetic management. In the operatingrooms, we are also well-prepared to respond 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 1,407 preoperative
patients in FY2020. We have participated in the
Perioperative Management Center Program and aredesigning 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 decreased fromthe previous year to 1,110 (1,559 in FY2019) in
FY2020 due to dynamic and timely changes in ICU
operation in response to the COVID-19 pandemic anda decrease in the number of surgeries as mentioned
above.
We also established an obstetric anesthesia team to
improve the safety and comfort of perinatal care. 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 FY2020 was 308(307 in FY2019). The number of neuraxial labor

analgesia decreased slightly to 365 (386 in FY2019) in
FY2020 due to the impact of COVID-19.
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, andconduct multidisciplinary pain evaluation andtreatment, including neurological, neuropsychiatricand psychiatric evaluations, in cooperation withmultiple departments. The number of outpatients in
FY2020 was 6,090 (6,508 in FY2019), of which 215
were first-time patients (298 in FY 2019), a decrease
thought to be due to the COVID-19. The number ofactive beds was 1, and the number of inpatients was 18.
There were 107 requests for pain consultation for
inpatients in FY2020.
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-toperson basis with our faculty staff members. The
lectures of the FY2020 were: History and mechanismsof anesthesia, Inhalational anesthesia, Intravenous
anesthesia, Regional and local anesthesia, Preoperativeevaluation, 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
management, and onsite anesthesia management to274

learn 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 intractable pains
and therapeutic methods focusing on pharmacotherapy,
nerve block therapy, exercise therapy, and cognitivebehavioral therapy. The short lectures cover seven
topics: General anesthesiology, Airway maintenanceand 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 fortracheal intubation, central venous puncture, andsubarachnoid spinal anesthesia. As a summary of theClinical Clerkship education, we ask the students tosubmit reports on anesthesia cases and reports onanesthetics
andcardiovascular
drugs,
withpresentations and discussions on the contents. In
accordance with the policy of the School of Medicine
in response to the outbreak of COVID-19, the ClinicalClerkship for the period from January to March 2021
was conducted online.
For post-graduate education, we accepted a total of
99 junior residents of PGY1 and 2 from the General
Education Center as rotators (1-2 months each,
averaging over 10 junior residents per month) in
FY2020. The training includes anesthesia management,
preoperative and intraoperative management, and basic
skills and knowledge in emergency and resuscitation
settings. For the 18 anesthesiology residents of PGY3+,
faculty staffs teach and supervise daily clinicalanesthesia, postoperative ICU care, obstetric anesthesia,
and pain clinic. The anesthesiology residents areencouraged to give presentations at scientific meetings,
including the Japanese 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 cultivatea professional attitude in residents and develop theircompetency 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 by anesthesia;
 Apoptotic signal transduction induced bysepsis or ischemia-reperfusion injury; A role of lipid mediators in organ damage
mediated by ischemia-reperfusion injury of amouse lower limb;
 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 of left/rightheart failure of animal models; Invention and validation of new anesthetic
procedures with emerging technologies;
 Epidemiological survey and outcome study
with large administrative database.

Publications1.

2.

Abe H, Inoue R, Tsuchida R, Azuma K, Ino K,
Konishi M, et al. Use of three-dimensional
printing of a lumbar skeletal model for intrathecal
administration of nusinersen: a brief technicalreport. Reg Anesth Pain Med. 2020;45(10):757–60.
Abe H, Sumitani M, Matsui H, Aso S, Inoue R,

275

Fushimi K, et al. Comparing outcomes after
peripheral nerve block versus general anesthesia
for lower extremity amputation: a nationwide
exploratory retrospective cohort study in Japan.
Reg Anesth Pain Med. 2020;45(6):399–404.
3. Ando M, Sumitani M, Sakamura M, Noguchi T,
Oki R, Abe H, et al. Tele virtual reality-based peer
support programme for cancer patients: apreliminary feasibility and acceptability study.
British Journal of Cancer Research. 2020; 3(4):443–8.
4. Azuma K, Abe H, Hozumi J, Inoue R, Konishi M,
Tsuchida R, et al. Prefectural adequacy of opioid
availability for cancer pain and its determinants inJapan: a preliminary study. JMA J. 2020;3(4):340–
6.
5. Hirose K, Uchida K, Umezu, S: Airtight, flexible,
disposable barrier for extubation. J Anesth. 2020;34(5):798–9.
6. Hosoki K, Mikami Y, Urushiyama H, Souma K,
Kawamura G, Uchida K, et al. Predictors of
postoperative acute exacerbation of interstitiallung disease: a case-control study. BMJ OpenRespir Res. 2020;7(1):e000634.
7. Ikeda T, Kato A, Bougaki M, Araki Y, Ohata T,
Kawashima S, et al. A retrospective review of 10year trends in general anesthesia for cesareandelivery at a university hospital: the impact of a
newly launched team on obstetric anesthesia
practice. BMC Health Serv Res. 2020;20:421.
8. Kakutani S, Asamoto M, Araki F, Chen YN,
Shinokawa M, Okagami Y, et al. Prospective
evaluation of visual function in patients withocular diseases after robot‐assisted laparoscopic
prostatectomy. Int J Urol. 2020;27(4):307–12.
9. Kasahara S, Niwa SI, Matsudaira K, Sato N, Oka
H, Yamada Y. Attention-deficit/hyperactivity
disorder and chronic pain. Psychosom Med. 2020;82(3):346–7.
10. Kariya T. Rapid spread of COVID-19 in New Yorkand the response of the community. Global Health& Medicine. 2020;2(2):123–6.
11. Morita Y, Kariya T, Nagai S, Itani A, Isley M,
Tanaka K. Hepatic vein flow index duringorthotopic liver transplantation as predictive
factor for postoperative early allograft
dysfunction. J Cardiothorac Vasc Anesth. 2020

12.

13.

14.

15.

16.

Dec 24.
Ninagawa J, Sumitani M, Nishizawa D,
Nagashima M, Mietani K, Abe H, et al.
Adiponectin receptor 1 gene is potentiallyassociated with severity of postoperative pain but
not cancer pain. Medicine (Baltimore). 2020;
99(5):e18924.
Owada H, Sumitani M, Inoue R, Kawashima M,
Ishii K, Shin M, et al. Peripheral nerve fieldstimulation successfully manages axial pain after
posterior cervical spine surgery: case report. Ann
Palliat Med. Epub 2020 Jul 15.
Saita K, Kariya T, Ezaka M, Nakao T, Kin N.
Bronchovenous fistula during adult cardiac
surgery: a case report. A A Pract. 2020;14(12):e01321.
Tsuchida R, Sumitani M, Abe H, Ando M, Saita K,
Hattori K, et al. Clopidogrel, an ADP-P2Y12
receptor antagonist, can prevent severe
postoperative pain: a retrospective chart review.
Life. 2020;10(6):92.
Tsuchida R, Sumitani M, Azuma K, Abe H,
Hozumi J, Inoue R, et al. A novel technique using
magnetic resonance imaging in the supine andprone positions for diagnosing lumbar adhesive
arachnoiditis: a preliminary study. Pain Pract.
2020;20(1):34–43.

276

Department of Acute Medicine
Professor
Naoto Morimura, M.D.

Associate Professor
Kent Doi, M.D.

Lecturer
Takehiro Matsubara, M.D. Takahiro Hiruma, M.D.

Project Lecturer
Yoshihiro Ueda, M.D.

Naoki Hayase, M.D.

Research Associate
Hiromu Maehara, M.D.

Shunsuke Tagami, M.D.

Yutaro Inoue, M.D.

Naho Misawa, M.D.

Hitomi Nakamura, M.D.

Daisuke Takai, M.D.

Jinsuke Mizuno, M.D.

Mio Kurimoto, M.D.

Takashi Gondo, M.D.

Yohei Ohsiro, M.D.

Hiroyasu Mizuhara, M.D.

Project Research Associate
Atsushi Shimada, 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 Facilities of
the University of Tokyo Hospital and at the same timeas the intensive care service for in-hospital patients, it
became a tertiary emergency care and critical carecenter in the metropolitan Tokyo and also became theprincipal teaching facility of the University of Tokyo.
It is a designated Level I Trauma Center, and also thehome 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 and fullmonitoring 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 are locatedadjacent 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 bedsin 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, highacuity 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

277

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 tertiary
emergency but also primary and secondary
emergency care on 24-hour-a-day basis. In 2017
fiscal year, we had about 6595 ambulance patientsout of total 17607 ER outpatients.
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 “the semiclosed ICU” model. We are responsible for the entire
care of the critically ill patients (i.e. patients withrespiratory insufficiency such as ARDS, with sepsis,with MOF, with shock), post-operative patients, andtertiary emergency patients, placing an emphasis on
evidence-based medical therapy. We had 2,300
ICU/CCU patients in the 2016.
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 are allocatedto three types of wards, that is, general ward, ICU2
and ICU/CCU in accordance with their criticalcondition. 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/365-day
basis. And in regard to out of hospital risk
management, our hospital has been authorized by the
Tokyo Metropolitan Government as a disaster basehospital, and also the Government has requested theformation of Disaster Medical Assistant Team(DMAT). We have oxygen and medical suction
equipment on the passageways in the ER in case oftreating the large number of disaster 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. BasicLife Support. exercise is also mandatory for the 2ndyear medical student.
One month of elective clinical clerkship for the 3rdyear. Immediate Cardiac Life Support (ICLS) courseand 1 day Hospital MIMMS (Major Incident Medical
Management and Support) course are held for theparticipants in the clinical clerkship program, andsuccessful 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 real practice of
emergency medicine as fellow passengers in theambulances and as one day trainees in the emergency
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 obtainthe 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, wetrain 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

278

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.

8.

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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.
Hirayama I, Inokuchi R, Ueda Y, Doi K. Heat
Stroke Lesions in the Globus Pallidus. Intern Med.
2020 Apr 1;59(7):1015-1016.
Hayase N, Doi K, Hiruma T, Matsuura R,
Hamasaki Y, Noiri E, Nangaku M, Morimura N.
Recombinant thrombomodulin prevents acutelung injury induced by renal ischemia-reperfusion
injury. Sci Rep. 2020 Jan 14;10(1):289.
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;49(4):386-393.
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.
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.
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.

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Tokunaga K, Nakamura K, Inokuchi R, Hayase N,
Terada R, Tomioka Y, Ikeda T, Kobayashi E,
Okazaki H, Sakuma I, Doi K, Morimura N.
Cardiac Variation of Internal Jugular Vein as aMarker of Volume Change in Hemorrhagic Shock.
Shock. 2020 Dec;54(6):717-722.
Doi K. The need for disruptive innovation in acutekidney injury. Clin Exp Nephrol. 2020 Nov;
24(11):979-988.
Doi K, Ikeda M, Hayase N, Moriya K, Morimura
N; COVID-UTH Study Group. Nafamostat
mesylate treatment in combination withfavipiravir for patients critically ill with Covid-19:
a case series. Crit Care. 2020 Jul 3;24(1):392.
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.
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.
Ostermann M, Bellomo R, Burdmann EA, Doi K,
Endre ZH, Goldstein SL, Kane-Gill SL, Liu KD,
Prowle JR, Shaw AD, Srisawat N, Cheung M,
Jadoul M, Winkelmayer WC, Kellum JA;
Conference Participants. Controversies in acutekidney injury: conclusions from a Kidney Disease:
ImprovingGlobalOutcomes(KDIGO)
Conference. Kidney Int. 2020 Aug;98(2):294-309.
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.
Komaru Y, Doi K, Nangaku M. Urinary
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Critically Ill Patients With Coronavirus Disease2019. Crit Care Explor. 2020 Aug 20;2(8):e0181.
Yamamoto M, Doi K, Hayase N, Asada T,
Akamatsu N, Kaneko J, Hasegawa K, Morimura
N. Pulse oximetry-based capillary refilling
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Yoshimoto K, Komaru Y, Iwagami M, Doi K.
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Gunshin M, Doi K, Morimura N. Use of highfidelity simulation technology in disasters: anintegrative literature review. Acute Med Surg.
2020 Dec 20;7(1):e596.
Fukushima K, Inokuchi R, Hirayama I, Hiruma T,
Doi K. Early diagnosis and antibiotic treatment for
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Health Sciences and Nursing
1. Health Sciences

281

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
Kazuhiro Watanabe, 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, 7
doctoral course students, 8 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.

282

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
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with schizophrenia: A cross‐sectional study.
Neuropsychopharmacol Rep. 2021;41:242-247.
Komase Y, Watanabe K, Kawakami N. Effects ofa gratitude intervention program on work
engagement among Japanese workers: a protocol
for a cluster randomized controlled trial. BMC
Psychol. 2021;9:35.
Yasuma N, Watanabe K, Nishi D, et al. Psychotic
Experiences and Hikikomori in a Nationally
Representative Sample of Adult Community
Residents in Japan: A Cross-Sectional Study
Front Psychiatry. 2021;11:602678.
Yasuma N, Imamura K, Watanabe K, et al.
Association between energy drink consumption
and substance use in adolescence: A systematic
review of prospective cohort studies. Drug andalcohol dependence. 2021;219:108470.

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Sasaki N, Imamura K, Kataoka M, et al.
COVID-19 measurements at the workplace invarious industries and company sizes: a
two-month follow-up cohort study of full-time
employees in Japan. Environ Occup Health Pract.
2021;3
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responses to COVID-19 associated with mental
health and work performance of employees inJapan. J Occup Health. 2020;62:e12134.
Sasaki N, Kuroda R, Tsuno K, et al. Exposure to
media and fear and worry about COVID-19.
Psychiatry Clin Neurosci. 2020;74:501-502.
Sasaki N, Watanabe K, Kawakami N. Personalvalues in adolescence and their associations withmetabolic biomarkers in adulthood: a Japanese
population-based study. Biopsychosoc Med.
2020;14:26.
Sasaki N, Kuroda R, Tsuno K, et al. Mental
health deteriorated mostly in the less educatedunder repeated COVID-19 outbreaks: A cohort
study of Japanese employees. J Epidemiol. 2020;
7.
Sasaki N, Kuroda R, Tsuno K, et al. The
deterioration of mental health among healthcare
workers during the COVID-19 outbreak: A
population-based cohort study of workers inJapan. Scand J Work Environ Health. 2020;46:
639-644.
Sasaki N, Imamura K, Tran TTT, et al. Effects ofsmartphone-based
stressmanagementon
improving work engagement among nurses inVietnam: a secondary analysis of a three-arm
randomized controlled trial.J Med Internet Res.
2021;23:e20445.

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14. Kawakami N, Sasaki N, Kurosa K, et al.
Downloading a government-issued COVID-19
contact tracing app may improve psychologicaldistress in the outbreak among employed adults:
a prospective study. JMIR Mental Health 2021;8:e23699.
15. Abbafati C, Abbas KM, Abbasi M, et al. Fiveinsights from the Global Burden of Disease Study
2019. Lancet. 2020;396:1135-59.
16. Kawakami N, Fukasawa M, Sakata K, et al.
Onset and remission of common mental disorders
among adults living in temporary housing forthree years after the triple disaster in Northeast
Japan: comparisons with the general population.
BMC Public Health. 2020;20:1271.
17. Kawakami N, Inoue A, Tsuchiya M, et al.
Construct validity and test-retest reliability of theWorld Mental Health Japan version of the World
HealthOrganization
Health and Work
Performance Questionnaire Short Version: apreliminary study. Industrial Health. 2020;58:
375-87.
18. Kawakami N, Tran TTT, Watanabe K, et al.
Internal consistency reliability, construct validity,
and item response characteristics of the Kessler 6
scale among hospital nurses in Vietnam. PLoS
One. 2020;15:e0233119
19. Vos T, Lim SS, Abbafati C, et al. Global burdenof 369 diseases and injuries in 204 countries andterritories, 1990-2019: a systematic analysis for
the Global Burden of Disease Study 2019. Lancet.
2020;396:1204-22.
20. Wang HD, Abbas KM, Abbasifard M, et al.
Global age-sex-specific fertility, mortality,
healthy life expectancy (HALE), and population
estimates in 204 countries and territories, 19502019: a comprehensive demographic analysis for
the Global Burden of Disease Study 2019. Lancet.
2020;396:1160-203.
21. Nishi D, Imamura K, Watanabe K, et al.
Internet-based cognitive behavioral therapy forprevention of depression during pregnancy and in
the postpartum (iPDP): a protocol for a large
scale randomized controlled trial. BMJ Open.
2020;10:e036482.
22. Asaoka H, Koido Y, Kawashima Y, et al.
Post-traumatic stress symptoms among medical

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31.

rescue workers exposed to COVID-19 in Japan.
Psychiatry Clin Neurosci. 2020;74:503-505.
Sasaki N, Watanabe K, Imamura K, et al.
Japanese version of the 42-item psychologicalwell-being scale (PWBS-42): a validation study.
BMC Psychol.2020;8:75.
Kawakami N, Watanabe K, Nishi D, et al. Timepreference and personal value: a populationbased cross-sectional study in Japan. BMC
Psychology 2020;8:85.
Levis B, Negeri Z, Sun Y, et al. Accuracy of the
Edinburgh Postnatal Depression Scale (EPDS)
for Screening to Detect Major Depression among
Pregnant and Postpartum Women: Systematic
Review and Meta-analysis of Individual
Participant Data. BMJ 2020;371:m4022.
Obikane E, Watanabe K, Nishi D, et al.
Association between personal values inadolescence and impaired bonding relationshipwith children. BMC Psychol. 2020;11:8:98.
Iida M, Watanabe K, Ando E, et al. The
Association Between Unit-Level Workplace
Social Capital and Intention to Leave Among
Employees in Health Care Settings: A
Cross-Sectional Multilevel Study. Journal of
Occupational and Environmental Medicine,2020;62:e186-e191.
Fukasawa M, Watanabe K, Nishi D, et al.
Longitudinal association between adolescentwork values and mental health and well-being in
adulthood: A 23-year prospective cohort study.
Sci Rep. 2020;10:13547.
Fukasawa M, Kawakami N, Umeda M, et al.
Long-lasting effects of distrust in governmentand science on mental health eight years after the
Fukushima nuclear power plant disaster. Social
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Yasuma, N, Watanabe, K, Nishi, D, et al.
Personal values in adolescence and sense ofcoherence in adulthood: A cross‐sectional study
based on a retrospective recall. Neuropsychopharmacol Rep. 2020;40:262-267
Yasuma, N, Narita Z, Sasaki N, et al. Antenatal
psychologicalintervention
foruniversal
prevention of antenatal and postnatal depression:
A systematic review and meta-analysis. J Affect
Disord. 2020;273:231-239

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32. Obikane E, Yamana H, Yasunaga H, et al.
Cumulative visits for care of minor injuries areassociated with traumatic brain injury in young
children. Acta Paediatr. 2020;109:2775-2782
33. Yasuma N, Sato S, Yamaguchi S, et al. Effects ofbrief family psychoeducation for caregivers ofpeople with schizophrenia in Japan provided byvisiting nurses: protocol for a cluster randomised
controlled trial. BMJ Open 2020;10:e034425

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Department of Biostatistics/
Epidemiology and Preventive
Health Sciences
Professor
Yutaka Matsuyama, Ph.D.

Associate Professor
Koji Oba, Ph.D.

Assistant Professor
Yoshinori Takeuchi, D.V.M., Ph.D, M.P.H., 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)

2863) 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 (2credits 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.
From FY2016, the industry, academia, andgovernment-collaborative program “Support Programfor Biostatisticians” was launched by Japan Agency
for Medical Research and Development for“cultivating talent of excellent biostatisticians,
supports the efforts of training them throughcollaboration between graduate schools that conduct
school education, and hospitals that conduct practicaltraining.” (AMED website, July 4, 2017) AMED
selected the University of Tokyo as one of the 2centers for conducting the project (principal
investigator: Professor Matsuyama). Our department
is also officially participating in the program, and will
provide more and more educational/practical supports
to future biostatisticians on the basis of our richexperience in biostatistical education and support invariety of research.

References
1.

2.

Kawahara T, Shinozaki T, Matsuyama Y. Doubly
robust estimator of risk in the presence of
censoring dependent on time-varying covariates:
application to a primary prevention trial forcoronary events with pravastatin. BMC Med Res
Methodol. 2020;20:204.
Yamashita S, Shinozaki T, Murata H, Matsuyama
Y, Babazono T. Panel of novel urine biomarkers
for incident microalbuminuria in people with
type 2 diabetes mellitus. Diabetic Medicine.
2020;37:1910–8.

287

3.

Watanabe Y, Matsuyama Y, Izumi N, Kubo S,
Kokudo N, Sakamoto M, Shiina S, Takayama T,
Nakashima O, Kudo M. Effect of surgical margin
width after R0 resection for intrahepaticcholangiocarcinoma: A nationwide survey of theLiver Cancer Study Group of Japan. Surgery.
2020;167:793–802.
4. Yoshida Y, Kashiwabara K, Hirakawa Y, Tanaka
T, Noso S, Ikegami H, Ohsugi M, Ueki K, Mita T,
Watada H, Koya D, Mise K, Wada J, Shimizu M,
Wada T, Ito Y, Narita I, Kashihara N, Nangaku M,
Matsuyama Y. Conditions, pathogenesis, andprogression of diabetic kidney disease and early
decliner in Japan. BMJ Open Diabetes Res Care.
2020;8:e000902.
5. Usui T, Yoshida Y, Nishi H, Yanagimoto S,
Matsuyama Y, Nangaku M. Diagnostic accuracyof urine dipstick for proteinuria category inJapanese workers. Clin Exp Nephrol. 2020;24:
151–156.
6. Hagiwara Y, Shiroiwa T, Taira N, Kawahara T,
Konomura K, Noto S, Fukuda T, Shimozuma K.
Mapping EORTC QLQ-C30 and FACT-G onto
EQ-5D-5L index for patients with cancer. Health
Qual Life Outcomes. 2020;18:306.
7. Takeuchi Y, Kashiwabara K, Hosoi H, Imai H,
Matsuyama Y. Longitudinal effects of anationwide lifestyle intervention program on
cardiometabolic outcomes in Japan: An
observational cohort study. Prev Med. 2020;141:
106301.
8. 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.
9. Hagiwara Y, Kawahara T, Shiroiwa T. What is avalid mapping algorithm in cost-utility analyses?
A response from a missing data perspective.
Value Health. 2020;23:1218–1224.
10. Satake H, Kato T, Oba K, Kotaka M, Kagawa Y,
Yasui H, Nakamura M, Watanabe T, Matsumoto T,
Kii A, Terazawa T, Makiyama A, Takano N,
Yokota M, Okita Y, Matoba K, Hasegawa H,
Tsuji A, Komatsu Y, Yoshino T, Yamazaki K,
Mishima H, Oki E, Nagata N, Sakamoto J. Phase

11.

12.

13.

14.

15.

16.

Ib/II Study of Biweekly TAS-102 in Combination
with Bevacizumab for Patients with Metastatic
Colorectal Cancer Refractory to Standard
Therapies (BiTS study). Oncologist. 2020;25:
e1855–e1863..
Miyasato Y, Oba K, Yasuno S, Matsuyama Y,
Masuda I. Associations between visceral obesity
and renal impairment in health checkup
participants: a retrospective cohort study. Clin
Exp Nephrol. 2020;24:935–945.
Kumazu Y, Oba K, Hayashi T, Yamada T, Hara K,
Osakabe H, Shimoda Y, Nakazono M, Nagasawa
S, Rino Y, Masuda M, Ogata T, Yoshikawa T,
Oshima T. Relationship Between the Waiting
Times for Surgery and Survival in Patients with
Gastric Cancer. World J Surg. 2020;44:1209–
1215.
Fujieda Y, Maeda H, Oba K, Okamoto K,
Fukudome I, Shiga M, Kawanishi Y, Akimori T,
Kuroiwa H, Nishimoto H, Namikawa T,
Murakami I, Kobayashi M, Hanazaki K. Lymphnode retrieval after colorectal cancer surgery: acomparative study of the efficacy between theconventional manual method and a new fat
dissolution method. Surg Today. 2020;50:726–
733..
Suzuki S, Akiyoshi T, Oba K, Otsuka F,
Tominaga T, Nagasaki T, Fukunaga Y, Ueno M.
Comprehensive Comparative Analysis ofPrognostic Value of Systemic Inflammatory
Biomarkers for Patients with Stage II/III Colon
Cancer. Ann Surg Oncol. 2020;27:844–852.
Ikeda T, Yamauchi Y, Uchida K, Oba K, Nagase T,
Yamada Y. Reference value for expiratory time
constant calculated from the maximal expiratory
flow-volume curve. BMC Pulm Med. 2019;19:
208.
Tanaka Y, Oba K, Koike T, Miyasaka N, Mimori
T, Takeuchi T, Hirata S, Tanaka E, Yasuoka H,
Kaneko Y, Murakami K, Koga T, Nakano K,
Amano K, Ushio K, Atumi T, Inoo M, Hatta K,
Mizuki S, Nagaoka S, Tsunoda S, Dobashi S,
Horie N, Sato N. Sustained discontinuation of
infliximab with a raising-dose strategy after
obtaining remission in patients with rheumatoid
arthritis: the RRRR study, a randomized
controlled trial. Ann Rheum Dis 2020;79:94–102.

288

17. Hagiwara Y, Shinozaki T, Matsuyama Y.
G‐estimation of structural nested restricted
mean time lost models to estimate effects oftime‐varying treatments on a failure timeoutcome. Biometrics. 2020;76:799–810.
(Only main publications)289

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
Reina Hayashi, M.D., Ph.D.

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

290

professor, an associate professor, a lecturer, anassociate, and a technical specialist. All five members,
four project researchers, eleven lecturers from otherorganizations, and five visiting researchers contributeto department teaching and research activities.
We have six department graduate students. Threeof them are doctoral program students.
In this annual report, the organization andteaching activities are reviewed followed by an
explanation of research activities.

Teaching 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.
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)
Graduate Courses
1) Biomedical Ethics I
2) Biomedical Ethics II

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.

Research activities
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/).
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
6) Publication of a medical ethics case book forJapan7) Comparative study of clinical ethics in the Asian
region2918) Historical analyses for the term “bioethics” in theJapanese context

References
1.

2.

3.

4.

5.

6.

7.

Endo Y, Miyasho T, Imahase H, Kawamura Y,
Sakamoto Y, Yamashita K. Use of perfusionindex to detect hemodynamic changes inendotoxemic pigs. J Vet Emerg Crit Care. 2020
Sep;30(5):534-542. doi: 10.1111/vec.12985.
Ino H, Nakazawa E, Akabayashi A. Drug
Repurposing for COVID-19: Ethical Considerations and Roadmaps. Camb Q Healthc Ethics.
2021 Jan;30(1):51-58.
doi: 10.1017/S0963180120000481. Epub 2020
Jun 5.
Mori T, Mori K, Nakazawa E, Bito S, Takimoto Y,
Akabayashi A. Characterizing patients issued
DNR orders who are ultimately discharged alive:
A retrospective observational study in Japan.
BMC Palliat Care. 2020 Jun 9;19(1):82. doi:
10.1186/s12904-020-00588-z.
Nakazawa E, Akabayashi A. Covid-19, global
ethics, and Jihi: A voice from East Asian
philosophy. Indian J Med Ethics. Published
online first on December 11, 2020. doi:
10.20529/IJME.2020.126
Nakazawa E, Ino H, Akabayashi A. 2020.
Chronology of COVID-19 cases on the Diamond
Princess cruise ship and ethical considerations: areport from Japan. Disaster Med Public HealthPrep. 2020 Aug;14(4):506-513. doi: 10.1017/dmp.
2020.50. Epub 2020 Mar 24.
Takimoto Y. [Mental Capacity of Brain Disease].
Brain Nerve. 2020 Jul;72(7):711-717. Japanese.
doi: 10.11477/mf.1416201588.
Akabayashi A., Bioethics Across the Globe:
Rebirthing Bioethics. Springer Nature Singapore,2020. Akabayashi A, Nakazawa E, Caplan AL.
The Goals of Medicine: Time to Take Another
Look. pp.42-46. Akabayashi A, Nakazawa E, Ino
H, Jecker NS. Lessons Learned from Fukushima:
Thyroid Cancer Screening Preparedness for
Radiation Exposure. pp.61-68. Akabayashi A,
Shimanouchi A, Nakazawa E, Akabayashi A. Do
Professional Athletes Have the Right to Dispute a
Referee’s Judgment? An Ethical Analysis of

Sumo Wrestling in Japan. pp.100-112.

Health Sciences and Nursing
2. Preventive and Administrative Nursing

293

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, MSN., R.N.

Project Assistant Professor
Hiroe Koyanagi, MSN, R.N.

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 Care andNursing 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 through lectures, discussions, and interprofessional 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
profession through a series of lectures from various

294

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 will assessclients’ 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, II (2 credits each)
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.

Advanced Clinical Nursing I (2 credits)
This course offers a critical reading of previous
research theories and discussions of relevant areas.
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 and organizational
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, 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.

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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
examples include organizational learning, intraorganizational communication and roles, diversity
climate in nursing organizations, and personenvironment 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, the functions of hospital
departments, and hospital ward construction.
Nursing Management in the Early Stages of an
Emerging Infectious Disease Pandemic
We conducted an interview survey to identify
nursing management and schemes to secure nursing
staff in the early stage of the COVID-19 pandemic in
infected patient acceptance hospitals, cluster infection
outbreak hospital/welfare facilities, and nonmedical/welfare facilities for mild cases. This study
was supported by a special research grant from the
Health Labor Sciences Research Grant.

References1.

2.

Takemura Y, Watanabe R, Kida R, Kanno Y.
Working conditions of shift-working nurses andconditions that enable them to continue working:An online survey. Journal of the Japan Academy of
Nursing Administration and Policies. 2020 Dec;
24(1):164-174. [in Japanese] doi: 10.19012/janap.
24.1_164
Kai T, Ichikawa N, Takemura Y, Kunie K, Kida R,
Matsuda M, et al. Relationship between support in
the workplace and nurses’ “sense of unintegration

3.

4.

5.

6.

7.

8.

9.

of thoughts” derived from anger toward patients notadhering to nurses’ guidance. Journal of Japan
Academy of Nursing Science. 2020 Jan;40:360368.[in Japanese] doi: 10.5630/jans.40.360
Ichikawa N, Yamamoto‐Mitani N, Takai Y,
Tanaka M, Takemura Y. Understanding andmeasuring nurses’ professionalism: Development
and validation of the Nurses’ Professionalism
Inventory. Journal of Nursing Management. 2020
Oct;28(7):1607-1618. doi: 10.1111/jonm.13116
Komagata M, Takemura Y, Ichikawa N, Takehara
K, Kunie K. Quality of work among part-timenurses and its relationship to job satisfaction andwork values: A cross-sectional study. Nursing and
Health Sciences. 2020 Dec;22(4):1010-1021. doi:
10.1111/NHS.12760
Isobe T, Kunie K, Takemura Y, Takehara K,
Ichikawa N, Ikeda M. Frontline nurse managers’
visions for their units: A qualitative study. Journalof Nursing Management. 2020 Jul;28(5):10531061. doi: 10.1111/jonm.13050
Funakoshi C, Kunie K, Takemura Y, Ichikawa N.
Classifying
NursesBasedon
Hospital
Organizational
ChangeExperience
andInvestigating the Characteristics of such
Classification: A Cluster Analysis Approach.
Journal of the Japan Academy of Nursing
Administration and Policies. 2020 Dec;24(1):94103.[in Japanese] doi: 10.19012/janap.24.1_94
Saiki M, Kunie K, Takemura Y, Takehara K,
Ichikawa N. Relationship between nurses’
perceptions of nursing assistant roles andinformation‐sharing behaviors: A cross-sectional
study. Nursing and Health Sciences. 2020 Sep;
22(3):706-713. doi: 10.1111/nhs.12717
Ishii K, Takemura Y, Ichikawa N, Kunie K, Kida R.
Verification of Reliability and Validity of theJapanese version of the Organizational Learning
Scale. Journal of the Japan Academy of Nursing
Administration and Policies. 2020 Dec;24(1):6371.[in Japanese] doi: 10.19012/janap.24.1_63
Ikeda M, Kanai H, Osaka M, Tamai N, Takemura
Y, Sanada H. Implementing appearance-careresearch for breast cancer patient into routine
clinical practice. Open Journal of Nursing. 2020
Mar 30;10(3):308-319. doi: 10.4236/ojn.2020.
103021

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10. Ozawa M, Takehara K, Takemura Y, Kunie K,
Ichikawa N. Workplace environmental factors
related to the nursing assessment implementation
for cancer patients before beginning outpatientchemotherapy for the first time: Focusing on
psychological and social aspects. Journal of theJapan Academy of Nursing Administration and
Policies. 2020 Dec;24(1):199-211.[in Japanese]doi: 10.19012/janap.24.1_199
11. Takemura Y, Kunie K, Ichikawa N. The effect ofwork environment on burnout among nursing
directors: A cross-sectional study. Journal of
Nursing Management. 2020 Jan;28(1):157-166
12. 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. First published: 29
November 2020. doi: 10.1111/jonm.13218
13. Ishii K, Takemura Y, & Ichikawa, N. Relationships
between the components of nurse managers'
transformational leadership and organizational
learning subprocesses in a hospital ward: A crosssectional study. Journal of Nursing Management.
First published: 31 October 2020. doi:10.1111/
jonm.13203

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Department of Family Nursing
Professor
Kiyoko Kamibeppu, Ph.D., R.N., P.H.N., F.A.A.N.

Lecturer
Iori Sato, Ph.D., R.N., P.H.N.

Assistant Professors
Sachiko Kita, Ph.D., R.N., M.W., P.H.N.
Takafumi Soejima, Ph.D., R.N., P.H.N.

Homepage

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

Introduction and Organization

Research

This department was established in 1992. Four
faculty members currently serve the department: aprofessor, a lecturer, and two assistant professors.
Enrolled at present are 4 doctoral students, 1 master’s
students, and 1 administrative staff.

Our department researches 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. Development of a Pediatric Quality of Life (QOL)
Inventory for children with chronic illness andtheir parents;
2. Lifetime support for survivors of childhood
cancer and their families: treatment and care in
their late effects, special needs education, andworking;
3. International collaborative research about
posttraumatic growth (PTG);
4. Transitional care for children, adolescent andyoung adult with childhood-onset chronic
diseases;
5. Research about prevention of deterioration of
postpartum depression, child abuse and neglect;
6. International collaborative research about family
polyvictimization;
7. Caregiving burden and utilization behavior ofsocial services in families of children withmedical complexity;
8. Livelihood supports for families of elderly people

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)298with dementia;
9. Support for bereavement from family members.
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.
Additionally, the department members are conducting
and publishing research that explore the various
experiences of children with cancer and their families
who were extensively affected by the Tohoku
Earthquake of 2011.
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 an evidence of its effectiveness. We
collaborate with the evidence-based clinic, with regard
to research, practice and graduate education.
In addition to our research activities, we holdbimonthly Family Care Group Supervisions, whereby

deeper understanding of family nursing practices is
promoted. In this we aim to enhance the quality ofclinical practice and research in family nursing andcontribute to the establishment of the science offamily nursing.

Publications
1. Morishita-Kawahara M, Kawahara T, Kamibeppu
K. Relation between Family Functioning and
Quality of Life among Family Caregivers ofPatients with Terminal Cancer Hospitalized in
General Wards. Open Journal of Nursing. 2020
Dec; 10: 1233-1240.
2. Morishita-Kawahara M, Kamibeppu K. Whatcontributes to satisfaction with care for family
caregivers of terminal cancer patients admitted togeneral wards? A qualitative study. Open Journalof Nursing. 2020 Nov; 10: 1081-1094.
3. Ikeda M, Tamai N, Kanai H, Osaka M, Kondo K,
Yamazaki T, Sanada H, Kamibeppu K. Effects of
the appearance care program for breast cancer
patients receiving chemotherapy: A Mixed method
study. Cancer Reports. 2020 Jun; 3(3): e1242.
4. Sato I, Soejima T, Ishida Y, Maeda M, Koh K,
Kamibeppu K. Simple change in logistic
procedure improves response rate to QOL
assessment: A report from the Japan children’s
cancer group. Journal of Patient-Reported
Outcomes. 2020 Jun; 4: 48.
5. Sato I, Sakka M, Soejima T, Kita S, Kamibeppu K.
Randomized comparative study of child andcaregiver responses to three software functions
added to the Japanese version of the electronic
Pediatric Quality of Life Inventory (ePedsQL)
questionnaire. Journal of Patient-Reported
Outcomes. 2020 Jun; 4: 49.
6. Ikeda M, Sato I, Soejima T, Setoyama A,
Kobayashi K, Fukuzawa R, Kamibeppu K.
Parents’ perception and judgment formation
process of their infants’ quality of life. Open
Journal of Nursing. 2020 Dec; 10: 1219-1232.
7. Tanaka S, Sato I, Takahashi M, Armstrong TS,
Cleeland CS, Mendoza TR, Mukasa A,
Takayanagi S, Narita Y, Kamibeppu K, Saito N.
Validation study of the Japanese version of M.D.
Anderson Symptom Inventory Brain Tumor

299

Module (MDASI-BT). Japanese Journal of
Clinical Oncology. 2020 Jul; 50(7): 787–793.
8. Kita S, Haruna M, Matsuzaki M, Kamibeppu K.
Does antenatal social support affect therelationships between intimate partner violence
during pregnancy and perinatal mental health?
Violence Against Women. 2020 May; 26(6-7):
573-589.
9. Kita S, Tobe H, Umeshita K, Hayashi M,
Kamibeppu K. Impact of Intimate Partner
Violence and Childhood Maltreatment onMaternal-Infant Maltreatment: A Longitudinal
Study. Japan Journal of Nursing Sciences. 2020
Jul; e12373.
10. 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. 2020 Jun.
11. Kita S, Hayashi M, Umeshita K, Tobe H, Uehara
N, Matsunaga M, Kamibeppu K. Intimate partner
violence and maternal child abuse: The mediating
effects of mothers’ postnatal depression, motherto-infant bonding failure, and hostile attributions
to children’s behaviors. Psychology of Violence,2020 May; 10(3), 279–289.
12. Soejima T, Sato I, Takita J, Koh K, Kaneko T,
Inada H, Ozono S, Kamibeppu K. Impacts ofphysical late effects on presenteeism in childhood
cancer survivors. Pediatrics International. 2020
Nov; 62:1241-1249.
13. Tobe H*, Kita S*, Hayashi M, Umeshita K,
Kamibeppu K. Mediating effect of resilienceduring pregnancy on the association between
maternal trait anger and postnatal depression.
Comprehensive Psychiatry. 2020 Jun; 102:
152190. * Equally contribution
14. Suzuki S*, Kita S*, Nakamura M, Kikuchi R,
Sato I, Iwasaki M, Otomo E, Sekiguchi H, Hirata
Y, Sato A, Sugiyama M, Kamibeppu K. Nurses’
perceptions regarding transitional care foradolescents and young adults with childhoodonset chronic diseases. Japan Journal of Nursing
Sciences, 2020 Jul; 17(3): e12323. * Equallycontribution
15. Suetsugu Y, Haruna M, Kamibeppu K. A

longitudinal study of bonding failure related to
aspects of traumatic birth experience among
Japanese mothers. BMC Pregnancy and Childbirth.
2020 Jul; 20: 434.
16. Nakajima S, Sato I, Soejima T, Koh K, Kato M,
Okamoto Y, Imamura T, Maeda M, Ishida Y,
Manabe A, Kamibeppu K. Comparison of childand family reports of health-related quality of life
in pediatric acute lymphoblastic leukemia patients
after induction therapy. BMC Pediatrics. 2020
Aug; 20: 390.

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Department ofCommunity Health Nursing /Public Health Nursing
Professor (concurrent)
Noriko Yamamoto-Mitani, Ph.D., R.N., P.H.N.

Lecturer
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.

Project Assistant Professor
Yuka Sumikawa, Ph. Ph.D., R.N., P.H.N.

Homepage

http://park.itc.u-tokyo.ac.jp/chn/

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 oflectures/practical training as a part of the education
program for 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 HealthNursing Practice I, Public Health Nursing Practice II.
There are 12 credits of lectures and five credits ofpractical training.
And we also assist undergraduate/graduate students
with their thesis.

301

Research activities
Our research focuses on the development andevaluation of health care programs, establishment ofcommunity 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.

elderly 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.
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 the

3.

4.

5.

Honda C, Yamana H, Matsui H, Nagata S,
Yasunaga H, Naruse T. Age in months and birthorder in infant nonfatal injuries: A retrospective
cohort study. Public Health in Practice. 2020,
100005.
Yoshioka-Maeda K, Iwasaki-Motegi R, Honda
C. Preventing the dysfunction of public healthcenters responding to COVID‐19 by focusing on
public health nurses in Japan. Journal Of
Advanced Nursing. 2020, DOI: 10.1111/jan.
14409.
Iwasaki‐Motegi R, Naruse T. Current topics
related to the professional behaviour of publichealth nurses in Japan. Journal of Advanced
Nursing. 2020, DOI: 10.1111/jan.14324.
Honda C, Yoshioka-Maeda K, Iwasaki-Motegi
R. Child abuse and neglect prevention by publichealth nurses during the COVID-19 pandemic in
Japan. Journal of advanced nursing. 2020, DOI:
10.1111/jan.14526.
Matsumoto H, Igarashi A, Suzuki M,
Yamamoto-Mitani N. Dementia education is thefirst step for cooperation: An observational studyof the cooperation between convenience storesand community general support centers.
Geriatrics & gerontology international (2020)
DOI: 10.1111/ggi.14000.

302

6.

7.

8.

9.

10.

11.

12.

13.

Yoshioka-Maeda K, Honda C, Iwasaki-Motegi
R. Preparing for Complex Emergencies While
Combating COVID-19: The Role of Public
Health Nurses in Japan. Asia Pacific Journal of
Public Health. 2020, 32(8), p, 489-490. 3
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.
Naruse T, G Tuckett A, Matsumoto H,
Yamamoto-Mitani N. Measurement Development
for Japanese Clients’ Experiences During Adult
Day Care Service Use (The J-AdaCa Tool).
Healthcare,. 2020, 8(4), 363.
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.
Yoshioka-Maeda K, Iwasaki-Motegi R, Honda
C. Resolution for the severe shortage of nurses
for combating COVID-19 in Japan. Asia Pacific
Journal of Public Health. 2020, JNA Activities (inpress).
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.
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.
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

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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
Maiko-Noguchi Watanabe, Ph.D., R.N.
Mariko Sakka, 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 in order to understand experiences ofindividual patients and/or nurses and to conceptualize

305

and theorize them.
1) Quality assurance and improvement for long-termcare for the elderly
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.
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.
3) Establishment of support system for the elderly in
the integrated community care
In the Japanese aged society, it is an urgent problem
to establish a local structure supporting the life of theelderly 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 examined what
combination of services the elderly persons are using
and what its related factors are. We will 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 an action research to promote collaboration
with the convenience stores in the elderly support incommunity.
4) End-of-life care decision making in communitydwelling elderly people
We conduct a 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
society, need to promote Advanced Care Planning, andhas been designed institutional plan. By conducting
collaborate research in the three countries, we will
clarify common issues in the Asian region andproblems inherent to Japan and propose concrete
policies that the administration should do. Hence, we
aim to contribute to promotion of Advanced Care
Planning considering cultural factor.
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 will develop the program for employedfamily caregivers to prevent leaving their job becauseof care giving for their parents with dementia, andenhance their work-life balance.
6) 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
have conducted a cohort study to examine the factors

306

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.

Publications
1.

2.

3.

4.

5.

6.

Honda C, Naruse T, Yamamoto-Mitani N.
Pregnant women's intentions to implement safety
practices for preventing infant injury: A
cross-sectional study. Int J Environ Res Public
Health. 2020 Dec 22;18(1):24.
Yamamoto-Mitani N, Saito Y, Futami A, Takaoka
M, Igarashi A. Staff nurses' evaluation of care
process quality and patient outcomes as quality
indicators in long-term care hospitals: A
cross-sectional questionnaire survey. Int J Older
People Nurs. 2020 Dec;15(4):e12334.
Inagaki A, Noguchi-Watanabe M, Sakka M,
Yamamoto-Mitani
N.
Homecarenurses’community involvement activities and preference
regarding the place for end-of-life period among
single older adults: A cross-sectional study inJapan. Health Soc Care Community. 2020 Dec
14.
Sakka M, Kita D, Sato I, Soejima T, Eguchi H,
TokitaM, et al. Reliability and validity of theJapanese version of the Caregiving Interface
Work Scale in employed Japanese family
caregivers. Geriatr Gerontol Int. 2020 Dec 14.
Igarashi A, Eltaybani S, Takaoka M, NoguchiWatanabe M, Yamamoto-Mitani N. Quality
assurance in long-term care and development ofquality indicators in Japan. Gerontol Geriatr Med.
2020 Nov 27.
Noguchi-Watanabe M, Yamamoto-Mitani N,
Nagami Y, Eltaybani S, Inagaki A, Taniguchi Y.
Homecare nurses’ length of conversation and

7.

8.

9.

10.

11.

12.

13.

14.

15.

intention to remain at the workplace: A multilevel
analysis. J Nurs Manag. 2020 Nov 11.
Kodama Y, Fukahori H, Tse M, YamamotoMitani N. Pain prevalence, pain management,
and the need for pain education in healthcare
undergraduates. Pain Manag Nurs. 2020 Oct;22(3):408-413.
Ichikawa N, Yamamoto-Mitani N, Takai Y,
Tanaka M, Takemura Y. Understanding andmeasuring nurses' professionalism: Development
and validation of the Nurses' Professionalism
Inventory. J Nurs Manag. 2020 Oct;28(7):16071618.
Matsumoto H, Igarashi A, Suzuki M,
Yamamoto-Mitani N. Dementia education is thefirst step for cooperation: An observational studyof the cooperation between convenience storesand community general support centers. Geriatr
Gerontol Int．2020 Oct;20(10):956-960.
Anezaki S, Sakka M, Noguchi-Watanabe M,
Igarashi A, Inagaki A, Tsuno Y, et al. Association
between participation in hospital-led community
activities and sense of security in continued
community living among older adults in rural
district of Japan: A cross-sectional study. Health
Soc Care Community. 2020 Oct 21.
Eltaybani S, Igarashi A, Yamamoto-Mitani N.
Palliative care in adult intensive care units: A
nationwide survey. Nurs crit care. 2020 Oct 26.
Naruse T, Tuckett AG, Matsumoto H,
Yamamoto-Mitani N. Measurement development
for Japanese Clients' Experiences during Adult
Day Care Service Use (The J-AdaCa Tool).
Healthcare (Basel). 2020 Sep 24;8(4):363.
Eltaybani S, Igarashi A, Yamamoto-Mitani N.
Assessing the palliative and end-of-life careeducation-practice-competence triad in intensive
care units: Content validity, feasibility, andreliability of a new tool. J Palliat Med. 2020 Aug
11;825859720948972.
Kibi Y, Mikoshiba N, Igarashi A, Sumitani M,
Yamamoto-Mitani N. Development of astylebook for women with cancer-related lymphedema troubled about clothing. Lymphoedema
Research and Practice. 2020;8(1): 27-39.
Eltaybani S, Igarashi A, Yamamoto-Mitani N.
Palliative and end-of-life care in Egypt: overview

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16.

17.

18.

19.

20.

21.

22.

and recommendations for improvement. Int J
Palliat Nurs. 2020;26(6):284-291.
Numata H, Noguchi-Watanabe M, Mukasa A,
Tanaka S, Takayanagi S, Saito N, et al. Medical
care-related decisions among patients diagnosed
with early stage malignant brain tumor: A
qualitative study. Glob Qual Nurs Res. 2020;7:
1-12.
McGilton K, Escrig-Pinol A, Gordon A, H. Chu
C, Zuniga F, Gea Sanchez M, et al. Uncovering
the devaluation of nursing home staff during
COVID-19: Are we fuelling the next health carecrisis? JAMDA. 2020;962-965.
Sato I, Sakka M, Soejima T, Kita S, Kamibeppu
K. Randomized comparative study of child andcaregiver responses to three software functions
added to the Japanese version of the electronic
Pediatric Quality of Life Inventory (ePedsQL)
questionnaire. Journal of Patient-Reported
Outcomes. 2020 Jun 23;4(1):49.
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. Appl Res Qual Life. 2020
Jun.
Sari DW, Igarashi A, Takaoka M, Yamahana R,
Noguchi-Watanabe M, Teramoto C, et al. Virtual
reality program to develop dementia-friendly
communities in Japan. Australas J Ageing. 2020
Sep;39(3):e352-e359.
Molassiotis A, Wang T, Hoang HTX, Tan JY,
Yamamoto-Mitani N, Cheng KF, et al. Doctoral
nursing education in east and Southeast Asia:
characteristics of the programs and students'
experiences of and satisfaction with their studies.
BMC Med Educ. 2020 May 8;20(1):143.
Eltaybani S, Abdelwareth M, Abou‐Zeid NA,
Ahmed N. Recommendations to prevent nursing
errors: Content analysis of semi‐structured
interviews with intensive care unit nurses in adeveloping country. J Nurs Manag. 2020 Apr;
28(3):690-698.

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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, 19
graduate students (12 in master’s courses, 7 indoctoral courses), a project researcher, and 5 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 cover the field of maternal andchild health emphasizing on the promotion of
women’s health and quality of life at every stage oflife.
We conduct the following research projects:
1. Creating evidence of health guidance during
pregnancy
1) Healthy lifestyle: adequate maternal nutrition,

309

weight management, exercise, physical activity,
sleep, and mental healthThis study examines the maternal body composition, lipid metabolic biomarkers, and nutritional intake to optimize weight management and ahealthy lifestyle during pregnancy to prevent
low birth weight. This study also investigates theeffect of physical activity on the mental andphysical health of pregnant women. It aims toprovide basic data for appropriate healthguidance during pregnancy.
2. Development of a support system for reliablechildbirth1) Midwifery care for positive childbirth experiences
This study evaluates care in-hospital midwifeled system and in-hospital midwifery clinic withthe aim of building midwifery care for a positive
birth experience.
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 therelationship between birth canal and delivery
mode using 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 Japan, Australia, and New
ZealandThis study is collaboration between the
University of the Sunshine Coast in Australia
and the Waikato Institute of Technology in New
Zealand to create and evaluate midwifery educational content using virtual reality technology.

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 the pelvic floor muscle training
program.
2) Risk factors of mastitis and breast abscessamong postpartum womenThis study uses a health insurance claims database to investigate the prevalence of mastitis andbreast abscess among postpartum women andfactors associated with their surgical treatment.
4. Development of a support system for women’s
health1) Support for health of working mothers andwomenThis study investigates the cadences of daily lifeand conditions of sleep such as excessive
daytime sleepiness and other related factors
among working mothers. This study also explores factors associated with work engagement
among working pregnant women.
2) Preconception careThis study uses health check-up database toinvestigate the prevalence of anemia among
women of reproductive age and factors related
to the condition.
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 moisturizing
skin care improving skin barrier functions
among healthy neonates. In addition, we investigate the relationship between newborns’ skinproblems and allergies (i.e., food allergy or
atopic dermatitis).
2) Effect of skin care 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

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as a skin condition.

Publications
1.

2.

3.

4.

5.

6.

7.

8.

Haruna M, Nishi D. Perinatal mental health and
COVID-19 in Japan. Psychiatry and clinicalneurosciences. 2020; 74(9): 502–503.
Yonezawa K, Haruna M, Kojima, R. Validity of
Infant Face Skin Assessment by Parents at Home.
Asian / Pacific Island Nursing Journal. 2020;
4(4): 128–134.
Usui Y, Haruna M, Shimpuku Y. Validity andreliability of the Karitane Parenting Confidence
Scale among Japanese mothers. Nursing &Health Sciences. 2020; 22(2): 205–211.
Hikita N, Haruna M, Matsuzaki M, Sasagawa E,
Murata M, Yura A, Oidovsuren O. Factors
associated with hypertension among men in
Darkhan-Uul Province, Mongolia: A crosssectional study. Asian / Pacific Island Nursing
Journal. 2020; 4(4): 151–158.
Matsubara R, Hikita N, Haruna M, Sasagawa E,
Yonezawa K, Maeda Y, Ikeda Y. Factors
Associated with Time Spent Performing
Housework/Childcare by Fathers of Children
Aged Under 12 Years: A Cross-Sectional Study inJapan. Asian / Pacific Island Nursing Journal,
2020; 5(3): 153–164.
Suetsugu Y, Haruna M, Kamibeppu K. A
longitudinal study of bonding failure related to
aspects of posttraumatic stress symptoms afterchildbirth among Japanese mothers. BMC
pregnancy and childbirth, 2020; 20(1): 434.
Kita S, Haruna M, Matsuzaki M, Kamibeppu K.
Does Antenatal Social Support Affect theRelationships Between Intimate Partner Violence
During Pregnancy And Perinatal Mental Health?.
Violence against women, 2020; 26(6-7): 573–
589.
Yokoyama M, Haruna M, Yonezawa K, Sasagawa
E, Hikita N. A review of the prevalence andfactors associated with the development andprevention of diaper dermatitis in infants. Journalof Japan Academy of Midwifery, 2020; 34(2):194–203. (in Japanese)

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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
Akiko Inagaki, R.N., P.H.N., Ph.D.
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,
9 doctoral course students, 3 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.

312

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; and reducing
the use of seclusion and restraint. We are conducting
studies in collaboration with researchers in otherinstitutions 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.

Kotake R, Kanehara A, Miyamoto Y, Kumakura
Y, Sawada U, Takano A, et al. Reliability andvalidity of the Japanese version of the INSPIRE
measure of staff support for personal recovery incommunity mental health service users in Japan.
BMC Psychiatry. 2020;20(1):51. DOI: 10.1186/
s12888-020-2467-y.
Iida M, Watanabe K, Ando E, Tsuno K, Inoue A,
Kurioka S, Kawakami N. The Association
Between Unit-Level Workplace Social Capitaland Intention to Leave Among Employees in
Health Care Settings: A Cross-Sectional
Multilevel Study. Journal of Occupational andEnvironmental Medicine. 2020;62(5): e186-e191.
DOI: 10.1097/JOM.0000000000001847.
Asaoka H, Koido Y, Kawashima Y, Ikeda M,
Miyamoto Y, Nishi D. Post-traumatic stresssymptoms among medical rescue workers
exposed to COVID-19 in Japan. Psychiatry andclinical neurosciences. 2020;74(9):503-505. DOI:
10.1111/pcn.13092.
Shiozawa T, Yamaguchi S, Matsunaga A, Sawada
U, Fujii C. Development of the Interpersonal
Processes of Care Survey-Japanese version.
Neuropsychopharmacology Reports. 2020;40(1):107-112. DOI: 10.1002/npr2.12097.
Yamaguchi S, Shiozawa T, Matsunaga A, Bernick
P, Sawada U, Taneda A, Osumi T, Fujii C.
Development and psychometric properties of a
new brief scale for subjective personal agency(SPA-5) in people with schizophrenia.
Epidemiology and psychiatric sciences. 2020;
29:e111. DOI: 10.1017/S2045796020000256.
Chiba R, Funakoshi A, Yamazaki Y, Miyamoto Y.
The Benefit Finding Questionnaire (BFQ): Scale
Development, Validation, and Its Psychometric
Properties Among People with Mental Illness.
Healthcare. 2020; 8(3): 303. DOI: 10.3390/
healthcare8030303.
Sawada K, Sakakibara E, Kanehara A, Koike H,
Suga M, Fujieda Y, Miyamoto Y, Fukuda M,
Kasai K. Is Utena's Brief Objective Measures(UBOM) useful in real-world behavioral
assessment of functioning? Validity and utility
testing in patients with schizophrenia. Psychiatry

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8.

9.

10.

11.

12.

13.

14.

and clinical neurosciences. 2020;74(1):40-8.
DOI: 10.1111/pcn.12929.
Takano A, Miyamoto Y, Shinozaki T, Matsumoto
T, Kawakami N. Effect of a web-based relapse
prevention program on abstinence among
Japanese drug users: A pilot randomized
controlled trial. Journal of substance abuse
treatment. 2020; 111: 37-46. DOI: 10.1016/j.jsat.
2019.12.001.
Fukasawa M, Watanabe K, Nishi D, Kawakami N.
Longitudinal association between adolescentwork values and mental health and well-being in
adulthood: A 23-year prospective cohort study.
Scientific reports. 2020;10(1):13547. DOI: 10.
1038/s41598-020-70507-y.
Fukasawa M, Kawakami N, Umeda M, Akiyama
T, Horikoshi N, Yasumura S, Yabe H, Suzuki Y,
and Bromet EJ. Long-lasting effects of distrust in
government and science on mental health eight
years after the Fukushima nuclear power plant
disaster. Social Science & Medicine. 2020;258:
113108. DOI: 10.1016/j.socscimed.2020.113108.
Sasaki N, Imamura K, Kataoka M, Kuroda R,
Tsuno K, Sawada U, Asaoka H, Iida M,
Kawakami N. COVID-19 measurements at theworkplace in various industries and company
sizes: a 2-month follow-up cohort study offull-time employees in Japan. Environmental andOccupational Health Practice. 2021;3(1):20200017. DOI: 10.1539/eohp.2020-0017-OA
Panthee B, Panthee S, Shimazu A, Kawakami N.
Validation of the Nepalese version of Recovery
Experience Questionnaire. Heliyon. 2020;6(4):e03645. DOI: 10.1016/j.heliyon.2020.e03645.
Tran TTT, Watanabe K, Imamura K, Nguyen HT,
Sasaki N, Kuribayashi K, Sakuraya A, Nguyen
NT, Bui TM, Nguyen QT, Truong TQ, Nguyen
GTH, Minas H, Tsustumi A, Shimazu A,
Kawakami N. Reliability and validity of theVietnamese version of the 9-item Utrecht WorkEngagement Scale. Journal of Occupational
Health. 2020; 62(1):e12157. DOI: 10.1002/13489585.12157.
Komase Y, Watanabe K, Sasaki N, Kawakami N.
Reliability and validity of the Japanese version of
the Gratitude at Work Scale (GAWS). Journal of

15.

16.

17.

18.

19.

20.

Occupational Health. 2020;62(1):e12185. DOI:
10.1002/1348-9585.12185.
Kawakami N, Fukasawa M, Sakata K, Suzuki R,
Tomita H, Nemoto H, Yasumura S, Yabe H,
Horikoshi N, Umeda M, Suzuki Y, Shimoda H,
Tachimori H, Takeshima T, Bromet EJ. Onset andremission of common mental disorders among
adults living in temporary housing for three years
after the triple disaster in Northeast Japan:
comparisons with the general population. BMC
Public Health. 2020;20(1) :1271 DOI: 10.1186/
s12889-020-09378-x.
Kawakami N, Inoue A, Tsuchiya M, Watanabe K,
Imamura K, Iida M, Nishi D. Construct validity
and test-retest reliability of the World Mental
Health Japan version of the World HealthOrganization Health and Work Performance
Questionnaire Short Version: a preliminary study.
Industrial Health. 2020;58(4):375-87. DOI: 10.
2486/indhealth.2019-0090.
Kawakami N, Tran TTT, Watanabe K, Imamura
K, Nguyen HT, Sasaki N, Kuribayashi K,
Sakuraya A, Nguyen QT, Nguyen NT, Bui TM,
Nguyen GTH, Minas H, Tsutsumi A. Internalconsistency reliability, construct validity, anditem response characteristics of the Kessler 6
scale among hospital nurses in Vietnam. Plos One.
2020;15(5):e0233119. DOI: 10.1371/journal.pone.
0233119.
Kawakami N, Yasuma N, Watanabe K, Ishikawa
H, Tachimori H, Takeshima T, Umeda M,
Shimoda H, Nishi D. Association of response rate
and prevalence estimates of common mental
disorders across 129 areas in a nationally
representative survey of adults in Japan. Social
Psychiatry and Psychiatric Epidemiology. 2020;55(10):1373-82. DOI: 10.1007/s00127-02001847-3.
Kawakami N, Watanabe K, Nishi D, Takagi D,
Hashimoto H, Tanaka SC. Time preference andpersonal value: a population-based crosssectional study in Japan. BMC Psychology. 2020;8(1):85. DOI: 10.1186/s40359-020-00458-6.
Fukasawa M, Kawakami N, Umeda M, Akiyama
T, Horikoshi N, Yasumura S, Yabe H, Suzuki Y,
and Bromet EJ. Distrust in government and its
relationship with mental health after the

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21.

22.

23.

24.

25.

26.

27.

Fukushima nuclear power plant accident.
International Journal of Social Psychiatry. 2020;
20764020968129. DOI: 10.1177/0020764020968
129.
Yasuma N, Sato S, Yamaguchi S, Matsunaga A,
Shiozawa T, Tachimori H, Watanabe K, Imamura
K, Nishi D, Fujii C, Kawakami N. Effects ofbrief family psychoeducation for caregivers ofpeople with schizophrenia in Japan provided byvisiting nurses: protocol for a cluster randomised
controlled trial. BMJ open. 2020;10(4):e034425.
Sasaki N, Watanabe K, Kawakami N. Personalvalues in adolescence and their associations withmetabolic biomarkers in adulthood: a Japanese
population-based
study.
BioPsychoSocial
medicine. 2020;14:26. DOI: 10.1186/s13030020-00197-5.
Kawakami N, Sasaki N, Kurosa K, Tsuno K,
Imamura K. Downloading a government-issued
COVID-19 contact tracing app may improve
psychological distress in the outbreak among
employed adults: a prospective study. JMIR
Mental Health (forthcoming). DOI:10.2196/
23699.
Abbafati C, Abbas KM, Abbasi M, Abbasifard M,
Abbasi-Kangevari M, Abbastabar H, Abd-Allah F,
Abdelalim A, Abdollahi M, Abdollahpour I,
Abedi A, Abedi P, Abegaz KH, Abolhassani H,
Abosetugn AE, Aboyans V, Abrams EM, Abreu
LG, Abrigo MRM, Abu Haimed AK, et al. Fiveinsights from the Global Burden of Disease Study
2019. Lancet. 2020;396(10258):1135-59. DOI:
10.1016/S0140-6736(20)31404-5.
Sasaki N, Watanabe K, Imamura K, Nishi D,
Karasawa M, Kan C, Ryff CD, Kawakami N.
Japanese version of the 42-item psychologicalwell-being scale (PWBS-42): a validation study.
BMC Psychology. 8(1):75, 2020. DOI: 10.1186/
s40359-020-00441-1.
Obikane E, Watanabe K, Nishi D, Kawakami N.
Association between personal values inadolescence and impaired bonding relationshipwith children. BMC Psychology. 2020;8(1):98.
DOI: 10.1186/s40359-020-00463-9.
Yasuma N, Watanabe K, Nishi D, Kawakami N.
Personal values in adolescence and sense ofcoherence in adulthood: A cross‐sectional study

based on a retrospective recall. Neuropsychopharmacology Reports. 2020; 40(3):262-7. DOI:
10.1002/npr2.12111.
28. Obikane E, Yamana H, Yasunaga H, Kawakami N.
Cumulative visits for care of minor injuries areassociated with traumatic brain injury in young
children. Acta paediatrica. 2020;109(12):2775-82.
DOI: 10.1111/apa.15315.

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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.

Associate
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 the establishmentof the Department of Wound Care Management in April
2006. We have been promoting the education ofundergraduate and graduate students, clinical activities
in hospitals relating to pressure injuries and diabetic
foot, and research activities on the topics ofgerontological nursing, wound care management, andnursing science and engineering.
Our department has recently established several
departments: Department of Life Support Technology(Molten), Department of Advanced Nursing
Technology, Department of Skincare Science, andDepartment of Imaging Nursing Science. We have beenpromoting 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 and research
involving the clinical division, the nursing department

at the University of Tokyo Hospital, and the Divisionof Health Sciences and Nursing at the Graduate Schoolof Medicine. Through this program, nurses canscientifically study the subject of nursing, including
research in epidemiological surveys and molecularand gene-level topics. Furthermore, the technology andmedical equipment developed by companies can beevaluated in the hospital, offering new nursing
technologies suitable for needs in clinical sites.
In April 2017, the Global Nursing Research Center(GNRC) was established with the aim to create a transdisciplinary research and educational environment that
fosters young researchers in nursing science in order topromote 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
associates, a project research associate, a project
academic support staff member, three part-time
lecturers for undergraduate courses, and seven part-316

time lecturers for graduate courses. The student bodyconsists of nine doctoral course students, sevenmaster’s course students, and two undergraduate
students. Our mission statement is “We wish to createa society that respects the beauty of aging andrecognizes it as to be a joyful process in life.”e) 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

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 2020 curriculum included:a) Introduction to anatomical pathologyb) Case studiesc) Introduction to anatomicopathological researchd) Approaches to anatomical pathologye) Anatomy using ultrasound equipment

1. Undergraduate course
For undergraduate education, our department takes partin lectures of Health Support Practice, Overview ofClinical 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 2020, 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 themesin the 2020 session included:a) Introduction to surgical treatmentb) Introduction to radiologyc) Surgical anesthesiad) Perioperative management

4) 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 ofgerontological nursing; and to promote anunderstanding of the ailments and conditions required
to provide proper care to the elderly. The main themes
covered in the 2020 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) Development of nursing skills for realization of
infusion therapy without patiencem) Relationship-building and communication skills
with the elderly
A portion of the above lectures was provided through317

cooperation from the Department of Geriatric Medicine
and other departments at The University of Tokyo
Hospital.

biology, engineering, and clinical nursing research.
Recent research papers were selected from these threefields and critically evaluated.

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: clinical observation, explorationof the mechanisms underlying the patient's symptoms,
development of objective measurement methods, andthe development of devices and systems forintervention and the clinical evaluation. This series oflectures is to learn about cutting-edge research, and tounderstand the linkage between research and clinicalactivities.

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 thiscourse was to understand and learn scientific ways ofthinking about gerontological considerations of the
future Japanese community. The main titles in 2020
were as follows:a) Dysphagiab) Nutrition management under invasive conditions
and nutrition therapy for CKD patientsc) End-of-Life care for the elderly: creating aprosperous last yearsd) How do we tackle aging and skin health?
e) Can the human body regenerate?
f) Considering the role of peri-anesthesia nurses fromperioperative nursing researchg) COVID-19 based on skin symptoms, disease
treatment based on COVID-19, and how to travel
during a COVID-19 epidemic

6) Clinical Practicum in Gerontological Nursing (A1in 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 2020, the practice was conducted online andconsisted mainly of online interviews and activities
with senior volunteers, case scenario exercises, andlectures on multidisciplinary cooperation in long-termcare nursing homes.
7) Bachelor’s theses
The following research themes were submitted in 2020:
 “Development of an AI-based fecal retention
assessment method for rectal echo videos taken byhome care nurses ” (in Japanese) “Development of a simple quantitative applicationof biofilm for use in pressure ulcer assessment” (inJapanese)
2. Graduate course
1) Gerontological Nursing I (S1; 2 credits)
The main theme of Gerontological Nursing I in 2020
was to understand the latest research related to the careof elderly persons and to discuss future perspectives ingerontological nursing from three viewpoints: basic

3) Wound Care Management I (S2; 2 credits)
The main purpose of Wound Care Management I in
2020 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 skin; wound healingb) Basics of pressure ulcer, nursing efforts regarding
wound carec) Prediction and prevention of woundsd) Assessment of woundse) Treatment and care of woundsf) Institutions and policies related to wound care andmanagement
4) Wound Care Management II (A2; 2 credits)
The main theme of Wound Care Management II in 2020
was to obtain deeper insight in our own researchknowledge through lectures and discussion by318

specialists from various basic and advanced research
fields in the Division of Care Innovation in GNRC. The
topics were as follows:5) Master’s theses
The following research themes were submitted in 2020:
 “Identification of microRNAs responsive to shareloading in rat skin”
 “Factors associated with the local increase of skintemperature, 'hotspots', of callus in diabetic foot: A
cross-sectional study”
 “Changes in the subcutaneous tissue and bloodvessel of peripheral intravenous catheter placementsites in hematology and oncology: A secondary
analysis using ultrasonographic images”
 “Standardization of a standing-position bladderobservation technique and bladder urine volume
estimation formula using ultrasonography”
6) Doctoral theses
The following research themes were submitted in 2020:
 “Development of a non-invasive urine volume
sensor by electrical impedance measurement”
 “Development of the measurement of taurine
concentration by the skin blotting: A non-invasive
identifying method for chronic dehydration ofvulnerable older people in home care setting”

Research activities
1. Activity policy
Our gerontological nursing research focuses on those
suffering from geriatric syndromes, such as pressure
injuries, incontinence, malnutrition, pain, dysphagia,
osteoporosis and dementia. Our wound caremanagement research focuses on pressure injuries,
diabetic foot ulcers, skin tears, ulcers with peripheral
vascular diseases, and malignant fungating wounds.
The majority of our clinical research has been
conducted at The University of Tokyo Hospital. We
regularly participate in pressure ulcer multidisciplinary team rounds.
In May 2020, we organized the 8th introductory
seminar for bioengineering nursing research as awebinar. In this webinar, a new research framework“Bioengineering Nursing,” consisting of nursing
biology (which investigates, in detail, the mechanismsof a target phenomenon), nursing engineering (whichdevelops technologies for the clarified target), andnursing translational research (which evaluates thetechnologies in the clinical field and further explores
new clinical problems) was introduced to many nursing
researchers and clinical nurses. This seminar had been
held onsite until 2019, but in 2020, due to the spread of
COVID-19, it was held as a webinar for the first time.
Since the first state of emergency was declared from
April 7, 2020, and the opportunities for interpersonal
interactions were expected to be drastically reduced
during the Golden Week holidays in May, the webinar
was held from May 2 to 5, also to provide
psychological and spiritual support to the students andresearchers. While many universities and research
institutes are looking for new ways to hold conferences
and seminars, we held a webinar pioneeringly, and it
was very well received with a total of 1,763 participants.
Regarding international activities, our department
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), and Nottingham Trent
University (UK). Professor Sanada has been working
as a member in both the Continental Board for World
Union of Wound Healing Societies and theInternational Board of Directors for International
Lymphoedema Framework.
2. Research fields and themes in 2020
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 theskin
・Development of a new technique for detecting woundbiofilm・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 and pre-injury

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status using ultrasonography and thermography
・Early detection of complications of peripheral intravascular catheter by thermography
・Development of an insole-type measurement system
for the simultaneous measurement of plantarpressure and shear force during gait・ Development of a fitting device for non-invasive
positive pressure ventilation oral-nasal mask using athree-dimensional solution
・Development of apps using communication robots
for the elderly
・Development of an absorbent pad for the preventionof incontinence-associated dermatitis
・Introduction of text mining to nursing3) Clinical studies:
・Novel assessment technologies for pressure injuries
・Cross-sectional study of diabetic foot (e.g., ulcers,
calluses, fissures, onychomycosis) and its risk
factors
・Cross-sectional study of malignant wounds in breast
cancer patients and their risk factors
・ Survey and international comparison of lymphoedema
・Methods for predicting skin tear development
・Establishment of a novel diagnosis method for silent
aspiration
・ Establishment of a novel assessment method forconstipation using ultrasonography
・Cross-sectional study of the skin of elderly people ina nursing home・Cross-sectional study of the skin of obese people
・Survey of the skin condition of wheelchair basketballathletes・Survey on the relationship between the microbiota inthe bed environment and the development ofpressure ulcer infections
・Survey of the effectiveness of biofilm removal on
wound healing
・Cross-sectional study of catheter failure and its risk
factors
・ Evaluation of the effectiveness of nurses whocompleted advanced nursing procedure training
・Development of a tele-nursing system and clinicalevaluation of its effectiveness
Several awards were given for our research, as follows:・Research Encouragement Award from the 8th Annual

Meeting of the Society for Nursing Science andEngineering (October, 2020)
Noyori S, Nagata T, Noguchi H, Nakagami G,
Kitamura A, Sanada H. Development of an
automatic estimation method for skin-tear severity:
A study of machine learning method (in Japanese).
Proceedings of the 8th Annual Meeting of theJapanese Society for Nursing Science andTechnology. 2020;66.
・Conference Award from the 8th Annual Meeting of
the Society for Nursing Science and Engineering(October, 2020)
Koyano Y, Nakagami G, Tamai N, Sugama J, Sanada
H. Morphological characteristics of skin tears toestimate the etiology-related external forces thatcause skin tears in an elderly population. Journal of
Nursing Science and Engineering. 2020;7:68-78.
・The 16th Health Society Award "Pioneer Category"(Co-sponsored by Japan Nursing Association andJohnson & Johnson Japan Corporate Group)(November 2020)
Sanada H
・Conference Award from JANS40 (December, 2020)
Takahashi T, Murayama R, Nakagami G, Abe M,
Matsumoto M, Sanada H. Development of an AIbased care recommendation system using ultrasoundimages to prevent peripheral intravenous infusion
problems (in Japanese). Proceedings of the 40th
Annual Meeting of the Japanese Society of Nursing
Science. 2020;61.
・International Lymphoedema Framework Japan 10th
Anniversary Award (December 2020)
Sanada H, Nakagami G, Dai M
・JWC WUWHS Gold Award, research on Advances in
infection and Biofilm, from Journal of Wound Care
(February, 2021)
Nakagami G

References
1.

Tanabe H, Takemura N, Terao H, Hagiwara H,
Zushi Y, Murayama R, Abe-Doi M, Sanada H.
Vascular endothelium damage from catheterinduced mechanical stimulation causes catheter
sleeve formation in a rabbit model. The Journal of
Vascular Access. 2020;21(3):379-386.

320

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3.

4.

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Kimura N, Nakagami G, Minematsu T, Sanada H.
Noninvasive detection of local tissue responses topredict pressure ulcer development in mice model.
Journal of Tissue Viability. 2020;29(1):51-57.
Matsumoto M, Yabunaka K, Yoshida M,
Nakagami G, Miura Y, Okawa Y, Sugama J, Okada
S, Ohta H, Sanada H. Improvement ofconstipation symptoms in an older adult patient bydefecation care based on using a hand-held
ultrasound device in home care settings: a casereport. Journal of Wound, Ostomy and Continence
Nursing. 2020;47(1):75-78.
Oe M, Sasaki S, Shimura T, Takaki Y, Sanada H.
Effects of multi-layer silicone foam dressings forthe prevention of pressure ulcers in high-riskpatients: A randomized clinical trial. Advances in
Wound Care. 2020;9(12):649-656.
Matsumoto M, Yoshida M, Yabunaka K,
Nakagami G, Miura Y, Fujimaki S, Okawa Y,
Sugama J, Okada S, Ohta H, Sanada H. Safety andefficacy of a defecation care algorithm based on
ultrasonographic bowel observation in Japanesehome-care settings: a single-case, multiplebaseline study. Geriatrics & Gerontology
International. 2020;20(3):187-194.
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. Japan Journal of Nursing Science. 2020;17(3):e12329.
Yanagi H, Terashi H, Takahashi Y, Okabe K,
Tanaka K, Kimura C, Ohura N, Goto T, Hashimoto
I, Noguchi M, Sasayama J, Shimada K, Sugai A,
Tanba M, Nakayama T, Tsuboi R, Sugama J,
Sanada H. The Japanese registry for surgery ofischial pressure ulcers: STANDARDS-I. Journalof Wound Care. 2020;27(3):174-183.
Takahashi T, Murayama R, Abe-Doi M, MiyaharaKaneko M, Kanno C, Nakamura M, Mizuno M,
Komiyama C, Sanada H. Preventing peripheral
intravenous catheter failure by reducing
mechanical irritation. Scientific Reports. 2020;
10(1550).
Tamai N, Minematsu T, Maeda T, Yabunaka K,
Sanada H. The relationship between skinultrasound images and muscle damage using skin

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blotting in wheelchair basketball athletes. Spinal
Cord. 2020;58:1022-1029.
Nakagami G, Morita K, Matsui H, Yasunaga H,
Fushimi K, Sanada H. Association between
pressure injury status and hospital discharge tohome: A retrospective observational cohort study
using a national inpatient database. Annals ofClinical Epidemiology. 2020;2(2):38-50.
Yoshida M, Kagaya H, Kamakura Y, Miura Y,
Saitoh E, Okawa Y, Sanada H. Safety and theeffectiveness of a new education program fornurses to assess swallowing function using
fiberoptic endoscopic evaluation of swallowing(FEES). Japan Journal of Nursing Science. 2020;17(2):e12313.
Kanno C, Murayama R, Abe-Doi M, Takahashi T,
Shintani Y, Nogami J, Komiyama C, Sanada H.
Developmentofanalgorithm
using
ultrasonography-assisted peripheral intravenous
catheter placement for reducing catheter failure.
Drug Discoveries & Therapeutics. 2020;14(1):2734.
Tanabe H, Kawasaki M, Ueda T, Yokota T, Zushi
Y, Murayama R, Abe-Doi M, Sanada H. A shortbevel needle with a very thin tip improves veinpuncture performance of peripheral intravenous
catheters: an experimental study. The Journal of
Vascular Access. 2020;21(6):969-976.
Ikeda M, Kanai H, Osaka M, Tamai N, Takemura
Y, Sanada H. Implementing appearance-care
program research for breast cancer patients into
routine clinical practice. Open Journal of Nursing.
2020;10:308-319.
Ikeda M, Tamai N, Kanai H, Osaka M, Sanada H,
Kamibeppu K. Effects of the appearance careprogram for breast cancer patients receiving
chemotherapy: A Mixed method study. Cancer
Reports. 2020:3(3):e1242.
Matsumoto M, Tsutaoka T, Nakagami G, Tanaka
S, Yoshida M, Miura Y, Sugama J, Okada S, Ohta
H, Sanada H. Deep learning-based classificationof rectal fecal retention and property using
ultrasound images in older adult patients. Japan
Journal of Nursing Science. 2020;11:e12340.
Koyano Y, Nakagami G, Tamai N, Sugama J,
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forces that cause skin tears in an elderly
population. Journal of Nursing Science andEngineering. 2020;7:68-78.
Tsunemi Y, Nakagami G, Takehara K, Tamai N,
Kitamura A, Mugita Y, Oe M, Kishida M, Sanada
H. Effects of skin care education for care staff atelderly care facilities on skin conditions of theresidents. The Journal of Dermatology. 2020;
47(4): 327-333.
Oe M, Rie YR, Defa A, i, Suriadi, Sakai Y, Imran,Takehara K, Nakagami G, Tamaki T, Sugama J,
Sanada H. Validity of DMIST for monitoringhealing of diabetic foot ulcers. Wound Repair andRegeneration. 2020;28(4):539-546.
Abe-Doi M, Murayama R, Tanabe H, Kamiyama
E, Komiyama C, Matsui Y, Sanada H. Usability
and feasibility test of a new thermosensitive liquid
crystal film for the early detection of extravasationin clinical practice: A pilot study. Journal of
Nursing Science and Engineering. 2020(7):89-98.
Defa A, i, Ogai K, Urai T, Aoki M, Minematsu T,
Okamoto S, Sanada H, Nakatani T, Sugama J.
Development of recurrent pressure ulcers, risk
factors in older patients: a prospective
observational study. Journal of Wound Care. 2020;
29(Sup4):S14-S24.
Tsuruoka K, Oe M, Minematsu T, Tomida S,
Ohashi Y, Mori Y, Nitta S, Qi Q, Abe M, Yamauchi
T, Sanada H. Skin characteristics associated withfoot callus in people with diabetes: A crosssectional study focused on Desmocollin1 incorneocytes. Journal of Tissue Viability. 2020;29(4):291-296.
Mugita Y, Nakagami G, Minematsu T, Kitamura A,
Sanada H. Combination of urease inhibitor andantiseptic inhibits urea decomposition-induced
ammonia production by Proteus mirabilis.
International Wound Journal. 2020;17(6):15581565.
Abe-Doi M, Murayama R, Tanabe H, Komiyama
C, Sanada H. Evaluation of a thermosensitive
liquid crystal film for catheterization site
assessment immediately following chemotherapy
administration: An observational study. European
Journal of Oncology Nursing. 2020;48:101802.
Oe M, Koike N, Tobe H, Ohashi Y, Kuramochi E,
Ikeda M, Suzuki R, Yamauchi T, Murayama R,

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Sanada H. Difficulties of self-monitoring blood
glucose in the aged with diabetes: An analysis
based on observations of self-monitoring blood
glucose. Journal of Nursing Science andEngineering. 2020;7:141-148.
Kunimitsu M, Nakagami G, Kitamura A,
Minematsu T, Koudounas S, Ogai K, Sugama J,
Takada C, Sanada H. Temporal changes in thediversity and composition of the bed microbiota ofpatients with pressure ulcers. Journal of theJapanese Society of Wound, Ostomy, andContinence Management. 2020;24(4):366-378.
Noguchi H, Oe M, Takehara K, Mori T, Sanada H.
Onsite visualization of shoe fitting for educationof the people with diabetes using 3D scanner: A
pilot study. Journal of Nursing Science andEngineering. 2020;7:162-169.
Koyano Y, Noguchi H, Sanada H. Can the use of ahuman-shaped communication robot enhance
motivation for inpatient rehabilitation?. Journal of
Nursing Science and Engineering. 2020;7:170176.
Dai M, Minematsu T, Nakagami G, Sugama J,
Sanada H. Awareness and attitudes oflymphoedema patients toward compression
stockings in the summer: a cross-sectionalquestionnaire survey. Journal of Lymphoedema.
2020;15:49-53.
Tamai N, Kuwata M, Urai T, Ushiro T, Yamashita
Y, Minematsu T, Dai M, Nakai A, Weijie K,
Kataoka Y, Nitta S, Noro S, Sanada H. Effect of an
education program on the prevention of skin tears
for nurses in a Japanese long-term care hospital: apre-post study. Journal of Japanese Society ofWound, Ostomy, and Continence Management.
2020:24(4):379-387.
Shikama M, Noguchi H, Nakagami G, Sanada H.
Reliability and validity of multi-contact pressure
measurement system for evaluating appropriate
NPPV mask fitting in healthy adults. Journal ofJapanese Society Wound, Ostomy, and ContinenceManagement. 2020;24(1):10-18.
Abe-Doi M, Murayama R, Komiyama C, Sanada
H. Changes in the Subcutaneous Tissue ofCatheterization Site from the Pre-catheterization
State to the Onset of Anticancer Drug-induced

322

Induration: A Case Report. Clinical case reports.
2020;9(1):57-60.
33. Nakayama E, Takahashi T, Kitamura A, Noguchi
H, Nakagami G, Kuwata M, Yotsudaru M, Sanada
H. Factors related to introduction and continuous
use of communication robots for patients withsymptoms of dementia from view of staff in along-term care hospital (in Japanese). Journal of
Nursing Science and Engineering. 2020;7:116129.
34. Kase M, Yoshida M, Shogenji M, Iizaka S,
Watanabe C, Taniguchi T, Sanada H, Tanaka H.
Effects of a continence self-management program
on independence of voiding behavior and lower
urinary tract symptoms (in Japanese). JapaneseSociety Wound, Ostomy, and ContinenceManagement. 2020;24(3):320-327.

International Health
1. International Social Medicine

324

Department of
Global Health Policy
Professor
Masahiro Hashizume, MD, PhD

Assistant Professor
Md. Mizanur Rahman, MSc, PhD

Project Assistant Professor
Shuhei Nomura, MSc, PhD
Ashraful Alam, MSc, PhD

Homepage

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

Introduction and Organization
As of March 2021 the department, headed by Professor
Masahiro Hashizume, included the following staff
complement; one assistant professors (Md. Mizanur
Rahman); one project assistant professors (Shuhei
Nomura, Ashraful Alam); five post-doctoral fellows;
10 adjunct lecturers; 15 doctoral students; and sevenmaster’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,
in order to ensure that student writing and presentation
skills are held 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
generation of leaders in global health. PhD students are
required to complete a minimum of 24 course credits
and a doctoral thesis with which needs to be publishedin a peer-reviewed journal. PhD students without MPH

325

degree 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 global burden of disease
Global environmental change and health
Global health governance
Population aging and its implications to 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 Monday seminar
Every Tuesday, 13:00-15:00 pm
1) Journal clubStudents present a brief summary of research articles
from the major medical, social science, economics
journals, which are relevant for global health policy.
The major objective is to share knowledge, evoke
debates and facilitate discussions.

ResearchResearch on nutrition and dietary policies using DALY
as an indicator for increasing healthy life. Joint
Research (Ajinomoto Co., Inc.). PI: Shuhei Nomura
Establishing an effective presence at the World Health
Assembly in Japan. Research on Global Health Issues(Ministry of Health, Labour and Welfare). PI: Shuhei
NomuraExposure to air pollution in Japan and its impact on
health and wellbeing (Dyson Technology) PI: Shuhei
NomuraTechnology based innovative solutions for improving
perinatal care utilization: a network meta-analysis(Oxford Policy Management) PI: Rahman Mizanur
Impact of mobile phone short messaging (SMS)intervention on antenatal and delivery care in
Bangladesh: a cluster-randomized controlled trial,
Grant-in-Aid for Scientific Research (Young
Researcher) (Ministry of Education, Culture, Sports,
Science and Technology). PI: Rahman Mizanur
Projections of excess mortality due to climate change- a multi-country environmental epidemiology study.
Grant-in-Aid for Scientific Research (B) (Ministry of
Education, Culture, Sports, Science and Technology)
PI: Masahiro Hashizume
A comprehensive study of the burden of disease inJapan. Grant-in-Aid for Scientific Research(A)(Ministry of Education, Culture, Sports, Science andTechnology). PI: Kenji Shibuya

Selected Publications
1.

2) Research seminar
A guest speaker or a master or doctoral student presents
his/her research. There is a 15-minute presentationfollowed by a 30-minute discussion.
2.

Sera F, Hashizume M, Honda Y, Lavigne E,
Schwartz J, Zanobetti A, Tobias A, Iñiguez C,
Vicedo-Cabrera AM, Blangiardo M, Armstrong B,
Gasparrini A. Air conditioning and heat-related
mortality: a multi-country longitudinal study.
Epidemiology. 2020;31(6):779-787.
Zeka A, Tobias A, Leonardi G, Bianchi F, Lauriola
P, Crabbe H, Vardoulakis S, Guo Y, Honda Y,

326

3.

4.

5.

6.

7.

Gasparrini A, Hashizume M, Vicedo AM,
Knudsen LE, Sera F, Ashworth M; ScientificCommittee of the International Network of Public
Health and Environmental Tracking. Responding
to COVID-19 requires strong epidemiologicalevidence of environmental and societal
determining factors. Lancet Planet Health. 2020;
4(9):e375-e376.
Hashizume M, Kim Y, Ng CFS, Chung Y,
Madaniyazi L, Bell ML, Guo YL, Kan H, Honda
Y, Yi SM, Kim H, Nishiwaki Y. Health effects ofAsian dust: a systematic review and meta-analysis.
Environ Health Perspect. 2020;128(6):66001.
Nomura S, Kawashima T, Yoneoka D, Tanoue Y,
Eguchi A, Gilmour S, Kawamura Y, Harada N,
Hashizume M. Trends in suicide in Japan bygender during the COVID-19 pandemic, up to
September 2020. Psychiatry Res. 2020; 295:
113622.
Nomura S, Kawashima T, Yoneoka D, Tanoue Y,
Eguchi A, Gilmour S, Hashizume M. Trends indeaths from road injuries during the COVID-19
pandemic in Japan, January to September 2020.
Inj Epidemiol. 2021;7(1):66.
Sultana S, Rahman MM, Sigel B, Hashizume M.
Associations of lifestyle risk factors withoverweight or obesity among adolescents: amulticountry analysis. Am J Clin Nutr. 2021 Mar
11;113(3):742-750.
Taniguchi H, Rahman MM, Swe KT, Hussain A,
Shibuya K, Hashizume M. Trends and projectionsof universal health coverage indicators in Iraq,
2000-2030: A national and subnational study. Soc
Sci Med. 2021 Feb;270:113630.

327

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 2021, the members of thedepartment include the department chair andprofessor, 1 lecturer, 4 assistant professors, 3

secretaries, 12 visiting lecturers, 18 doctoral
students, 15 master's degree students, and 43 visiting
scientists. More than half of the students in thisdepartment 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:328

1) 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.

Research
The major objectives of our research activities are
the following two:3.

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.

4.

5.

6.

7.

Exploring health literacy and its associatedfactors among Palestinian university students: across-sectional study. Sarhan MBA, Fujii Y,
Kiriya J, Fujiya R, Giacaman R, Kitamura A,
Jimba M. Health Promot Int. 2020 Nov 3:
daaa089.
"Are Filipinos Aging Well?": Determinants ofSubjective Well-Being among Senior Citizens of
the Community-Based ENGAGE
Study.
Carandang RR, Shibanuma A, Asis E, Chavez
DC, Tuliao MT, Jimba M. Int J Environ Res
Public Health. 2020 Oct 20;17(20):7636.
Effective school-based preventive interventions
for alcohol use in Africa: a systematic review.
Tomokawa S, Miyake K, Akiyama T, Makino Y,
Nishio A, Kobayashi J, Jimba M, Ayi I, Njenga
SM, Asakura T. Afr Health Sci. 2020 Sep; 20(3):1397-1406.
Seeking connection: a mixed methods study ofmental well-being and community volunteerism
among international migrants in Japan. Miller R,
Ong KIC, Choi S, Shibanuma A, Jimba M. BMC
Public Health. 2020 Aug 20;20(1):1272.
新型コロナウイルス感染症－ヘルスプロモーショ
ンの役割－ 神馬征峰. 日本健康教育学会誌.
2020;22(2):69-71.
Positive Deviance for Dual-Method Promotion
among Women in Uganda: A Qualitative Study.
Kosugi H, Shibanuma A, Kiriya J, Ong KIC,
Mucunguzi S, Muzoora C, Jimba M. Int J
Environ Res Public Health. 2020 Jul 12; 17(14):E5009.
Psychometric properties of an Arabic-language

329

8.

9.

10.

11.

12.

13.

14.

health literacy assessment scale for adolescents(HAS-A-AR) in Palestine. Sarhan MBA,
Shannon HS, Fujiya R, Jimba M, Giacaman R.
BMJ Open. 2020 Jun 21;10(6):e034943. doi:
10.1136/bmjopen-2019-034943.
The Influence of Breastfeeding Peer Support on
Breastfeeding Satisfaction Among Japanese
Mothers: A Randomized Controlled Trial. Hongo
H, Green J, Shibanuma A, Nanishi K, Jimba M. J
Hum Lact. 2020 May;36(2):337-347.
Depressed mood, suicidal behaviors, and healthrisk behaviors among youths in the
Commonwealth of the Northern Mariana Islands:
the 2017 CNMI Youth Risk Behavior Survey.
Sakamoto JL, Shibanuma A, Jimba M. BMC
Public Health. 2020 Apr 15;20(1):489.
Factors determining job satisfaction of malaria
community microscopists in Palawan, thePhilippines: a cross-sectional mixed-methods
study. Matsumoto-Takahashi ELA, TongolRivera P, Villacorte EA, Angluben RU, Jimba M,
Kano S. Int Health. 2020 Apr 14. pii: ihaa015.
Effectiveness of peer counseling, social
engagement, and combination interventions in
improving depressive symptoms of communitydwelling Filipino senior citizens. Carandang RR,
Shibanuma A, Kiriya J, Vardelon KR, Asis E,
Murayama H, Jimba M. PLoS One. 2020 Apr 1;
15(4):e0230770.
Tobacco use and E-cigarette regulation:
Perspectives of University Students in the AsiaPacific. Wipfli H, Bhuiyan MR, Qin X,
Gainullina Y, Palaganas E, Jimba M, Saito J,
Ernstrom K, Raman R, Withers M. Addict Behav.
2020 Mar 28;107:106420.
Positive deviance for dual-method promotion
among women in Uganda: study protocol for acluster randomized controlled trial. Kosugi H,
Shibanuma A, Kiriya J, Ong KIC, Mucunguzi S,
Muzoora C, Jimba M. Trials. 2020 March 17;
21:270. doi: 10.1186/s13063-020-4192-8.
Dissemination and implementation of the e-MCH
H andbook, UNRWA's newly released maternaland child health mobile application: a crosssectional study. Nasir S, Goto R, Kitamura A,
Alafeef S, Ballout G, Hababeh M, Kiriya J, Seita
A, Jimba M. BMJ Open. 2020 Mar 9; 10(3):e034885. doi: 10.1136/bmjopen-2019-034885.
15. Patients help other patients: Qualitative study ona longstanding community cooperative to tackle
leprosy in India. Jung SH, Han HW, Koh H, Yu
SY, Nawa N, Morita A, Ong KIC, Jimba M, Oh J.
PLoS Negl Trop Dis. 2020 Jan 13;14(1):e0008016.

International Health
2. International Biomedical Sciences

331

Department of Human Genetics
Professor
Akihiro Fujimoto, Ph.D.

Assistant professor
Mihoko Shimada, Ph.D.

Project Assistant researcher
James WONG Jing Hao, Ph.D., Saeideh ASHOURI, 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, 1 assistant professor, 2 research associate, 2
graduate student, 3 undergraduate students, and 2
research assistants/technicians. We also accept a few
graduate students from other 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).

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 ofgenomic, 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.

Shibayama, Y. et al. Aberrant (pro)renin receptor
expression induces genomic instability inpancreatic ductal adenocarcinoma throughupregulation of SMARCA5/SNF2H. Commun.
Biol. 3, 724 (2020).
Takeda, H. et al. Multiregional whole-genome
sequencing of hepatocellular carcinoma withnodule-in-nodule appearance reveals stepwise
cancer evolution. J. Pathol. (2020) doi:10.1002/
path.5533.
Tanaka, A. et al. Systematic clustering algorithm
for chromatin accessibility data and its
application to hematopoietic cells. PLOS
Comput. Biol. 16, e1008422 (2020).

332

4.

5.

Fujimoto, A. et al. Comprehensive analysis ofindels in whole-genome microsatellite regions
and microsatellite instability across 21 cancer
types. Genome Res. 30, 334–346 (2020).
Campbell, P. J. et al. Pan-cancer analysis ofwhole genomes. Nature 578, 82–93 (2020).

333

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

33410) 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.

335

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 to the professorship of the
Human Ecology Department on April 1, 1965. Following
the retirement of Professor Uraguchi as of March 31,
1966, Professor Haruo Katsunuma (also appointed as
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 Departmentt
until August 31, 1971, when he was transferred to the
Faculty of Medicine, Tohoku University, as a professor.
After Professor Katsunuma left the Departmentnt on
March 31, 1972, Professor Akira Koizumi became thehead of the Human Ecology Department on April 1, 1972.
Professor Koizumi was transferred to the Public Healthprogram, School of Medicine on March 31, 1976, andAssociate Professor Shosuke Suzuki served as a
Department head from April 1, 1976 to April 15, 1979.
Tsuguyoshi Suzuki was appointed as a professor of the
Human Ecology program as of April 16, 1979. He
founded the theoretical framework of the current humanecology curriculum, which is based on studying theadaptation mechanisms of humans to the environment.
After Associate Professor Shosuke Suzuki was transferredto the Faculty of Medicine, Gunma University, as
professor on July 31, 1981, Ryutaro Ohtsuka was
appointed as an associate professor on September 1 of thesame year. Associate professor Ohtsuka established themethodology of collecting quantitative information on
demography, nutrition, and subsistence targeting smallscale 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 as a professor as of April 1 of thesame year.
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 aprofessor as of April 1, 2005. Masahiro Umezaki was
appointed as an associate professor in August 2005. While
relying on quantitative research based on fieldwork, he
has also been exploring new research topics, including theapplication of spatial information sciences on healthsciences, the roles of gut microbiota in human nutrition,
mitigation/alleviation strategies of depopulation andaging in human populations, and medical anthropology.
Professor Chiho Watanabe was transferred from the
University of Tokyo to the National Institute ofEnvironmental Studies as of April 1, 2017. Masahiro
Umezaki was appointed as a professor as of January 1,
2018. Shoko Konishi was appointed as an associate

336

professor as of June 1, 2018. Dr. Konishi has been
studying the associations between fecundity and fertility
and environmental factors from the perspectives of
population studies, environmental sciences, anthropology,
and sociology.
In fiscal year 2020, the Departmentt had four faculty
members: Drs. Umezaki, Konishi, Kosaka, and Takayasu.
The Department also had 14 extra-university lecturersdelivering lectures in either graduate or undergraduate
courses. Professor Umezaki held additional roles in the
Network for Education and Research in Asia (ASNET) as
well as in the Earth Observation Data Integration and
Fusion Research Initiative (EDITORIA) at the Universityof Tokyo.

Teaching activities
The Department is one of the six Departments of the
School of International Health. Human Ecology Special
Lecture I focuses on the basic components of humanecology, such as demography, nutrition, and environment,
and introduces the notion of human ecosystems. In
Human Ecology Special Lecture II, the emphasis is on
recent topics and ongoing research in the field of humanecology and related areas. With these classes for graduate
students, we attempt to describe human ecology as a basic
component of international health, and provide examplesof the recent issues that have been dealt with andapproaches used in this field. Graduate course lectures are
given in English.
The Department is in charge of a part of the School ofIntegrated Health Sciences, providing undergraduate
course lectures on Human Ecology, Environment and
Health, Demography, International Health, and Medical
Anthropology. We are also responsible for organizing
Pharmacology and Toxicology, Physiology, andEnvironmental Engineering/Human Engineering. At theundergraduate level, our emphasis is on introducing
global-scale issues, such as population explosion, foodsecurity, and environmental issues, in relation to the
problems that the Asia-Pacific region (including Japan)
has been facing. Another emphasis is on the relation
between human activities and chemical contamination of
the environment.

Research activities
Human ecology is the understanding of the humanpopulation in the context of their respective ecology as
well as in the global context. Most of our research tackles
the tasks in the field of Environmental Health and/or
Population Ecology [of humans], but with a morecomprehensive and broader context. Therefore, we needto adopt different approaches, including fieldwork,
experimentation, and GIS (Geographic Information
System)/GPS (Global Positioning System) analyses. Our
study fields include Asian-Oceanian (including Japan)
rural and urban communities, focusing on population,
nutrition, growth, environment, and sustainability.
Experimental studies on the effects of perinatal exposure
to heavy metals have been conducted, emphasizing thefactors that modify these effects. Almost all our studies
require a transdisciplinary approach. As such, we arecollaborating with various local and international research
institutes. The following is a list of major activities
conducted in the past year.
1. Adaptation to low-protein diet
The inconsistency between Papua New Guinea
highlanders’ protein-deficient diet and their muscularphysique is well known. Moreover, although theirprotein intake is less than biologically adequate,
disorders related to protein deficiency have rarely beenreported in this setting. We have speculated that the
population has adapted to a low-protein diet by utilizing
air nitrogen fixed by intestinal bacteria and/or byintensive “recycling” of the urea that passes into thegastrointestinal tract. Recent advances in sequencing
techniques have enabled us to examine the unsolved
question of Papua New Guinea highlanders’ adaptation
to a low-protein diet in a more direct way. In our
project, we evaluated the gut microbiota of healthy
individuals in four Papua New Guinea communities
with different degrees of protein deficiency. The
association between gut microbiota and variation inprotein intake and nutritional biomarkers wasinvestigated. Shotgun metagenomic analysis further
demonstrated that some genes related to nitrogen
fixation and urease are enriched in Papua New Guinea
communities compared with other countries.
Gnotobiotic animal experiments revealed different
nutritional responses to a low-protein diet depending on

337

the type of gut microbiota transplanted.
2. Adaptive strategy to aging and depopulation
Japan is one of the countries experiencing postdemographic transition (i.e., low fertility, aging, andpopulation decrease). Targeting Japanese ruralcommunities, the front-runners of this global issue, we
conducted population projection and studies on theirfood habits, nutritional intake, and subjective
perceptions of health. We also conducted a study toidentify mitigation and alleviation strategies against
aging and depopulation that have been formulated inlocal communities.
A case study in Nagasaki city, focusing on theresidential zones on a steep slope and the residents’aging, suggested that more older people resided in ahouse on a steep slope and without direct roadway
access.
3. Nutrition and eating behaviors
We have been conducting field surveys every year in
the same villages in West Java, Indonesia. Although we
did not managed to conduct a field survey in 2020, we
performed further analysis and discussion about
previously collected data.
4. Interdisciplinary Investigation on the Technology, theEnvironment, and Fertility
Japan has the highest number of assisted
reproductive technology use in the world. Our ongoingproject is testing a hypothesis that exposure totechnology and environmental chemicals are both linked
to increasing infertility in the country. In two hospitalsin Tokyo and Tsukuba 198 male participants wererecruited. Questionnaire survey was conducted to gather
information about lifestyle and sexual function. Urineand semen specimens were collected for quantificationof environmental exposure and reproductive biomarkers
measurement respectively.
The other part of the IITEF project was the largescale online questionnaire survey targeting 8,000 men
living across Japan. Participants were males aged 20 to
54 years old and responded to questions onsocioeconomic status and sexual behavior.
5. Health transition in Lao People’s Democratic
Republic

Diet in the northern parts of Laos has beencharacterized by consumption of large amounts of ricewith dishes made of wild plants. Wild plants of bitterand even astringent taste, which are supposed tocontain more phytochemicals, are preferred overdomesticated vegetables. It has been suspected thatphytochemicals have roles in nutritional adaptation
among the local people through interactions withintestinal bacteria. As the people have gradually been
involved in the market economy, their diet has changed
toward more consumption of animal meat and oil andless consumption of phytochemicals. We initiated a
research project to investigate the potential healthimpact of such dietary changes in Northern Laos. The
questionnaire survey and sampling of biological
specimens were conducted in three communities in
Oudomxay Province (one peri-urban and two farming
communities). By evaluating biomarkers of oxidative
stress, chronic inflammation, and gut microbiota
composition in three communities at different levels ofmodernization, we sought to clarify the biological link
between dietary transition and the recent emergence of
non-communicable diseases in rural Laos.
6. Potential fetal microbiome transfer from intrauterine
exposure
Mounting evidence of bacteria in fertilization
products analyzed using DNA-based technologies ischallenging the sterile womb hypothesis. We conducted
cultivation-based and 16S rRNA sequence analyses
using a mouse model in mid and late gestation thatsuggested the presence of bacteria in fetal, placental,
and uterine tissues. This low-abundance fetal
microbiome appears to be volatile and transient innature, in contrast to the relatively stable bacterial
composition that matures during infancy. The similarity
between the bacterial compositions of maternal andfetal tissues suggests a vertical transmission that 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 the mother and development of
immunity in the fetus.
7. Child undernutrition in Cebu, Philippines
Focusing on school children in vulnerable
communities, we investigated factors associated with

338

the nutritional status of children in a rural municipality
in Cebu, Philippines. Children aged 6–12 years and theirparents were asked to participate. The results showed ahigh prevalence of stunting and underweight in thiscommunity. Children’s nutritional status was associatedwith household income and size, parents’ nutritional
status, and severe food insecurity. This work has been
published.

7.

8.

8. Mouse gut microbiome transitions
Gut microbiome and aging have been discussed
based on the average flora of people of different ages.
Meanwhile, few studies have been conducted on the
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 gut microbiome related to pregnancy and lifespan.

References
1.

2.

3.

4.

5.

6.

Kosaka S, Nakao R, Ohnishi M, Umezaki M. (inpress). The proportion of older population in
Nagasaki, Japan, is higher in areas with poor
walkability and accessibility. Jpn J Health Hum Ecol.
Jonduo M, Lorry W, Geraldine M, Hattori M, Suda
W, Takayasu L, Abdad Y, Greenhill A, Horwood, P,
Pomat W, Umezaki M. (2020). Gut microbiota
composition in obese and non-obese adult relatives
from the highlands of Papua New Guinea. FEMS
Microbiol Lett. 367(19), fnaa161.
Masuoka H, Suda W, Tomitsuka E, Shindo C,
Takayasu L, Horwood P, Greenhill A, Hattori M,
Umezaki M, Hirayama K. (2020). The influences oflow protein diet on the intestinal microbiota of mice.
Sci Rep.
Ieiri MCA, Kosaka S, Umezaki M. (2020). Factors
affecting undernutrition among school children in
Cebu, Philippines. Ecol Food Nutr. 1-16.
Wai KM, Umezaki M, Umemura M, Mar O,
Watanabe C. (2020) Protective role of selenium inthe shortening of telomere length in newborns
induced by in utero heavy metal exposure. Environ
Res, 183, 109202.
Konishi S, Saotome TT, Shimizu K, Oba MS,
O’Connor KA. (2020) Coital frequency and theprobability of pregnancy in couples trying toconceive their first child: A prospective cohort study

in Japan. Int J Environ Res Public Health, 17,4985;
doi:10.3390/ijerph17144985.
Takewaki D, Suda W, Sato W, Takayasu L, Kumar N,
Kimura K, Kaga N, Mizuno T, Miyake S, Hattori M,
Yamamura T. (2020) Alterations of the gut ecologicaland functional microenvironment in different stagesof multiple sclerosis. Proc Natl Acad Sci USA.
117(36):22402-22412.
Watanabe K, Morohoshi S, Kunihiro T, Ishii Y,
Takayasu L, Ogata Y, Shindo C, Suda W. (2020)
Fluviibacter phosphoraccumulans gen. nov., sp. nov.,a polyphosphate-accumulating bacterium of
Fluviibacteraceae fam. nov., isolated from surface
river water. Int J Syst Evol Microbiol. 70(10), 55515560.

339

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

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 Drug discovery and development against protozoan
infections such as malaria and amebiasis
 Elucidation of divergence of RNA maturation andtranslation

References
1. Watanabe, N., Nakada-Tsukui, K., and Nozaki, T.
Two isotypes of phosphatidylinositol 3-phosphatebinding sorting nexins play distinct roles introgocytosis in Entamoeba histolytica. Cell
Microbiol, 22(3):e13144, 2020. doi: 10.1111/cmi.
13144.
2. Iwasaki, K., Iwasaki, A., Sumimoto, S., Matsubara,T., Sato, T., Nozaki, T., Saito-Nakano, Y., Suenaga,
K. Ikoamide, an antimalarial lipopeptide from an
Okeania sp. marine Cyanobacterium. J Nat Prod. 83,
481-488, 2020. doi: 10.1021/acs.jnatprod.9b01147
3. Nakada-Tsukui, K. and Nozaki, T. The emerging
role of trogocytosis in the evasion of cancers andparasitic protists from immune cells. Editorial
Commentary, Biotarget. 4:4. 2020. doi: 10.21037/
biotarget.2020.03.02
4. Samie, A. Mahlaule, L., Mbati, P., Nozaki, T.,
ElBakri, A. Prevalence and distribution of
Entamoeba species in a rural community in northern
South Africa. Food Waterborne Parasitol. 18:
e00076,2020.
doi.org/10.1016/j.fawpar.2020.
e00076
5. Pramisandi, A., Dobashi, K., Mori, M., Nonaka, K.,
Matsumoto, A., Tokiwa, T., Higo, M.,
Kristiningrum, Amalia, E., Nurkanto, A., Inaoka, D.
K., Waluyo, D., Kita, K., Nozaki, T., Omura, S.,
Shiomi, K. Microbial inhibitors active against
Plasmodium falciparum dihydroorotate dehydrogenase derived from an Indonesian soil fungus
Talaromyces pinophilus BioMCC-f.T.3979. J. Gen.
Appl. Microbiol. 66:273-278, 2020. doi: 10.2323/jgam.2019.11.007. Correction: 84(4):1423, 2021.
doi: 10.1021/acs.jnatprod.1c00282.
6. Kurisawa N, Iwasaki A, Jeelani G, Nozaki T,
Suenaga K. Iheyamides A-C, antitrypanosomal
linear peptides isolated from a marine dapis sp.
Cyanobacterium. J Nat Prod. 83(5):1684-1690, 2020.
doi: 10.1021/acs.jnatprod.0c00250. Correction: J
Nat Prod. 2021 Apr 23;84(4):1423. doi: 10.1021/acs.
jnatprod.1c00282.

7. Wardana, F. Y., Sari, D. K., Adianti, M.,
Permanasari, A. A., Tumewu, L., Nozaki, T.,
Widyawaruyanti, A., Hafid, A. F. In vitro
anti-amebic activity of cage xanthones from
Cratoxylum sumatranum stem bark against
Entamoeba histolytica. Pharmacogn J. 12(3):452-458, 2020.
8. Watanabe, N., Nakada-Tsukui, K., Maehama, T.,
and Nozaki, T. Dynamism of PI4-phosphate during
interaction with human erythrocytes in Entamoeba
histolytica. Special Issue “Virulence and Parasitismof Parasitic Protozoa”, Microorganisms, 8(7), 1050,
2020. doi.org/10.3390/microorganisms8071050
9. Nakada-Tsukui, K. #, Marumo, K, and Nozaki, T.#
A lysosomal hydrolase receptor, CPBF2, isassociated with motility and invasion of the enteric
protozoan parasite Entamoeba histolytica. Mol.
Biochem. Parasitol. (# correspondence) 239:111299,
2020. doi: 10.1016/j.molbiopara.2020.111299.
10. Santos, H. J., Chiba, Y., Makiuchi, T., Arakawa, S.,
Murakami, Y., Tomii, K., Imai, K., Nozaki, T.
Import of Entamoeba histolytica mitosomal ATP
sulfurylase relies on internal targeting sequences.
Special Issue “Virulence and Parasitism of Parasitic
Protozoa”, Microorganisms, 8, 1229, 2020.
doi:10.3390/microorganisms8081229.
11. Kawano-Sugaya, T., Izumiyama, S., Yanagawa, Y.,
Saito-Nakano, Y.,Watanabe, K., Kobayashi, S.,
Nakada-Tsukui, K., Nozaki, T. Near-chromosome
level genome assembly reveals ploidy diversity andplasticity in the intestinal protozoan parasite
Entamoeba histolytica. BMC Genomics 21:813,
2020. doi.org/10.1186/s12864-020-07167-9
12. Sato, D., Hartuti, E. D., Inaoka, D. K., Sakura, T.,
Amalia, E., Nagahama, M., Yoshioka, Y., Tsuji, N.,
Nozaki, T., Kita, K., Harada, S. Matsubayashi, M.,
and Shiba, T. Structural and biochemical features ofEimeria tenella dihydroorotate dehydrogenase, apotential drug target. Genes (Basel), 11, E1468;
2020. doi:10.3390/genes11121468
13. Iwasaki, A., Ohtomo, K., Kurisawa, N., Shiota, I.,
Rahmawati, Y., Jeelani, G., Nozaki, T., Suenaga, K.
Isolation, structure determination and total synthesisof 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.

341

14. 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. J. Gen.
Appl. Microbiol., 67, 114-117, 2021. doi 10.2323/
jgam.2020.08.004
15. 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 adenylatekinase 2 from the endoplasmic reticulum in
Plasmodium falciparum. Front Cell Inf Microbiol
10:610200, 2021. doi: 10.3389/fcimb.2020.610200..

School of Public Health
1. Epidemiology and Health Sciences

343

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
the same 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 a practical study for public health and thus
a central field of health science. However, botheducation and research 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 amain 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
and one 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

344with various kinds of disease.
Another characteristic is collection of researchfindings (scientific papers) derived from epidemiologic research all over the world on the association ofnutrition with health and disease, which is applied for
health control through nutrition improvement anddisease control.

References
1. Miyake Y, Tanaka K, Okubo H, Sasaki S,
Arakawa M. Maternal B vitamin intake during
pregnancy and childhood behavioral problems inJapan: The Kyushu Okinawa Maternal and Child
Health Study. Nutr Neurosci 2020; 23(9): 706-13.
2. Fujiwara A, Murakami K, Sasaki S. Relative
validity of starch and sugar intake in Japanese
adults as estimated with comprehensive and brief
self-administered diet history questionnaires. J
Epidemiol 2020; 30(8): 315-25.
3. Murakami K, Livingstone MBE, Shinozaki N,
Sugimoto M, Fujiwara A, Masayasu S, Sasaki S.
Food combinations in relation to the quality ofoverall diet and individual meals in Japanese
adults: a nationwide study. Nutrients 2020; 12(2):327.
4. Murakami K, Livingstone MBE, Fujiwara A,
Sasaki S. Application of the Healthy Eating
Index-2015 and the Nutrient-Rich Food Index 9.3
for assessing overall diet quality in the Japanesecontext: Different nutritional concerns from the
US. PLoS One 2020; 15(1): e0228318.
5. Shinozaki N, Murakami K, Masayasu S, Sasaki S.
Validity of a dish composition database for
estimating protein, sodium and potassium intakes
against 24 h urinary excretion: comparison with astandard food composition database. Public
Health Nutr 2020; 23(8): 1297-306.
6. Okuda M, Fujiwara A, Sasaki S. Added and freesugars intake and metabolic biomarkers inJapanese adolescents. Nutrients 2020; 12(7):2046.
7. Nishida Y, Tanaka S, Nakae S, Yamada Y, Shirato
H, Hirano H, Sasaki S, Katsukawa F. Energy gap
between doubly labeled water-based energy
expenditure and calculated energy intake fromrecipes and plate waste, and subsequent weightchanges in elderly residents in Japanese long-termcare facilities: CLEVER Study. Nutrients 2020;12(9): 2677.
8. Murakami K, Shinozaki N, Livingstone MBE,
Fujiwara A, Asakura K, Masayasu S, Sasaki S.
Meal and snack frequency in relation to dietquality in Japanese adults: a cross-sectional study
using different definitions of meals and snacks. Br
J Nutr 2020;124(11) : 1219-28.
9. Hashimoto A, Murakami K, Kobayashi S, Suga H,
Sasaki S; Three-generation Study of Women on
Diets and Health Study Group. Associations ofeducation with overall diet quality are explainedby different food groups in middle-aged and oldJapanese women. J Epidemiol 2020; 31(4): 280-6.
10. Yuan X, Murakami K, Asakura K, Uechi K,
Masayasu S, Sasaki S. Formulas developed basedon the ratio of urea nitrogen to creatinine
concentrations obtained from multiple spot urine
samples are acceptable to predict protein intake atgroup level but not at individual level. Nutr Res
2020; 78: 50-9.
11. Sugimoto M, Murakami K, Fujiwara A, Asakura
K, Masayasu S, Sasaki S. Association between
diet-related greenhouse gas emissions and nutrient
intake adequacy among Japanese adults. PLoS
One 2020; 15(10): e0240803.
12. Miyazawa I, Morino K, Fuse K, Kondo K, Ohi A,
Nishida K, Kurihara M, Yasuhara S, Nakanishi N,
Nishida Y, Nakae S, Yamada Y, Tanaka S, Ebine N,
Sasaki S, Katsukawa F, Sasaki M, Ugi S,
Maegawa H; CLEVER-DM Study ResearchGroup. Impact of obesity on underreporting ofenergy intake in type 2 diabetic patients: Clinical
Evaluation of Energy Requirements in Patientswith Diabetes Mellitus (CLEVER-DM) study.
Clin Nutr ESPEN 2020; 39: 251-4.
13. Nishida Y, Tanaka S, Nakae S, Yamada Y, Morino
K, Kondo K, Nishida K, Ohi A, Kurihara M,
Sasaki M, Ugi S, Maegawa H, Ebine N, Sasaki S,
Katsukawa F. Validity of the Use of a Triaxial
Accelerometer and a Physical Activity
Questionnaire for Estimating Total Energy
Expenditure and Physical Activity Level among
Elderly Patients with Type 2 Diabetes Mellitus:
CLEVER-DM Study. Ann Nutr Metab 2020;
76(1): 62-72.

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14. Kawamoto T, Miyake Y, Tanaka K, Nagano J,
Sasaki S, Hirota Y. Maternal prenatal stress andinfantile wheeze and asthma: The Osaka Maternaland Child Health Study. J Psychosom Res 2020;
135: 110143.
15. Miyake Y, Tanaka K, Okubo H, Sasaki S,
Arakawa M. Maternal consumption of vegetables,
fruit, and antioxidants during pregnancy and risk
for childhood behavioral problems Nutrition
2020; 69: 110572.
16. Kimura Y, Suga H, Kobayashi S, Sasaki S;
Three-Generation Study of Women on Diets and
Health Study Group. Intake of coffee associatedwith decreased depressive symptoms among
elderly Japanese women: A Multi-Center
Cross-Sectional Study. J Epidemiol 2020; 30(8):338-44.
17. Ishitsuka K, Sasaki S, Yamamoto-Hanada K,
Mezawa H, Konishi M, Ohya Y; Japan
Environment and Children's Study Group.
Changes in dietary intake in pregnant womenfrom periconception to pregnancy in the Japan
Environment and Children's Study: A Nationwide
Japanese Birth Cohort Study. Matern Child
Health J 2020; 24(3): 389-400.
18. Horiguchi H, Oguma E, Sasaki S, Miyamoto K,
Hosoi Y, Ono A, Kayama F. Exposure Assessmentof Cadmium in Female Farmers in CadmiumPolluted Areas in Northern Japan. Toxics 2020;8(2): 44.
19. Ando E, Morisaki N, Asakura K, Ogawa K,
Sasaki S, Horikawa R, Fujiwara T. Association
between dietary intake and serum biomarkers oflong-chain PUFA in Japanese preschool children.
Public Health Nutr 2020; 24(4): 593-603.
20. Murakami K, Shinozaki N, Livingstone MBE,
Fujiwara A, Asakura K, Masayasu S, Sasaki S.
Characterisation of breakfast, lunch, dinner, andsnacks in the Japanese context: an exploratory
cross-sectional analysis. Public Health Nutr
2020; : 1-13.
21. Tanaka Y, Nakagami T, Oya J, Ukita-Shibasaki C,
Takehana Y, Sasaki S, Babazono T. Impact ofbody mass index and age on the relative accuracyof self-reported energy intakes among Japanesepatients with type 2 diabetes. Diabetol Int 2020;11(4): 360-7.

22. Shinozaki N, Murakami K. Evaluation of theability of diet-tracking mobile applications toestimate energy and nutrient intake in Japan.
Nutrients 2020; 12(11): E3327.
23. Okuda M, Asakura K, Sasaki S. Estimation ofdaily sodium and potassium excretion fromovernight urine of Japanese children andadolescents. Environ Health Prev Med 2020;25(1): 74.
24. Yoshii Y, Murakami K, Asakura K, Masayasu S,
Sasaki S. A longer time spent at childcare isassociated with lower diet quality among children
aged 5-6 years, but not those aged 1.5-2 and 3-4
years: Dietary Observation and Nutrient intake forGood health Research in Japanese young children(DONGuRI) study. Public Health Nutr 2020; :1-13.
25. Sasaki S; for Working Group 1 of the Healthy
Diet Research Committee of International Life
Sciences Institute, Japan. What is the scientificdefinition of the Japanese diet from the viewpointof nutrition and health? Nutr Rev 2020; 78(Supplement 3): 18-26.
26. Sugimoto M, Murakami K, Fujiwara A, Asakura
K, Masayasu S, Sasaki S. Association between
diet-related greenhouse gas emissions and nutrient
intake adequacy among Japanese adults. PLoS
One 2020; 15(10): e0240803.
27. Shinozaki N, Murakami K, Asakura K, Masayasu
S, Sasaki S. Identification of dish-based dietary
patterns for breakfast, lunch, and dinner and theirdiet quality in Japanese adults. Nutrients 2020;13(1): 67.

346

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.

347

References
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8.

Abe H, Sumitani M, Matsui H, Aso S, Inoue R,
Fushimi K, Uchida K, Yasunaga H, Yamada Y.
Comparing outcomes after peripheral nerve block
versus general anesthesia for lower-extremity
amputation:anationwide
exploratory
retrospective cohort study in Japan. Regional
Anesthesia & Pain Medicine 2020;45(6):399-404
Ando T, Kawashima M, Jo T, Masuda K,
Yamauchi Y, Tanaka G, Kage H, Suzukawa M,
Nagai H, Matsui H, Fushimi K, Yasunaga H,
Nagase T. Early Arterial Embolization andMortality in Mechanically Ventilated Patientswith Hemoptysis: a Nationwide Retrospective
Cohort Study. Crit Care Med. 2020 Oct;48(10):1480-1486
Aso S, Matsui H, Fushimi K, Yasunaga H.
Vasopressin versus epinephrine as adjunctvasopressors for septic shock. Intensive Care
Medicine. 2020;46;1484–1485
Aso S, Yasunaga H. Introduction to Instrumental
Variable
Analysis.
AnnalsofClinical
Epidemiology. 2020;2(3):69-74
Aso S, Matsui H, Yasunaga H. Influence of the
Fukushima Daiichi Nuclear Power Plant accident
on the use of computed tomography in children
with mild head injuries. Journal of Epidemiology.
2020;30(12):542-546
Fujiogi M, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Fujishiro J. Clinical features,practice patterns and outcomes of omphalocele: adescriptive study using a nationwide inpatient
database in Japan. Annals of Clinical
Epidemiology. 2020;2(2):61–68.
Funakoshi H, Matsui H, Fushimi K, Yasunaga H.
Association between Preventive Administrationof Fasudil Hydrochloride and Post-interventional
Neurological Outcomes in Patients with
Aneurysmal Subarachnoid Hemorrhage. Annalsof Clinical Epidemiology. 2020;2(4):107-112
Hashimoto Y, Michihata N, Yamana H, Shigemi
D, Morita K, Matsui H, Yasunaga H, Aihara M.
Ophthalmic corticosteroids in pregnant womenwith allergic conjunctivitis and adverse neonatal
outcomes: propensity score analyses. American
Journal of Ophthalmology. 2020;220:91-101

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Hashitmoto Y, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Aihara M. Reoperation rates after
Ex-PRESS versus trabeculectomy for primary
open-angle or normal-tension glaucoma: A
national database study in Japan. EYE. 2020;34(6):1069-1076.
Hatachi T, Michihata N, Takeuchi M, Matsui H,
Fushimi K, Yasunaga H. Early steroid pulse
therapy among children with influenza virusassociated encephalopathy. Journal of Intensive
Care. 2020;8:62.
Hattori Y, Tahara S, Aso S, Matsui H, Fushimi K,
Yasunaga H, Morita A. Pituitary surgery’s
epidemiology using a national inpatient databasein Japan. Acta Neurochirurgic. 2020;162(6):1317-1323.
Hayakawa I, Okubo Y, Nariai H, Michihata N,
Matsui H, Fushimi K, Yasunaga H. Recent
treatment patterns and variations for pediatricacute encephalopathy in Japan. Brain andDevelopment. 2020;42(1):48-55.
Hayashi K, Sasabuchi Y, Matsui H, Nakajima M,
Ohbe H, Ono K, Yasunaga H. The clinical effectof the AN69ST membrane as a cytokine
adsorption therapy for sepsis due to acutepanperitonitis: a retrospective cohort study.
Blood Purification. 2020;49(3):364-371.
Hironaka K, Aso S, Suzuki M, Matano F, Matsui
H, Fushimi K, Yasunaga H, Morita A. Outcomesin elderly Japanese patients treated for
aneurysmal subarachnoid hemorrhage: A
retrospective nationwide study. Journal of Stroke
and Cerebrovascular Diseases. 2020;29(6):104795.
Hirose N, Ishimaru M, Morita K, Yasunaga H. A
review of studies using the Japanese National
Database of Health Insurance Claims andSpecific Health Checkups. Annals of Clinical
Epidemiology. 2020;2(1):13-26.
Honda C, Yamana H, Matsui H, Nagata S,
Yasunaga H, Naruse T. Age in months and birthorder in infant nonfatal injuries: A retrospective
cohort study. Public Health in Practice. 2020;
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Hosoi T, Yamana H, Tamiya H, Matsui H,
Fushimi K, Akishita M, Yasunaga H, Ogawa S.
Association between comprehensive geriatric

348

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assessment and short-term outcomes among older
adult patients with stroke: a nationwide
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Ikawa F, Michihata N, Matsushige T, Abiko M,
Ishii D, Oshita J, Okazaki T, Sakamoto S, Kurogi
R, Iihara K, Nishimura K, Morita A, Fushimi K,
Yasunaga H, Kurisu K. In-hospital mortality andpoor outcome after surgical clipping andendovascularcoilingforaneurysmal
subarachnoid hemorrhage using nationwide
databases: a systematic review and meta-analysis.
Neurosurgical Review. 2020;43(2):655-667.
Ikawa F, Michihata N, Akiyama Y, Iihara K,
Morita A, Kato Y, Yamaguchi S, Kurisu K,
Fushimi K, Yasunaga H. Propensity Score
Matching Analysis for the Patients of Unruptured
Cerebral Aneurysm from a Post Hoc Analysis of
a Nationwide Database in Japan. World
Neurosurg. 2020;136:e371-e379.
Itoh H, Kaneko H, et al. Serial Change in Clinical
Presentations and Outcomes of 5,740 Patients
Requiring Repeated Hospital Admissions (Fouror More Times) due to Worsened Heart Failure.
Int Heart J. 2020;61(6):1253-1257
Jo T, Yasunaga H, Yamauchi Y, Mitani A,
Hiraishi Y, Hasegawa W, Sakamoto Y, Matsui H,
Fushimi K, Nagase T. Inhaled corticosteroid
withdrawal may improve outcomes in elderly
patients with COPD exacerbation: A nationwide
database study. ERJ Open Research. 2020;6(1):00246-2019.
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, Komuro I. Transcatheter Aortic
Valve Implantation and Surgical Aortic Valve
Replacement for Aortic Stenosis in Japan:
Analysis of a Nationwide Inpatient Database.
Circulation Reports 2020;2(12):753-758.
Kaneko H, Itoh H, Yotsumoto H, Kiriyama H,
Kamon T, Fujiu K, Morita K, Michihata N, Jo T,
Morita H, Yasunaga H, Komuro I. Characteristics
and Outcomes of Super-Elderly Patients (aged

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29.

30.

≥90 Years) Hospitalized for Heart Failure:
Analysis of a Nationwide Inpatient Database.
Circulation Reports. 2020;2(8):393-399
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.
Association of Cancer with Outcomes in Patients
Hospitalized for Heart Failure. Circulation
Journal. 2020;84(10):1771-1778.
Kaneko H, Itoh H, Yotsumoto H, Kiriyama H,
Kamon T, Fujiu K, Morita K, Michihata N, Jo T,
Morita H, Yasunaga H, Komuro I. Association of
Body
WeightGain
withSubsequent
Cardiovascular Event in Non-Obese General
Population without Overt Cardiovascular Disease.
Atherosclerosis. 2020;308:39-44.
Kaneko H, Itoh H, Kamon T, Fujiu K, Morita K,
Michihata N, Jo T, Morita H, Yasunaga H,
Komuro I. Association of Cardiovascular Health
Metrics with Subsequent Cardiovascular Diseasein Young Adults. Journal of the American College
of Cardiology. 2020;76 (20):2414–2416
Kaneko H, Itoh H, Yotsumoto H, Kiriyama H,
Kamon T, Fujiu K, Morita K, Michihata N, Jo T,
Morita H, Yasunaga H, Komuro I. Association
between the number of hospital admissions andin-hospital outcomes in patients with heart failure.
Hypertension Research. 2020;43(12):1385-1391
Kaneko H, Itoh H, Kiriyama H, Kamon T, Fujiu
K, Morita K, Michihata N, Jo T, Takeda N,
Morita H, Yasunaga H, Komuro I. Restfulness
from sleep and subsequent cardiovascular diseasein the general population. Scientific Reports.
2020;10(1):19674.
Kaneko H, Itoh H, Kiriyama H, Kamon T, Fujiu
K, Morita K, Michihata N, Jo T, Takeda N,
Morita H, Yasunaga H, Komuro I. Association of
Isolated Diastolic Hypertension based on the
Cut-Off Value in the 2017 ACC/AHA Blood
Pressure
Guidelines
with
Subsequent
Cardiovascular Event in General Population.
JAHA. 2020;9(19):e017963.
Kido T, Iwagami M, Yasunaga H, Abe T,
Enomoto Y, Matsui H, Fushimi K, Takada H,
Tamiya N. Outcomes of paediatric out-of-hospital
cardiac arrest according to hospital characteristic
defined by the annual number of paediatric

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patients with invasive mechanical ventilation: anationwide study in Japan. Resuscitation. 2020;
148:49-56.
Kitamura T, Nakajima M, Kawamura I, Ohbe H,
Sasabuchi Y, Matsui H, Fushimi K, Fukamizu S,
Yasunaga H. Patient Characteristics, Procedure
Details Including Catheter Devices, andComplications of Catheter Ablation for
Ventricular Tachycardia. Journal of Arrhytmia.
2020;36(3):464-470
Koizumi M, Suzuki S, Matsui H, Fushimi K,
Yamasoba T, Yasunaga H. Trends incomplications after functional endoscopic sinus
surgery in Japan: a comparison with a previous
study (2007–2013 vs. 2013–2017). Auris Nasus
Larynx. 2020;47(5):814-819
Kondo Y, Ohbe H, Yasunaga H, Tanaka H. Initial
Focused Assessment with Sonography in Trauma
versus Initial Computed Tomography for Patientswith Hemodynamically-Stable Torso Trauma.
Emergency Medical Journal. 2020;37(1):19-24
Kondo Y, Ohbe H, Matsui H, Fushimi K, Tanaka
H, Yasunaga H. Proton pump inhibitors versus
histamine-2 receptor antagonists for stress ulcer
prophylaxis during extracorporeal membrane
oxygenation: A propensity score-matchedanalysis. BMJ Open. 2020;10(9):e037534
Konishi T, Fujiogi M, Niwa T, Morita K, Matsui
H, Fushimi K, Tanabe M, Seto Y, Yasunaga H.
Comparison of outcomes after differentiatedthyroid cancer surgery performed with andwithout energy devices: a population-based
cohort study using a nationwide database inJapan. International Journal of Surgery. 2020;77:
198-204
Konishi T, Fujiogi M, Michihata N, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yausnaga H. Treatments and outcomes of
encapsulating peritoneal sclerosis in patients
undergoing peritoneal dialysis: 295 cases from anationwide inpatient database in Japan.
Peritoneal Dialysis International. 2020;40(6):593-599
Konishi T, Fujiogi M, Michihata N, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yausnaga H. Impact of body mass index on
outcomes following breast cancer surgery: a

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nationwide inpatient database study in Japan.
Clinical Breat Cancer. 2020;20(6):e663-e674.
Kurakawa K, Okada A, Jo T, Ono S, Bessho K,
Michihata N, Matsui H, Yamaguchi S, Fushimi K,
Kadowaki T, Yasunaga H. Effects of prophylactic
antibiotics on length of stay and total costs forpediatric acute pancreatitis: a nationwide
database study in Japan. Pancreas. 2020;49(10):1321-1326
Makito K, Matsui H, Fushimi K, Yasunaga H.
Incidences and risk factors for post-dural
puncture headache after neuraxial anaesthesia: anational inpatient database study in Japan.
Anaesthesia and Intensive Care. 2020;48(5):381-388
Makito K, Matsui H, Fushimi K, Yasunaga H.
Volatile versus Total Intravenous Anesthesia for
Cancer Prognosis in Patients Having Digestive
Cancer Surgery: A Nationwide Retrospective
Cohort Study. Anesthesiology. 2020;133(4):764773
Matsuda K, Jo T, Miyauchi M, Toyama K,
Nakazaki K, Matsui H, Fushimi K, Yasunaga H,
Kurokawa M. Primary prophylaxis with
pegfilgrastim in patients with newly-diagnosed
diffuse large B-cell lymphoma: propensity score
and instrumental variable analyses. Leukemia
Lymphom. 2020;61(10):2435-2441
Minami T, Yamana H, Matsui H, Fushimi K,
Yasunaga H. Postoperative Outcomes afterTubeless, Totally Tubeless, Standard andStandard with ureteral stent Percutaneous
Nephrolithotomy: a Nationwide Retrospective
Study in Japan. Urologia Internationalis. 2020;
104(5-6):445-451
Miyakuni Y, Nakajima M, Ohbe H, Sasabuchi Y,
Kaszynski RH, Ishimaru M, Matsui H, Fushimi K,
Yamaguchi Y, Yasunaga H. Angiography versus
colonoscopy in patients with severe lower
gastrointestinal
bleeding:anation-wide
observational study. Acute Medicine & Surgery.
2020;7(1):e533.
Miyamoto Y, Ohbe H, Matsui H, Fushimi K,
Yasunaga H. Effect of carbazochrome sodium
sulfonate in patients with colonic diverticular
bleeding: propensity score matching analyses
using a nationwide inpatient database. Internal

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46.

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Medicine. 2020;59(15):1789-1794
Miyamoto Y, Iwagami M, Aso S, Matsui H, Doi
K, Yasunaga H. Pregabalin and injury: a nested
case-control
andcase-crossoverstudy.
Pharmacoepidemiology and Drug Safety. 2020;29(5):558-564
Miyamoto Y, Aso S, Iwagami M, Morita K,
Fushimi K, Hamasaki Y, Nangaku M, Doi K,
Yasunaga
H.
Expanded
indication
forrecombinant tissue plasminogen activator from 3
to 4.5 hours after onset of stroke in Japan.
Journal of Stroke and Cerebrovascular Diseases.
2020;29(12):105341
Miyamoto Y, Aso S, Iwagami M, Yasunaga H,
Matsui H, Fushimi K, Hamasaki Y, Nangaku M,
Doi K. Association between intravenous thiamineand mortality in patients with septic shock: A
nationwide observational study. Crit Care Med.
2020;48(8):1135-1139
Mouri H, Jo T, Matsui H, Fushimi K, Yasunaga H.
Impact of glucocorticoid supplementation on
reducing perioperative complications in patientson long-term glucocorticoid medication: apropensity score analysis using a nationwide
inpatient database. American Journal of Surgery.
2020;220(3):648-653
Mouri H, Jo T, Matsui H, Fushimi K, Yasunaga H.
Effect of Sugammadex on Postoperative
Myasthenic Crisis in Myasthenia Gravis Patients:
Propensity Score Analysis of a Japanese
Nationwide Database. Anesthesia and Analgesia.
2020;130(2):367-373.
Nakagami G, Morita K, Matsui H, Yasunaga H,
Fushimi K, Sanada H. Association between
pressure injury status and hospital discharge tohome: a retrospective observational cohort study
using a national inpatient database. Annals ofClinical Epidemiology. 2020;2(2):38–50.
Nakajima M, Aso S, Matsui H, Fushimi K,
Yasunaga H. Hyperbaric oxygen therapy andmortality from carbon monoxide poisoning: anationwide observational study. Am J Emerg Med.
2020;38(2):225-230
Nakajima M, Aso S, Matsui H, Kaszynski RH,
Fushimi K, Yamaguchi Y, Yasunaga H.
Prevalence of myocardial injury required
percutaneous coronary intervention in acute

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carbon monoxide poisoning. European Journal of
Emergency Medicine 2020;27(3):213-216.
Nakajima M, Ono S, Michihata N, Kaszynski RH,
Matsui. H, Yamaguchi Y, Yasunaga H.
Epinephrine autoinjector prescription patterns
for severe anaphylactic patients in Japan: A
retrospective analysis of health insurance claims
data. Allergology International. 2020;69:424-428
Nakajima M, Kaszynski RH, Goto H, Matsui H,
Fushimi K, Yamaguchi Y, Yasunaga H. Current
trends and outcomes of extracorporeal
cardiopulmonary resuscitation for out-of-hospital
cardiac arrest in Japan: A nationwide
observational study. Resuscitation Plus 2020;4:100048
Nakamura K, Ohbe H, Matsui H, Takahashi Y,
Marushima A, Inoue Y, Fushimi K, Yasunaga H.
Changes in Real-World Practice Patterns ofAntiepileptic Drugs for Status Epilepticus: aNationwide Observational Study in Japan.
Neurologia medico-chirurgica. 2020;60(3):156163
Nakamura K, Ohbe H, Matsui H, Naraba H,
Nakano H, Takahashi Y, Fushimi K, Yasunaga H.
Phenytoin versus fosphenytoin for second-line
treatment of status epilepticus: propensity scorematching analysis using a nationwide inpatient
database. Seizure. 2020;80:124-130
Obikane E, Yamana H, Yasunaga H, Kawakami N.
Cumulative visits for care of minor injuries areassociated with traumatic brain injury in young
children. Acta Paediatrica. 2020;109(12):27752782
Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H.
Differences in effect of early enteral nutrition on
mortality among ventilated adults with shock
requiring low-, medium-, and high-dose
noradrenaline: a propensity-matched analysis.
Clinical Neutrition. 2020;39(2):460-467
Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H.
Early enteral nutrition in patients with severe
traumaticbrain
injury:apropensity
score-matched analysis using a nationwide
inpatient database in Japan. American Journal of
Clinical Nutrition. 2020;111:378–384
Ohbe H, Morita K, Matsui H, Fushimi K,
Yasunaga H. Stress ulcer prophylaxis plus enteral

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nutrition versus enteral nutrition alone incritically ill patients at risk for gastrointestinal
bleeding:
apropensity-matchedanalysis.
Intensive Care Medicine. 2020;46(10):1948-1949
Ohbe H, Ogura T, Matsui H, Yasunaga H.
Extracorporeal cardiopulmonary resuscitation for
acute aortic dissection during cardiac arrest: anationwide retrospective observational study.
Rescuscitation. 2020;156:237-243
Ohbe H, Goto T, Miyamoto Y, Yasunaga H. Riskof cardiovascular events after spouse’s ICU
admission. Circulation. 2020;142(17):1691-1693
Okada A, Yamana H, Yamaguchi S, Kurakawa K,
Matsui H, Fushimi K, Nangaku M, Kadowaki T,
Yasunaga H. Outcomes of Lactulose plus
Branched-Chain Amino Acid Infusion andLactulose Alone for Hepatic Encephalopathy: A
Retrospective Cohort Study Using a National
Inpatient Database. Hepatology Research. 2020;50(6):693-703
Okubo Y, Miura M, Kobayashi T, Morisaki N,
Michihata N, Matsui H, Fushimi K, Yasunaga H.
The impact of changes in clinical guideline onpractice patterns and healthcare utilizations for
Kawasaki disease in Japan. Frontiers in Pediatrics,
section Pediatric Immunology. 2020;8:114.
Okubo Y, Uda K, Kinoshita N, Horikoshi Y,
Miyairi I, Michihata N, Matsui H, Fushimi K,
Yasunaga H. National trends in appropriate
antibiotics use among pediatric inpatients with
uncomplicated lower respiratory tract infectionsin Japan. Journal of Infection and Chemotherapy.
2020;26(11):1122-1128
Okubo Y, Horimukai K, Michihata N, Morita K,
Matsui H, Fushimi K, Yasunaga H. Recent
Practice Patterns and Variations in Children
Hospitalized for Asthma Exacerbation in Japan.
Int Arch Allergy Immunol. 2020; 181(12); 926933
Ono S, Ono Y, Koide D, Yasunaga H.
Relationshipbetweensevererespiratory
depression and codeine-containing antitussives inchildren: a nested case-control study. Journal of
Epidemiology. 2020;30(3):116-120
Ono S, Ono Y, Koide D, Yasunaga H. Association
between routine nephropathy monitoring andsubsequent change in estimated glomerular

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filtration rate in patients with diabetes mellitus: aJapanese non-elderly cohort study. Journal of
Epidemiology. 2020;30(8):326-331
Otaka S, Aso S, Matsui H, Fushimi K, Yasunaga
H. Early versus late rib fixation in patients withtraumatic rib fractures: a nationwide study.
Annals of Thoracic Surgery. 2020;110(3):988992.
Otaka S, Aso S, Matsui H, Fushimi K, Yasunaga
H. Effectiveness of surgical fixation for rib
fractures in relation to its timing: A retrospective
Japanese nationwide study. European Journal ofTrauma and Emergency Surgery 2020;18:1-8.
Sakamoto T, Fujiogi M, Matsui H, Fushimi K,
Yasunaga
H.
Short-term
outcomesoflaparoscopic and open total gastrectomy for
gastric cancer: a nationwide retrospective cohort
analysis. Annals of Surgical Oncology. 2020;27(2):518-526
Sakamoto T, Fujiogi M, Matsui H, Fushimi K,
Yasunaga H. Timing of cholecystectomy after
percutaneous transhepatic gallbladder drainage
for acute cholecystitis: a nationwide inpatient
database study. HPB. 2020;22:920-6
Sakamoto T, Fujiogi M, Matsui H, Fushimi K,
Yasunaga H. Clinical features and outcomes ofnonocclusive mesenteric ischemia after cardiac
surgery: a retrospective cohort study. Heart andVessels. 2020;35(5):630-636
Sakamoto T, Fujiogi M, Lefor AK, Matsui H,
Fushimi K, Yasunaga H. Stent as a bridge tosurgery or immediate colectomy for malignant
right colonic obstruction: propensity-scored,
national database study. Brit J Surg. 2020;
107(10):1354-1362.
Sato D, Uda K, Kumazawa R, Matsui H,
Yasunaga H. Mortality and morbidity following
postoperative use of short-term, low-dose
quetiapine versus risperidone in patients withdiabetes: analysis using a national inpatient
database. Pharmacoepidemiology and Drug
Safety. 2020;29(12):1703-1709.
Shigemi D, Ishimaru M, Matsui H, Fushimi K,
Yasunaga H. Suicide attempts during pregnancy
and perinatal outcomes. Journal of PsychiatricResearch. 2020;133:101-105
Shigemi D, Ishimaru M, Matsui H, Fushimi K,

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79.

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Yasunaga H. Suicide attempts among pregnant
and postpartum women in Japan: a nationwide
retrospective cohort study. J Clin Psychiatry.
2020;81(3):19m12993
Shigemi D, Morishima T, Shibata A, Tabuchi T,
Yasunaga H, Miyashiro I. Comparison of overallmortality between hysterectomy and concurrent
chemoradiotherapy for the primary treatment oflocalized or regionally extended cervical cancer.
Annals of Clinical Epidemiology. 2020; 2(3):75-83
Shoji K, Michihata N, Miyairi I, Matsui H,
Fushimi K, Yasunaga H. Recent Epidemiology of
Pneumocystis Pneumonia in Japan. Journal of
Infection and Chemotherapy. 2020;26(12):12601264
Suzuki J, Sasabuchi Y, Hatakeyama S, Matsui H,
Sasahara T, Morisawa Y, Yamada T, Yasunaga H.
Histamine-2 receptor antagonists versus proton
pump inhibitors for septic shock after lower
gastrointestinal tract perforation: A retrospective
cohort study using a national inpatient database.
Journal of Intensive Care. 2020;8:56.
Suzuki J, Sasabuchi Y, Hatakeyama S, Matsui H,
Sasahara T, Morisawa Y, Yamada T, Yasunaga H.
The effect of antithrombin added to recombinanthuman soluble thrombomodulin for severe
community-acquired
pneumonia-associateddisseminated intravascular coagulation: aretrospective cohort study using a nationwide
inpatient database. J Intensive Care. 2020;8:8
Suzuki T, Michihata N, Yoshikawa T, Hata T,
Matsui H, Fushimi K, Yasunaga H. High-doseversus low-dose intravenous immunoglobulin fortreatment of children with Kawasaki disease
weighing 25 kg or more. European Journal of
Pediatrics. 2020;179(12):1901-1907
Takiguchi T, Nakajima M, Ohbe H, Sasabuchi Y,
Matsui H, Fushimi K, Kim S, Yokota H,
Yasunaga H. Vasodilator therapy and mortality in
non-occlusive mesenteric ischemia: a nationwide
observational study. Crit Care Med. 2020;48(5):e356-e361.
Tanaka H, Yamana H, Matsui H, Fushimi K,
Yasunaga H. Proportion and risk factors ofcholesterol
crystalembolization
after
cardiovascular procedures: a retrospective

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national database study. Heart and Vessels. 2020;35(9):1250-1255
Taniguchi K, Ohbe H, Yamakawa K, Matsui H,
Fushimi K, Yasunaga H. Antithrombin use andmortality in patients with stage IV solid
tumor-associated disseminated intravascular
coagulation: A nationwide observational study inJapan. BMC Cancer. 2020;20(1):867
Tsuda Y, Tsoi K, Stevenson JD, Laitinen M,
Ferguson P, Wunder J, Griffin A, van de Sande
MAJ, van Praag VM, Leithner A, Fujiwara T,
Yasunaga H, Matsui H, Parry MC, Jeys LM.
Development and external validation of
nomograms to predict sarcoma-specific death anddisease progression after surgical resection of
localised high-grade conventional primary central
chondrosarcoma
anddedifferentiatedchondrosarcoma: a retrospective, multicentre,
cohort study. The Bone & Joint Journal. 2020;
102-B(12):1752-1759
Ugata Y, Michihata N, Matsui H, Fushimi K,
Yasunaga H. Periprocedural hypotension after
conscious sedation versus local anesthesia during
defibrillator implantation for left ventricular
dysfunction: Analysis of a national inpatient
database in Japan. Heart and Vessels. 2020;
35:118–124
Ugata Y, Michihata N, Matsui H, Fushimi K,
Yasunaga H. Optimal timing and safety of
non-vitamin K antagonist oral anticoagulant for
atrial-fibrillation-related ischemic stroke. Annalsof Clinical Epidemiology. 2020;2(1):3-12.
Yamagami R, Inui H, Jo T, Kawata M, Taketomi
S, Kono K, Kawaguchi K, Sameshima S, Kage T,
Matsui H, Fushimi K, Yasunaga H, Tanaka S.
Unicompartmental
Knee
Arthroplastyis
Associated with Lower Proportions of SurgicalSite Infection Compared with Total Knee
Arthroplasty: A Retrospective Nationwide
Database Study. The Knee. 2020;28:124-130
Yamana H, Ono S, Okada A, Jo T, Yasunaga H.
Association
betweenmandatory
healthexamination attendance and diabetes treatment
initiation among employees being treated for
hypertension. Journal of Occupational Health.
2020;62(1):e12183.
Yamana H, Ono S, Michihata N, Jo T, Yasunaga

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H.
Outpatientprescriptionof
Kampo
formulations in Japan. Internal Medicine. 2020;
59(22):2863-2869
92. Yasunaga H. Protection of personal informationin real-world data in Japan. Annals of Clinical
Epidemiology. 2020;2(1):1-2.
93. Yasunaga H. Introduction to Applied Statistics—
Chapter 1 Propensity Score Analysis. Annals ofClinical Epidemiology. 2020;2(2):33–37
94. Yonezawa N, Jo T, Matsui H, Fushimi K,
Yasunaga H. Effect of Early Tracheostomy on
Mortality of Mechanically Ventilated Patients
With Guillain–Barré Syndrome: A Nationwide
Observational Study. Neurocritical Care. 2020;33(3):759-768.

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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

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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

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characteristics with their communication behaviors,
and impacts of the communication on patient
outcomes.
7.
■ 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.

8.

References
1.

2.

3.

4.

5.

6.

Okuhara T, Ishikawa H, Ueno H, Okada H,
Kiuchi T. Examining Long-Term Effects of
Human Papillomavirus Vaccine Recommendation
Messages: A 4-Month Follow-up Survey of a
Randomized Controlled Study in Japan.
Healthcare. 2020;8(4):549.
Okuhara T, Okada H, Kiuchi T. Predictors of
Staying at Home during the COVID-19 Pandemic
and Social Lockdown based on Protection
Motivation Theory: A Cross-sectional Study inJapan. Healthcare.2020;8:275.
Okuhara T, Ishikawa H, Ueno H, Okada H,
Kiuchi T. Dual-process theories to counter
against anti-vaccination movement. Preventive
Medicine Reports. 2020;20:101205.
Goto E, Ishikawa H, Okuhara T, Ueno H, Okada
H, Fujino Y, Kiuchi T. Presenteeism among
workers: health-related factors, work-related
factors, and health literacy. Occupational
Medicine. 2020;70(8):564-569.
Okuhara T, Okada H, Kiuchi T. Examining
persuasive message type to encourage staying at
home during the COVID-19 pandemic and social
lockdown: A randomized controlled study inJapan. Patient Education and Counseling. 2020;
103(12):2588-2593.
Yokota R, Okuhara T, Ueno H, Okada H,
Furukawa E, Kiuchi T. Online JapaneseLanguage Information on Lifestyle Factors

9.

Associated With Reduced Fertility: Content
Analysis. Journal of Medical Internet Research.
2020;22(8):e19777.
Miyaji T, Kawaguchi T, Azuma K, Suzuki S,
Sano Y, Akatsu M, Torii A, Kamimura T, Ozawa
Y, Tsuchida A, Eriguchi D, Hashiguchi M,
Nishino M, Nishi M, Inadome Y, Yamazaki T,
Kiuchi T, Yamaguchi T. Patient-generated healthdata collection using a wearable activity tracker
in cancer patients-a feasibility study. Support
Care Cancer. 2020; 28, 5953-5961.
Okuhara T, Ishikawa H, Ueno H, Okada H, Kato
M, Kiuchi T. Influence of high versus low
readability level of written health information on
self-efficacy: a randomized controlled study ofthe processing fluency effect. Health Psychology
Open 2020; 7(1):2055102920905627.
Haragi M, Yamaguchi R, Okuhara T, Kiuchi T.
Questionnaire survey of a mock jury on theirimpressions of medical-legal illustrations aimed
at reducing trauma and PTSD of jurors. Journalof Visual Communication in Medicine. 2020;14:
1-9.

School of Public Health
2. Behavioral Health Sciences

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Departments ofHealth and Social Behavior &Health Education and HealthSociology
Professor in health and social behavior
Hideki Hashimoto, M.D., D.PH.

Associate Professor in health education and health sociology
Naoki Kondo, M.D., Ph.D. (moved to Kyoto University in September 2021)

Lecturer
Daisuke Takagi, Ph. D.

Associate
Masamitsu Kamada, Ph. D.

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.

359

1. Graduate Courses, School of Public Health
1) Health and Society I & II: The course highlights
the significance of social determinants of health(SDH) as a key exposure causing social gradientof health. A series of omnibus lectures, eachfocusing a specific topic of SDH (e.g. income
distribution,
gender,job
stress,anddiscrimination), are provided by invitedlecturers specialized in the field. The course isfollowed by course II which offers application ofconcepts into practice through in-classdiscussion and group works.
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).
The department contributed to extend educational
environment in the new frame of School curriculum
policy, and management of educational duties withlimited resources became a challenge.

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

360

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.
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 also joined with Departments of
Public Health, Medical Informatics, and Health
Economics and Clinical Epidemiology the management of National claim Data Base and onsite research
center under the contract with the Ministry of Health,Welfare, and Labour to extend empirical healthcare
research using a representative big administrative data
until 2019. Since 2020, the project is undermanagement by the Department of Clinical
Epidemiology and Health Economics, led by Prof. H.
Yasunaga.
Dr. Kondo also is an active and leading coreresearcher in another 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. The team has been developing community
diagnosis tool using JAGES data to support
participating municipalities to effectively findleverage population for policy intervention. The
developed tools have been disseminated andstandardized for wider use in municipalities.
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.

Other Social activities
Some faculty members and graduate students
contributed to support public health centers andtracing activities by a special section in the Ministryof Health, Labour, Welfare for contact tracing,
epidemiology survey, consultation, and patient
trajectory. The part of activity results was publishedin Japanese for reference to support academic-public
sector collaboration for risk management under the
emergency situations.

Publications
1.

2.

3.

Kasajima M, Hashimoto H, Suen SC, Chen B,
Jalal H, Eggleston K, Bhattacharya J. Future
projection of the health and functional status ofolder people in Japan: A multistate transition
microsimulation model with repeated crosssectional data. Health Econ. 2020 Jul 14. doi:
10.1002/hec.3986.
Kawaguchi H, Moriyama M, Hashimoto H. Does
disease management for diabetic nephropathy
reduce medical expenditure? Evidence from athree-period difference-in-differences analysis.
BMC Health Serv Res. 2020 May 11;20(1):403.
doi:10.1186/s12913-020-05297-0.
Kato A, Fujimaki Y, Fujimori S, Isogawa A,
Onishi Y, Suzuki R, Ueki K,Yamauchi T,
Kadowaki T, Hashimoto H. How self-stigma
affects patient activation in persons with type 2
diabetes: a cross-sectional study. BMJ Open.

361

2020 May 17; 10(5): e034757. doi: 10.1136/
bmjopen-2019-034757.
4. Takagi D, Yokouchi N, Hashimoto H.Smoking
behavior prevalence in one’s personal social
network and peer’s popularity: A populationbased study of middle-aged adults in Japan.
Social Science & Medicine, Volume 260, 2020,
https://doi.org/10.1016/j.socscimed.2020.11320
7.
5. Yokouchi N, Hashimoto H. Evolving selfconcept in the workplace and associatedexperience of stress: A case of a large Japanesecompany, Journal of Workplace Behavioral
Health, 2020, DOI: 10.1080/15555240.2020.
1809438
6. Kawakami N, Watanabe K, Nishi D, Takagi D,
Hashimoto H, Tanaka SC. Time preference andpersonal value: a population-based crosssectional study in Japan. BMC Psychol. 2020
Aug 17; 8(1): 85. doi: 10.1186/s40359-02000458-6.
7. Kasajima M, Hashimoto H. Social policies andchange in education-related disparities inmortality in Japan, 2000–2010, SSM –Population Health, 12, 2020. https://doi.org/10.
1016/j.ssmph.2020.100692.
8. Lee W, Ebi KL, Kim Y, Hashizume M, Honda Y,
Hashimoto H, Choi HM, Choi M, Kim H. Heatmortality risk and the population concentrationof metropolitan areas in Japan: a nationwide
time-series study. Int J Epidemiol. 2020 Dec 21:
dyaa245. doi: 10.1093/ije/dyaa245.
9. Yano M, Hashimoto H. Qualitative study on
decision making process in “voluntary”
withdrawal of drivers license. Jp J Public Health67(11):811-818, 2020.
10. N Hatakeyama, M Kamada, N Kondo. Parental
working hours and children’s sedentary time: across-sectional analysis of the J-SHINE. J
Epidemiol 2020 https://doi.org/10.2188/jea.
JE20200170.
11. EK Yeoh, KC Chong, CJ. Chiew, VJ. Lee, CW
Ng, H Hashimoto, S Kwon, W Wang, NS Chau,
HK Yam, TY Chow, CT Hung. Assessing theimpact of non-pharmaceutical interventions on
the transmissibility and severity of COVID-19
during the first five months in the Western

Pacific Region, One Health, 2021, 100213.
https://doi.org/10.1016/j.onehlt.2021.100213.
12. Sumino K, et al. Report of Public Health
Activities. Collaborative activities between
academic institutes and public health centers
under public health emergency of COVID-19.
https://doi.org/10.11236/jph.20-088.

School of Public Health
3. Health Services Sciences

363

Department of Clinical
Information Engineering
Professor
Hiroshi Oyama, M.D., Ph.D.
Research Associate

Toki Saito, Ph.D.
Ayako Kohyama-Koganeya, Ph.D.

Homepage:

http://park.itc.u-tokyo.ac.jp/CIEMedUTokyo/wp/

Introduction and Organization
Information engineering in Japan places a great dealof weight on computer hardware, software, and dataprocessing. It is a discipline that seeks objective dataand emphasizes the conception of new methods ofdata transfer, storage, processing, and input/output. It
also targets research on developing computer devices
and systems.
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 be used as atool to help human thinking, such as in presentations,design, and discovery. When computers became
connected to each other through the internet, thedistribution of information became very easy andrapid, not only within organizations, but alsointernationally.
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 the Ministry of Education,
Culture, Sports, Science, and Technology, of Japan.

Teaching activities
The purpose of the Department of Clinical
Information Engineering is to nurture talented people
who have special knowledge and skills at aninternational level in order to apply advanced
information technologies to practical projects inclinical medicine and the health sciences. It offers
courses on information system design, development
methodology, evaluation and project management inbiomedicine, health care and public health in the
School of Public Health, and data mining and virtual
reality for clinical decision-making in social medicine.
Famous visiting lecturers and researchers from the
National Cancer Center and other universities havegiven lectures here, furthering our hope of becoming aworld leader in this field.

364

The education of graduate students is based on
weekly conferences at which the students present the
progress on their own research projects and discuss
their future directions.

References
1.

Research activities
Our research covers the biomedical computer
applications that focus on biomedical data (collection,
analysis, and representation). It constitutes a
combination of information science, computer science,and clinical science designed to assist in the
management and processing of data, information, andknowledge to support the practice and delivery ofclinical care. Our laboratory is engaged in thefollowing research activities:(1) Computer Graphics & Virtual Reality (VR) for
Medical Science: Our research has three goals:(1) to improve the living conditions of in-patientswith limited physical activity by providing virtual
experiences; (2) to develop new diagnostic
methods using medical imaging; and (3) todevelop a surgical edutainment and preoperative
surgical planning support system in virtual space.
The advantages of simulating surgical procedures
using VR techniques include: (1) practicing thesurgical procedure and image-based training; (2)planning the surgical procedure for individual
patients preoperatively using VR images modeledfrom the patient's preoperative computed tomography (CT) or magnetic resonance (MR) images,
in collaboration with the Department of Neurosurgery; (3) allowing supervisors to evaluate aprocedure objectively; and (4) helping patientsand their families to better understand the surgicalprocedure before and after the operation.
(2) Social Information Engineering for Public Health(Public Health Informatics): Our laboratory
researches new tools and methodologies for
applying information and computer science andtechnology to public health practice, research,and learning.
At present, we are studying
differences in the computerization of publichealth in the US and Japan.

2.

Sato S, Guan LW, Nagayo Y, Saito T, KohyamaKoganeya A, Kashiwagi K, et al. Effects ofVirtual Reality Practices as Simulation-based
Education on Multi Tasks of Nursing. J Med
Virtual Real. 2020;17(1):15–22.
Morita I, Kohyama-Koganeya A, Saito T, Obuchi
C, Oyama H. VRAT: A Proposal of Training
Method for Auditory Information Processing
Using Virtual Space. J Med Virtual Real. 2020;17(1):23–32.

365

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 since April 2018,
and affiliated with the School of International Health(SIH), Graduate School of Medicine since July 2018as an Associate Department. 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 a short-term effect ofenvironmental risk factors on human health.
This year, we contributed to the postgraduate course
under Graduate School of Medicine, entitled “General

Lecture in Medical SciencesⅩⅩⅩⅡ（Basic Tools forPopulation/Public Health Research）,” by providing a
lecture series on Medical Statistics (Part1).
GEH journal club
GEH 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 Tuesday, 11:00-12:30
Students present fundamental knowledge and skills of
R language and its applications that they learned from
R textbooks and/or research articles in the field ofenvironmental epidemiology. Sharing the basic andadvanced methodologies and discussion help students
facilitate developing their capability to implement
research projects.

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:366

1. Global perspectives of seasonal variability ofsuicide and the short-term associations between
suicide and ambient temperature and air pollution
including daily time-series database across 19
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. Establishment of an early warning system for
malaria incidence in southern Africa

Publications
1. Lee W, Kim Y, Sera F, Gasparrini A, Park R,
Choi MH, Prifti K, Bell ML, Abrutzky R, Guo Y,
Tong S, Coelho MSZS, Saldiva PHN, Lavigne E,
Orru H, Indermitte E, Jaakkola JJK, Ryti NRI,
Pascal M, Goodman P, Zeka A, Hashizume M,
Honda Y, Diaz M, Valencia CDC, Overcenco A,
Nunes B, Teixeira JP, Scovronick N, Acquaotta F,
Tobias A, Vicedo-Cabrera AM, Ragettli MS, Guo
YL, Chen BY, Li S, Armstrong B, Zanobetti A,
Schwartz J, Kim H. Projections of excess
mortality related to diurnal temperature range
under climate change: A multi-country study. The
Lancet Planetary Health 2020:4: e512–21.
2. Yu J, Yang D, Kim Y, Hashizume M, Gasparrini
A, Armstrong B, Honda Y, Tobias A, Sera F,
Vicedo-Cabrera AM, Kim H, Íñiguez C, Lavigne
E, Ragettli MS, Scovronick N, Acquaotta F, Chen
B, Guo YL, Coelho MSZS, Saldiva PHN,
Zanobetti A, Schwartz J, Bell ML, Diaz M,
Valencia CDC, Holobâc I, Fratianni S, Chung Y.
Seasonality of Suicide: A Multi-Country MultiCommunity Observational Study. Epidemiology
and Psychiatric Sciences 2020:29: e163.
3. Lee W, Hwang S-S, Song I, Park C, Kim H, Song
I-K, Choi HM, Prifti K, Kwon Y, Kim J, Oh S,
Yang J, Cha M, Kim Y, Bell ML, Kim H.
COVID-19 in South Korea: epidemiological andspatiotemporal patterns of the spread and the roleof aggressive diagnostic tests in the early phase.
International Journal of Epidemiology 2020:49:
1106–1116.
4. Hashizume M, Kim Y, Ng CFS, Chung Y,
Madaniyazi L, Bell ML, Guo YL, Kan H, Honda
Y, Yi SM, Kim H, Nishiwaki Y. Health effects ofAsian dust: a systematic review and meta-analysis.
Environmental Health Perspectives 2020:128(6):066001.
5. Sim K, Kim Y, Hashizume M, Gasparrini A,
Armstrong B, Sera F, Ng CFS, Honda Y, Chung
Y. Nonlinear temperature-suicide association in
Japan from 1972–2015: its heterogeneity and therole of climate, demographic, and socioeconomic
factors. Environment International 2020:142:
105829.

Endowed Department

368

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 Researcher
Kiminori Shimamoto, M.E.

Homepage https://ai-health.m.u-tokyo.ac.jp/
Introduction and Organization

Teaching activities

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
basedoninformation
andcommunications technology (ICT) as well as artificial
intelligence (AI), become indispensable. This course
was established 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.

We have promoted activities to train researchers aswell as students in this area inside and outside theuniversity. In 2020, 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 practical training
for the Nara Institute of Science and Technology
doctoral students and Kobe University School of
Medicine 6th-year students (M4); research guidance
was provided at the individual level.

Research activities
Development of natural language
technique for medical treatment

processing

Symptoms and clinical findings, the relationshipbetween these and treatment actions are freely

369

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.
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 theglomerulus. 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.

Gave 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.

References
1. 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.
Comput Inform Nurs. 2021 May 12.
2. Yamaguchi R, Kawazoe Y, Shimamoto K, Shinohara
E, Tsukamoto T, Shintani-Domoto Y, Nagasu H,
Uozaki H, Ushiku T, Nangaku M, Kashihara N,
Shimizu A, Nagata M, Ohe K. Glomerular
Classification
Using
Convolutional
NeuralNetworks Based on Defined Annotation Criteria andConcordance Evaluation Among Clinicians. Kidney
Int Rep. 2020 Dec 13;6(3):716-726.
3. Iwai S, Mitani T, Hayakawa J, Shinohara E, Imai
T, Kawazoe Y, Ohe K. Development ofgraph-basedalgorithm
fordifferentiating
pathophysiological conditions. Applied Medical
Informatics. Vol. 42, No. 2/2020.
4. Kenya Sakka, Kotaro Nakayama, Nisei Kimura,Taiki Inoue, Yusuke Iwasawa, Ryohei Yamaguchi,
Yoshimasa Kawazoe, Kazuhiko Ohe, Yutaka
Matsuo. Character-level Japanese Text Generation
with Attention Mechanism for Chest Radiography
Diagnosis AAAI Workshop on Artificial
Intelligence, February 7-8, 2020, New York, USA.

370

Health Economy and Society
PolicyProject Professor
Tomoyuki Takura, Ph.D, MEng.

Project Lecturer
Sayaka Horiuchi, MPH, MD
Mariko Tsuji, MD
Ayako Fuchigami, MD
Ayako Okuma, MD

Homepage

http://plaza.umin.ac.jp/hehp/

Introduction and Organization
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.

Education
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371

and health behavior (adherence) on the disease
burden and the financial burden (includinginternational comparison).
3) Testing and developing methods for evaluating laborproductivity (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 also have aplan to start a study that applies computational financeto forecast the market value of research anddevelopment projects.

5.

References
1.

2.

3.

4.

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 Jan 18. doi: 10.1007/s12350-02002502-9.
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 ofhealthcare big data of patients with circulatory
diseases. BMC medicine. 2021 Jan 8;19(1):15.
doi: 10.1186/s12916-020-01874-6.
Kamiya K, Sato Y, Takahashi T, TsuchihashiMakaya M, Kotooka N, Ikegame T, Takura T,
Yamamoto T, Nagayama M, Goto Y, Makita S,
Isobe M. Multidisciplinary Cardiac Rehabilitationand Long-Term Prognosis in Patients With Heart
Failure. Circ Heart Fail. 2020;13(10):e006798.
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,

6.

7.

8.

9.

Manabu Ito, Naohisa Miyakoshi, Hideki
Murakami, Kazuo Yonenobu, Tomoyuki Takura,
Joji Mochida. Comparison of the Effectiveness of
Pharmacological Treatments for Patients with
Chronic Low Back Pain: A Nationwide,
Multicenter Study in Japan. Spine Surg Relat Res.
2020 Nov 20; 5(4): 252-263. doi: 10.22603/ssrr.
2020-0083. eCollection 2021.
Miyakoshi N, Kudo D, Matsuyama Y, Yamashita
T, Kawakami M, Takahashi K, Yoshida M, Kaito
T, Imagama S, Ohtori S, Taguchi T, Haro H,
Taneichi H, Yamazaki M, Inoue G, Nishida K,
Yamada H, Kabata D, Shintani A, Iwasaki M, Ito
M, Murakami H, Yonenobu K, Takura T, Mochida
J. Impact of Consultation Length on Satisfactionin Patients with Chronic Low Back Pain: A
Nationwide Multicenter Study in Japan. Spine
Surg Relat Res. 2020;4(3):208-215.
Imagama Shiro, Murakami Hideki, Kaito Takashi,
Matsuyama Yukihiro, Yamashita Toshihiko,
Kawakami Mamoru, Takahashi Kazuhisa, Yoshida
Munehito, Ohtori Seiji, Taguchi Toshihiko, Haro
Hirotaka, Taneichi Hiroshi, Yamazaki Masashi,
Inoue Gen, Nishida Kotaro, Yamada Hiroshi,
Kabata Daijiro, Shintani Ayumi, Iwasaki Motoki,
Ito Manabu, Miyakoshi Naohisa, Yonenobu
Kazuo, Takura Tomoyuki, Mochida Joji. Impact ofbackgroundfactorsonoutcomesofpharmacological therapy for chronic low backpain: A nationwide multicenter prospective study.
J Orthop Sci. 2021 26(1):92-102.
Ueda Kaname, Takura Tomoyuki, Fujikoshi Shinji,
Meyers Juliana, Nagar Saurabh P, Enomoto
Hiroyuki. Longitudinal Assessment of PainManagement Among the Employed Japanese
Population with Knee Osteoarthritis. Clinicalinterventions in aging. 2020 15; 1003-1012.
Tomoaki Nakata, Tomoyuki Takura, Hiroyoshi
Yokoi, Kenichi Nakajima, Shun Kohsaka,
Akiyoshi Hashimoto, Masato Nakamura. Designof the Japanese Comprehensive Health-Economic
Assessment for Appropriate Cardiac Imaging
Strategy Including Outcome and CostEffectiveness in Stable Coronary Artery Disease
Study (J-CONCIOUS). Circulation Reports. 2020;2(12): 759-763
Tomoyuki Takura, Hideki Kawanishi. Health372

Economic Evaluation of Peritoneal Dialysis Basedon Cost-Effectiveness in Japan. ISPD Asia-Pacific
Chapter Newsletter. 2020; 18 (1): 18-21

373

Department of medical researchand the management ofmusculoskeletal pain
Professor
Koh Matsudaira, M.D,Ph.D.

Associate Professor
Hiroyuki Oka, M.D,Ph.D.

Assistant professor
Tomoko Fujii, 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.,
ChugaiPharmaceutical Co., Ltd., SOMPO Holdings, Inc.,
NuVasive Japan Co., Ltd., Promotion of Practical Useof AI Medical Diagnosis Support Equipment,
MS&AD InterRisk Research & Consulting, Inc,
Inotech Co., Ltd., The Association for Preventive
Medicine in Japan, DeNA Co., Ltd., Ibuki LLC. The
department is a collaboration among the Departmentof Orthopaedics, 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.

374

Research activities
We will explore the risk factors that contribute todetermining the therapeutic strategy for treatingmusculoskeletal pain and the prognosis.

3.

Prospects for future research
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.

7.

References
1.

2.

Yoshimoto T, Oka H, Fujii T, Nagata T,
Matsudaira K. The Economic Burden of Lost
Productivity due to Presenteeism Caused byHealth Conditions Among Workers in Japan. J
Occup Environ Med. 62(10):883-888. 2020
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,

8.

Haga N, Tanaka S. Prediction of pathologicalfracture in patients with lower limb bonemetastasis using computed tomography imaging.
Clin Exp Metastasis. 37(5):607-616.2020
Oshima Y, Inanami H, Iwai H, Koga H, Takano Y,
Oshina M, Oka H, Tanaka S. Is Microendoscopic
Discectomy Effective for Patients With
Concomitant Lumbar Disc Herniation andSpondylolysis? Global Spine J. 10(6):700-705.
2020
Murakami K, Nagata K, Hashizume H, Oka H,
Muraki S, Ishimoto Y, Yoshida M, Tanaka S,
Minamide A, Nakagawa Y, Yoshimura N,
Yamada H. Prevalence of cervical anterior andposterior spondylolisthesis and its association
with degenerative cervical myelopathy in a
general population. Sci Rep. 10(1):10455. 2020
Kakihana H, Jinnouchi H, Kitamura A,
Matsudaira K, Kiyama M, Hayama-Terada M,
Muraki I, Kubota Y, Yamagishi K, Okada T,
Imano H, Iso H. Overweight and Hypertension in
Relation to Chronic Musculoskeletal Pain Among
Community- Dwelling Adults: The Circulatory
Risk in Communities Study (CIRCS). J
Epidemiol. 2020.
Otsuka S, Moriguchi J, Nishida N, Ohashi F,
Saito N, Okuda T, Kawamata K, Matsudaira K,
Tabuchi M, Oka H. The effects of a two-minute
original exercise program supported by the
workplace unit on the workers' work
engagement: the "Bipoji" exercise. J Phys Ther
Sci. 32(6):410-413. 2020
Umezaki S, Shinoda Y, Mukasa A, Tanaka S,
Takayanagi S, Oka H, Tagawa H, Haga N,
Yoshino M. Factors associated with healthrelated quality of life in patients with glioma:
impact of symptoms and implications forrehabilitation. Jpn J Clin Oncol. 50(9):990-998.
2020
Horii C, Asai Y, Iidaka T, Muraki S, Oka H,
Tsutsui S, Hashizume H, Yamada H, Yoshida M,
Kawaguchi H, Nakamura K, Akune T, Oshima Y,
Tanaka S, Yoshimura N. The incidence and risk
factors for adjacent vertebral fractures incommunity- dwelling people with prevalentvertebral fracture: the 3rd and 4th survey of the
ROAD study. Arch Osteoporos. 15(1):74. 2020

375

9.

Inanami H, Iwai H, Kaneko T, Oshina M,
Manabe N, Takano Y, Yuzawa Y, Segawa T,
Yanagisawa K, Hirai S, Saiki F, Fukushima M,
Oka H, Matsudaira K, Oshima Y, Koga H.
Relationship between lumbar lordosis and theratio of the spinous process height to the anterior
spinal column height. Sci Rep. 10(1):6718. 2020
10. Nagata K, Oshima Y, Nakamoto H, Sakamoto R,
Ohtomo N, Izuka M, Nakajima K, Yoshimoto T,
Fujii T, Matsudaira K, Tanaka S, Oka H. Validityof the Japanese Core Outcome Measures Index(COMI)-Back for thoracic and lumbar spine
surgery: a prospective cohort study. Eur Spine J.
29(6):1435-1444. 2020

376

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.

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 byosteoclasts and osteoblasts, respectively.
An

377

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 (Asano et al, Nat Metab, 2019).
Soluble RANKL deficiency in mice markedly
suppressed the metastasis of murine melanoma cellline B16F10 and breast cancer cell line EO771, bothof which express RANK, to bone. Interestingly, therecent human study indicates that breast cancer
patients with high levels of serum RANKL had anincreased risk of developing bone metastases. Thus,
to measure the serum RANKL level may help identify
the patients who have a high risk of development ofbone metastasis.

378

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
reduced the number of both common lymphoidprogenitors in the bone marrow and lymphocytes in379

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. Tsukasaki M, Huynh NC, Okamoto K, Muro R,
Terashima A, Kurikawa Y, Komatsu N,
Pluemsakunthai W, Nitta T, Abe T, Kiyonari H,
Okamura T, Sakai M, Matsukawa T, Matsumoto
M, Kobayashi Y, Penninger JM, Takayanagi H.
Stepwise cell fate decision pathways duringosteoclastogenesis at single-cell resolution.
Nature Metabolism, 2: 1382-1390, 2020
2. Tsukasaki M, Asano T, Muro R, Huynh NC,
Komatsu N, Okamoto K, Nakano K, Okamura T,
Nitta T, Takayanagi H. OPG production matterswhere it happened. Cell Reports, 32: 108124,
2020

380

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.,
Katsura Soma, M.D.,Ph.D., Katsuhiro Koyama, M.D., Ph.D., Fujiwara Takayuki, M.D.,
Ph.D., Nakao Takahiro, M.D., Ph.D., Fujita Kanna, 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
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 three project associate
professors, five project research associates and two
project researchers, along with a medical staff ofapproximately 50 employees in the health-screening

center.

Clinical Activities
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

381

themes include image analysis such as computerassisted detection, or epidemiologic studies employing
health-screening data.
3)

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.

4)

5)

6)

7)

8)

References
1)

Nomura Y, Nemoto M, Hayashi N, Hanaoka S,
Murata M, Yoshikawa T, et al. Pilot study oferuption forecasting with muography using
convolutional neural network. Scientific reports
2020;10(1):-.
2) Nomura Y, Miki S, Hayashi N, Hanaoka S, Sato I,
Yoshikawa T, Masutani Y, Abe O
Novel platform for development, training, andvalidation of computer-assisted detection

9)/diagnosis software
Int J Comput Assist Radiol Surg. 2020 Apr;
15(4):661-672
Ueha R, Maeda E, Ino K, Shimizu T, Sato T,
Goto T, Yamasoba T. Sleep-Induced G
lottis Closure in Multiple System Atrophy
Evaluated by Four-Dimensional Computed
Tomography. Front Med (Lausanne). 2020 Apr
17;7:132.
Saito A, Amiya E, Soma K, Inaba T, Maki H,
Hatano M, Yao A, Morita H, Komuro I.
Fractional exhaled nitric oxide in adult congenital
heart disease.
Nitric oxide : biology and chemistry. 2020 Aug 1;
100-101:45-9.
Yoshikawa M, Asaba K. Single-nucleotide
polymorphism rs4664308 in PLA2R1 gene isassociated with the risk of idiopathic
membranous nephropathy: a meta-analysis.
Scientific Reports. 2020 Aug;10(1):13119.
Saito A, Amiya E, Soma K, Inaba T, Maki H,
Hatano M, Yao A, Morita H, Komuro I.
Fractional exhaled nitric oxide in adult congenital
heart disease.
Nitric oxide : biology and chemistry. 2020 Aug 1;
100-101:45-9.
Nomura Y, Sato I, Hanawa T, Hanaoka S, Nakao
T, Takenaga T, Hoshino T, Sekiya Y,
Miki S, Yoshikawa T, Hayashi N, Abe O
Development of training environment for deeplearning with medical images on supercomputer
system based on asynchronous parallel Bayesian
optimization
J Supercomput. 2020 Sep;76(9):7315-7332
Usui Y, Kurokawa R, Maeda E, Mori H,
Amemiya S, Sato J, Ino K, Torigoe R, Abe O.
Evaluation of peripheral bronchiole visualization
using model-based iterative reconstruction inquarter-detector computed tomography.
PLoS One. 2020 Sep 18;15(9):e0239459.
Kurokawa R, Gonoi W, Yokota H, Isshiki S,
Ohira K, Mizuno H, Kiguchi T, Inui S, Kurokawa
M, Kato S, Matsuki M, Takeda T, Yokoyama K,
Ota Y, Nakai Y, Maeda E, Mori H, Abe O.
Computed tomography findings of early-stage
TAFRO syndrome and associated adrenal

382

abnormalities. Eur Radiol. 2020 Oct; 30(10):5588-5598.
10) Saito A, Soma K, Masuzawa A, Hatsuse S,
Nakayama Y, Amiya E, Yao A, Hirata Y, Komuro
I. Symptomatic Right Ventricular Outflow Tract
Obstruction Due to Sinus of Valsalva Aneurysm.
Circulation journal: official journal of theJapanese Circulation Society. 2020 Nov 25;
84(12): 2324.
11) Yoshikawa M, Asaba K, Nakayama T.
The APLNR gene polymorphism rs7119375 is
associated with an increased risk of developmentof essential hypertension in the Chinese
population:A
meta-analysis.
Medicine(Baltimore). 2020 Dec;99(50):e22418.
12) Takahashi R, Ijichi H, Sano M, Miyabayashi K,
Mohri D, Kim J, Kimura G, Nakatsuka T,
Fujiwara H, Yamamoto K, Kudo Y, Tanaka Y,
Tateishi K, Nakai Y, Morishita Y, Soma K,
Takeda N, Moses HL, Isayama H, Koike K.
SolubleVCAM-1
promotes
gemcitabine
resistance via macrophage infiltration andpredicts therapeutic response in pancreatic cancer.
Scientific reports. 2020 Dec 3;10(1):21194.

383

Department of Home Care
Medicine
Project Associate Professor
Takashi Yamanaka, M.D., Ph.D.

Project Lecturer
Jiro Okochi, M.D., Ph.D.

Project Assistant Professor
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.

Project Academic Support Staff
Satomi Kudo

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., AKTIO
Corporation and Ain Pharmaciez. Our department
collaborates with Department of Geriatric Medicine.
We have taken over educational activities and research
activities from Center 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 got the third prize forthe best clinical department in clinical clerkshipprogram, Faculty of Medicine rated by medical
students in 2018.
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 database of patients who receive home
medical care
3) Follow-up study on QOL or prognosis of patients
who receive home medical care and their care

384

4)
5)

giversDrug treatment in home medical care
Skills of medical therapeutics and care in homecare medicine

Publications
1.

2.

3.

Tsuchiya-Ito R, Kusumoto N, Maruyama-Sakurai
K, Tamai A, Yokoyama H, Watanabe A, Fujiwara
T, Yamanaka T. Determinants of the
Implementation of Home Evaluations among
Patients with Fall-Related Fractures at a
Convalescent Rehabilitation Ward in Tokyo: A
Cross-Sectional Study. Journal of Aging andEnvironment 2020 doi:10.1080/26892618.2020.
1859036.
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 Services. Quarterly 2020 doi: 10.
1080/01621424.2020.1845272.
Pazan F, Gercke Y, Weiss C, Wehling M,
Akazawa H, Kojima T, Kumaki R, Akishita M,
Takeya Y, Ohno Y, Yamanaka T, Kozaki K,
Suzuki, Mizukami K, Mizokami F, Ikeda Y,
Shimizu A. The JAPAN-FORTA (Fit fOR The
Aged) list: Consensus validation of a clinical tool
to improve drug therapy in older adults. Archivesof Gerontology and Geriatrics 2020;91:104217.

385

Department of
Therapeutic Strategy forHeart Failure
Research Associate Professor
Masaru Hatano, M.D., Ph.D

Research Lecturer
Eisuke Amiya, M.D., Ph.D
Yumiko Hosoya, M.D., Ph.D

Research Assistant Professor
Seitaro Nomura, M.D., Ph.D

Project Researcher
Naoko Kato, 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

386

and Jarvik 2000) considering patients’ physics andclinical status).
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:

5:

Amiya E. MicroRNA-17: A Modulator ofInterferon
Regulatory
Factor
9-Induced
Phenotypic Switching in Vascular Smooth Muscle
Cells. Am J Hypertens. 2020 Dec 31;33(12):10781080.
Narita K, Amiya E, Hatano M, Ishida J, Maki H,
Minatsuki S, Tsuji M, Saito A, Bujo C, Ishii S,
Kakuda N, Shimbo M, Hosoya Y, Endo M,
Kagami Y, Imai H, Itoda Y, Ando M, Shimada S,
Kinoshita O, Ono M, Komuro I. Differences in the
prognoses of patients referred to an advanced
heart failure center from hospitals with different
bed volumes. Sci Rep. 2020 Dec 3;10(1):21071.
Saito A, Soma K, Masuzawa A, Hatsuse S,
Nakayama Y, Amiya E, Yao A, Hirata Y, Komuro
I. Symptomatic Right Ventricular Outflow Tract
Obstruction Due to Sinus of Valsalva Aneurysm.
Circ J. 2020 Nov 25;84(12):2324.
Yamada S, Nomura S. Review of Single-Cell
RNA Sequencing in the Heart. Int J Mol Sci. 2020
Nov 6;21(21):8345.
Koyama S, Ito K, Terao C, Akiyama M, Horikoshi
M, Momozawa Y, Matsunaga H, Ieki H, Ozaki K,
Onouchi Y, Takahashi A, Nomura S, Morita H,
Akazawa H, Kim C, Seo JS, Higasa K, Iwasaki M,
Yamaji T, Sawada N, Tsugane S, Koyama T,
Ikezaki H, Takashima N, Tanaka K, Arisawa K,

387

Kuriki K, Naito M, Wakai K, Suna S, Sakata Y,
Sato H, Hori M, Sakata Y, Matsuda K, Murakami
Y, Aburatani H, Kubo M, Matsuda F, Kamatani Y,
Komuro I. Population-specific and trans-ancestry
genome-wide
analyses identify distinct and shared genetic risk locifor coronary artery disease. Nat Genet. 2020 Nov;
52(11):1169-1177.
6: Atsukawa M, Tsubota A, Hatano M, Kondo C,
Shioda K, Ohno H, Kawano T, Hayama K, Arai T,
Nakagawa-Iwashita A, Itokawa N, Kaneko K,
Yoshida Y, Koeda M, Okubo T, Yamamoto T,
Yamamoto T, Taniai N, Yoshida H, Kanazawa H,
Shimizu W, Iwakiri K. Prevalence andcharacteristics of portopulmonary hypertension in
cirrhotic patients who underwent both hepatic veinand pulmonary artery catheterization. Hepatol Res.
2020 Nov;50(11):1244-1254.
7: Kawakubo Y, Uehara M, Minatsuki S, Amiya E,
Komuro I. Multiple coronary aneurysms
characterized by cobblestone-like appearance withsilent ischaemia in a patient with neurofibromatosis type 1. Eur Heart J Cardiovasc
Imaging. 2020 Oct 20;21(11):1236.
8: Tsuji M, Amiya E, Bujo C, Maki H, Ishida J,
Hatano M, Ono M, Komuro I. Takotsubo
syndrome in the same heart before and after hearttransplantation. ESC Heart Fail. 2020 Sep 10;7(6):4311–4..
9: Ito M, Nomura S, Morita H, Komuro I. Trends
and Limitations in the Assessment of theContractile Properties of Human Induced
Pluripotent Stem Cell-Derived Cardiomyocytes
From Patients With Dilated Cardiomyopathy.
Front Cardiovasc Med. 2020 Sep 3;7:154.
10: Yamaguchi T, Sumida TS, Nomura S, Satoh M,
Higo T, Ito M, Ko T, Fujita K, Sweet ME, Sanbe
A, Yoshimi K, Manabe I, Sasaoka T, Taylor MRG,
Toko H, Takimoto E, Naito AT, Komuro I.
Cardiac dopamine D1 receptor triggers ventriculararrhythmia in chronic heart failure. Nat Commun.
2020 Aug 31;11
11: Narita K, Amiya E, Komuro I. Efficacy and
Safety of Direct Oral Anticoagulant for Treatment
of Atrial Fibrillation in Cerebral Amyloid
Angiopathy. Cureus. 2020 Aug 30;12(8):e10143.

12: Taya M, Amiya E, 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 importanceof respiratory muscle fatigue in patients withcardiovascular disease. Medicine (Baltimore).
2020 Aug 21;99(34):e21794.
13: Shiraishi Y, Amiya E, Hatano M, Katsuki T,
Bujo C, Tsuji M, Nitta D, Maki H, Ishida J,
Kagami Y, Endo M, Kimura M, Ando M, ShimadaS, Kinoshita O, Ono M, Komuro I. Impact oftacrolimus versus cyclosporin A on renal function
during the first year after heart transplant. ESC
Heart Fail. 2020 Aug;7(4):1842-1849.
14: Saito A, Amiya E, Soma K, Inaba T, Maki H,
Hatano M, Yao A, Morita H, Komuro I.
Fractional exhaled nitric oxide in adult congenital
heart disease. Nitric Oxide. 2020 Aug 1;100-101:
45-49.
15: Minatsuki S, Kodera S, Kiyosue A, Saito A, Maki
H, Hatano M, Takimoto E, Komuro I. Balloon
pulmonary angioplasty improves quality of life inJapanese patients with chronic thromboembolic
pulmonary hypertension. J Cardiol. 2020 Aug;76(2):205-210.
16: Tanabe N, Ogo T, Hatano M, Kigawa A, Sunaya
T, Sato S. Safety and effectiveness of riociguat forchronic thromboembolic pulmonary hypertension
in real-world clinical practice: interim data frompost-marketing surveillance in Japan. Pulm Circ.
2020 Jul 23;10(3):2045894020938986.
17: Amiya E. Nrf-2: The Target of Vascular
Dysfunction in Diabetes. Am J Hypertens. 2020
Jul 18;33(7):597-598.
18: Matsunaga H, Ito K, Akiyama M, Takahashi A,
Koyama S, Nomura S, Ieki H, Ozaki K, Onouchi
Y, Sakaue S, Suna S, Ogishima S, Yamamoto M,
Hozawa A, Satoh M, Sasaki M, Yamaji T, Sawada
N, Iwasaki M, Tsugane S, Tanaka K, Arisawa K,
Ikezaki H, Takashima N, Naito M, Wakai K,
Tanaka H, Sakata Y, Morita H, Sakata Y, Matsuda
K, Murakami Y, Akazawa H, Kubo M, Kamatani
Y, Komuro I. Transethnic Meta-Analysis of
Genome-Wide Association Studies Identifies
Three New Loci and Characterizes PopulationSpecific Differences for Coronary Artery Disease.
Circ Genom Precis Med. 2020 Jun;13(3):e002670.

388

19: Tahara N, Dobashi H, Fukuda K, Funauchi M,
Hatano M, Ikeda S, Joho S, Kihara Y, Kondo T,
Matsushita M, Minamino T, Nakanishi N, Okano
Y, Ozaki Y, Saji T, Sakai S, Tanabe N, Watanabe
H, Yamada H, Yoshioka K, Hatta M, Sasayama S.
Long- term treatment of pulmonary arterial
hypertension with macitentan in Japanese patients.
Curr Med Res Opin. 2020 Jun;36(6):921-928.
20: Aozasa N, Hatano M, Saigusa R, Nakamura K,Takahashi T, Toyama T, Sumida H, Tamaki Z,
Maki H, Minatsuki S, Komuro I, Sato S, Asano Y.
Clinical significance of endothelial vasodilatory
function evaluated by EndoPAT in patients withsystemic sclerosis. J Dermatol. 2020 Jun;47(6):609-614.
21: Sugihara T, Hasegawa H, Uchida HA, Yoshifuji
H, Watanabe Y, Amiya E, Maejima Y, Konishi M,
Murakawa Y, Ogawa N, Furuta S, Katsumata Y,
Komagata Y, Naniwa T, Okazaki T, Tanaka Y,
Takeuchi T, Nakaoka Y, Arimura Y, Harigai M,
Isobe M; Japan Research Committee of the
Ministry of Health, Labour, and Welfare for
Intractable Vasculitis (JPVAS). Associatedfactors of poor treatment outcomes in patientswith giant cell arteritis: clinical implication oflarge vessel lesions. Arthritis Res Ther. 2020 Apr
7;22(1):72.
22: Minatsuki S, Kiyosue A, Kodera S, Hara T, Saito
A, Maki H, Hatano M, Takimoto E, Ando M,
Komuro I. Effectiveness of balloon pulmonary
angioplasty in patients with inoperable chronic
thromboembolic pulmonary hypertension despite
having lesion types suitable for surgical treatment.
J Cardiol. 2020 Feb;75(2):182-188.
23: Watanabe A, Amiya E, Hatano M, Watanabe M,
Ozeki A, Nitta D, Maki H, Hosoya Y, Tsuji M,
Bujo C, Saito A, Endo M, Kagami Y, Nemoto M,
Nawata K, Kinoshita O, Kimura M, Ono M,
Komuro I. Significant impact of left ventricularassist device models on the value of flowmediated dilation: effects of LVAD on endothelial
function. Heart Vessels. 2020 Feb;35(2):207-213.
24: Saito A, Amiya E, Hatano M, Shiraishi Y, Nitta
D, Minatsuki S, Maki H, Hosoya Y, Tsuji M, Bujo
C, Nawata K, Kinoshita O, Kimura M, Endo M,
Kagami Y, Nemoto M, Ikeda Y, Morita H, Ono M,
Komuro I. Controlling Nutritional Status Score As

25:

26:

27:

28:

29:

a Predictive Marker for Patients With Implantable
Left Ventricular Assist Device. ASAIO J. 2020
Feb;66(2):166-172.
Narita K, Amiya E, Kakuda N, Kaneko H,
Hatano M, Komuro I. The Efficacy of Lactulose
for the Treatment of Hyperammonemic
Encephalopathy Due to Severe Heart Failure.
Diagnostics (Basel). 2020 Jan 27;10(2):70.
Minatsuki S, Kiyosue A, Kodera S, Hirose K,
Saito A, Maki H, Hatano M, Takimoto E, Ando J,
Komuro I. Novel Balloon Pulmonary Angioplasty
Techniquefor
Chronic
Thromboembolic
Pulmonary Hypertension. Int Heart J. 2020;61(5):999-1004.
Maki H, Hara T, Tsuji M, Saito A, Minatsuki S,
Inaba T, Amiya E, Hosoya Y, Hatano M, Morita
H, Yao A, Kinugawa K, Komuro I. The Clinical
Efficacy of Endothelin Receptor Antagonists inPatients with Pulmonary Arterial Hypertension.
Int Heart J. 2020;61(4):799-805.
Maki H, Kubota K, Hatano M, Minatsuki S,
Amiya E, Yoshizaki A, Asano Y, Morita H, Sato
S, Komuro I. Erratum: Characteristics ofPulmonary Arterial Hypertension in Patients with
Systemic
Sclerosis
andAnticentriole
Autoantibodies. Int Heart J. 2020;61(3):629.
Maki H, Kubota K, Hatano M, Minatsuki S,
Amiya E, Yoshizaki A, Asano Y, Morita H, Sato
S, Komuro I. Characteristics of Pulmonary
Arterial Hypertension in Patients with Systemic
Sclerosis and Anticentriole Autoantibodies. Int
Heart J. 2020;61(2):413-418.

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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).

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,
survival analysis, longitudinal data analysis, Bayesian390

statistics, 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
has algebraic structure, techniques from algebraic

391

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.

6.

Hasegawa H, Tsukada Y, Wakabayashi M, Nomura
S, Sasaki T, Nishizawa Y, Ikeda K, Akimoto T and
Ito M. Impact of intraoperative indocyanine green
fluorescence angiography on anastomotic leakage
after laparoscopic sphincter-sparing surgery formalignant rectal tumors. Int J Colorectal Dis.
35(3):471-480, 2020.
Oki T, Aokage K, Nomura S, Tane K, Miyoshi T,
Shiiya N, Funai K, Tsuboi M and Ishii G. Optimal
method for measuring invasive size that predicts
survival in invasive mucinous adenocarcinoma of
the lung. Journal of Cancer Research and ClinicalOncology.1-8, 2020.
Nomura S, Miyauchi Y, Ajisawa Y, Isogaya K and
Sozu T. Study Designs in Multi-arm Trials for
Breast Cancer: A Systematic Literature Review ofMajor Journals. Ther Innov Regul Sci. 54(5):11851191, 2020.
Sugimoto M, Kendrick M L, Farnell M B, Nomura
S, Takahashi N, Kobayashi T, Kobayashi S,
Takahashi S, Konishi M and Gotohda N.
Relationship between pancreatic thickness andstaple height is relevant to the occurrence ofpancreatic fistula after distal pancreatectomy. HPB(Oxford). 22(3):398-404, 2020.
Nomura S, Shinozaki T and Hamada C.
Performance of randomization-based causal
methods with and without integrating external data
sources for adjusting overall survival in case ofextensive treatment switches in placebo-controlled
randomized oncology phase 3 trials. Journal ofbiopharmaceutical statistics. 30(2):377-401, 2020.
Okamoto I, Nokihara H, Nomura S, Niho S,
Sugawara S, Horinouchi H, Azuma K, Yoneshima Y,
Murakami H, Hosomi Y, Atagi S, Ozaki T, Horiike
A, Fujita Y, Okamoto H, Ando M, Yamamoto N,
Ohe Y and Nakagawa K. Comparison of
Carboplatin Plus Pemetrexed Followed by
MaintenancePemetrexedWith
Docetaxel
Monotherapy in Elderly Patients With Advanced
Nonsquamous Non-Small Cell Lung Cancer: A

Phase 3 Randomized Clinical Trial. JAMA Oncol.
6(5):e196828, 2020.
7. Kotani D, Bando H, Taniguchi H, Masuishi T,
Komatsu Y, Yamaguchi K, Nakajima T, Satoh T,
Nishina T, Esaki T, Nomura S, Takahashi K, Iida S,
Matsuda S, Motonaga S, Fuse N, Sato A, Fujii S,
Ohtsu A, Ebi H and Yoshino T. BIG BANG study(EPOC1703): multicentre, proof-of-concept, phase
II study evaluating the efficacy and safety of
combination therapy with binimetinib, encorafeniband cetuximab in patients with BRAF non-V600E
mutated metastatic colorectal cancer. Esmo Open.
5(1), 2020.
8. Enokida T, Ogawa T, Homma A, Okami K, Minami
S, Nakanome A, Shimizu Y, Maki D, Ueda Y,
Fujisawa T, Motegi A, Ohkoshi A, Taguchi J,
Ebisumoto K, Nomura S, Okano S and Tahara M. A
multicenter phase II trial of paclitaxel, carboplatin,and cetuximab followed by chemoradiotherapy inpatients with unresectable locally advanced
squamous cell carcinoma of the head and neck.
Cancer Med. 9(5):1671-1682, 2020.
9. Fukuoka S, Hara H, Takahashi N, Kojima T,
Kawazoe A, Asayama M, Yoshii T, Kotani D,
Tamura H, Mikamoto Y, Hirano N, Wakabayashi M,
Nomura S, Sato A, Kuwata T, Togashi Y, Nishikawa
H and Shitara K. Regorafenib Plus Nivolumab inPatients With Advanced Gastric or Colorectal
Cancer: An Open-Label, Dose-Escalation, andDose-Expansion Phase Ib Trial (REGONIVO,
EPOC1603). J Clin Oncol. 38(18):2053-2061,
2020.
10. Shimura M, Nomura S, Wakabayashi M, Maruo K
and Gosho M. Assessment of Hazard Ratios in
Oncology Clinical Trials Terminated Early for
Superiority: A Systematic Review. JAMA Netw
Open. 3(6):e208633, 2020.
11. Gotohda N, Nomura S, Doi M, Karasawa K, Ohki T,
Shimizu Y, Inaba Y, Takeda A, Takaki H, Anai H,
Ikeda M, Sugimoto M and Akimoto T. Clinicalimpact of radiofrequency ablation and stereotactic
body radiation therapy for colorectal liver
metastasis as local therapies for elderly, vulnerable
patients. Jgh Open. 4(4):722-728, 2020.
12. Kobayashi S, Takahashi S, Takahashi N, Masuishi T,
Shoji H, Shinozaki E, Yamaguchi T, Kojima M,
Gotohda N, Nomura S, Yoshino T and Taniguchi H.

392

13.

14.

15.

16.

17.

18.

Survival Outcomes of Resected BRAF V600E
Mutant Colorectal Liver Metastases: A Multicenter
Retrospective Cohort Study in Japan. Ann Surg
Oncol. 27(9):3307-3315, 2020.
Nomura S, Goto Y, Mizutani T, Kataoka T, Kawai S,
Okuma Y, Murakami H, Tanaka K and Ohe Y. A
randomized phase III study comparing continuationand discontinuation of PD-1 pathway inhibitors forpatients with advanced non-small-cell lung cancer(JCOG1701, SAVE study). Jpn J Clin Oncol. 50(7):821-825, 2020.
Kawazoe A, Fukuoka S, Nakamura Y, Kuboki Y,
Wakabayashi M, Nomura S, Mikamoto Y, Shima H,
Fujishiro N, Higuchi T, Sato A, Kuwata T and
Shitara K. Lenvatinib plus pembrolizumab inpatients with advanced gastric cancer in thefirst-line or second-line setting (EPOC1706): an
open-label, single-arm, phase 2 trial. Lancet Oncol.
21(8):1057-1065, 2020.
Udagawa H, Kirita K, Naito T, Nomura S, Ishibashi
M, Matsuzawa R, Hisakane K, Usui Y, Matsumoto
S, Yoh K, Niho S, Ishii G and Goto K. Feasibility
and utility of transbronchial cryobiopsy in precision
medicine for lung cancer: Prospective single-arm
study. Cancer Sci. 111(7):2488-2498, 2020.
Okano N, Morizane C, Nomura S, Takahashi H,
Tsumura H, Satake H, Mizuno N, Tsuji K, Shioji K,
Asagi A, Yasui K, Kitagawa S, Kashiwada T,
Ishiguro A, Kanai M, Ueno M, Ogura T, Shimizu S,
Tobimatsu K, Motoya M, Nakashima K, Ikeda M,
Okusaka T and Furuse J. Phase II clinical trial of
gemcitabine plus oxaliplatin in patients withmetastatic pancreatic adenocarcinoma with a family
history of pancreatic/breast/ovarian/prostate cancer
or personal history of breast/ovarian/prostate cancer(FABRIC study). Int J Clin Oncol. 25(10):18351843, 2020.
Kawazoe A, Kuboki Y, Shinozaki E, Hara H,
Nishina T, Komatsu Y, Yuki S, Wakabayashi M,
Nomura S, Sato A, Kuwata T, Kawazu M, Mano H,
Togashi Y, Nishikawa H and Yoshino T. Multicenter
Phase I/II Trial of Napabucasin and Pembrolizumabin Patients with Metastatic Colorectal Cancer(EPOC1503/SCOOP Trial). Clin Cancer Res:
26(22). 5887-5894, 2020.
Nomura S. Sample Size Determination inGroup-Sequential Trials Assessing Interim Futility

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by Intermediate Composite Endpoints. Statistics inBiopharmaceutical Research.1-12, 2020.
Kuwata T, Wakabayashi M, Hatanaka Y, Morii E,
Oda Y, Taguchi K, Noguchi M, Ishikawa Y,
Nakajima T, Sekine S, Nomura S, Okamoto W,
Fujii S, Yoshino T and Group S C-J G-S P. Impactof DNA integrity on the success rate of tissue-basednext-generation
sequencing:
Lessonsfromnationwide cancer genome screening project
SCRUM-Japan GI-SCREEN. Pathol Int: 70(12).
932-942, 2020.
Kawazoe A, Takahari D, Keisho C, Nakamura Y,
Ikeno T, Wakabayashi M, Nomura S, Tamura H,
Fukutani M, Hirano N, Saito Y, Kambe M, Sato A
and Shitara K. A multicenter phase II study of
TAS-114 in combination with S-1 in patients withpretreated advanced gastric cancer (EPOC1604).
Gastric Cancer: 24(1). 190-196, 2021.
Yoh K, Seto T, Satouchi M, Nishio M, Yamamoto N,
Murakami H, Nogami N, Nosaki K, Kohno T, Tsuta
K, Nomura S, Ikeno T, Wakabayashi M, Sato A,
Matsumoto S and Goto K. Final survival results for
the LURET phase II study of vandetanib in
previously treated patients with RET-rearranged
advanced non-small cell lung cancer. Lung Cancer:
155. 40-45, 2021.
Kobayashi S, Nakamura Y, Taniguchi H, Odegaard
J I, Nomura S, Kojima M, Sugimoto M, Konishi M,
Gotohda N, Takahashi S and Yoshino T. Impact ofPreoperative Circulating Tumor DNA Status on
Survival Outcomes After Hepatectomy for
Resectable Colorectal Liver Metastases. Ann Surg
Oncol: 2021.
Shimoyama R, Omori S, Nomura S, Kenmotsu H,
Takahashi T, Harada H, Ishikura S, Mizutani T,
Ando M, Kataoka T, Fukuda H, Ohe Y and Lung
Cancer Study Group in the Japan Clinical Oncology
G. A multi-institutional randomized phase III study
comparing weekly carboplatin plus nab-paclitaxel
and daily low-dose carboplatin as regimens forconcurrent chemoradiotherapy in elderly patientswith unresectable locally advanced non-small celllung cancer: Japan Clinical Oncology Group Study
JCOG1914. Jpn J Clin Oncol: 2021.
Aso S, Matsui H, Fushimi K, Yasunaga H.
Dexmedetomidine and Mortality From Sepsis
Requiring Mechanical Ventilation: A Japanese

393

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Nationwide Retrospective Cohort Study. J Intensive
Care Med. 2020 Jul 22:885066620942154.
Aso S, Yasunaga H. Introduction to Instrumental
Variable Analysis. Annals of Clinical Epidemiology.
2020;2(3):69-74.
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.
Otaka S, Aso S, Matsui H, Fushimi K, Yasunaga H.
Association between parenteral nutrition in theearly phase and outcomes in patients withabdominal
traumaundergoing
emergency
laparotomy: A retrospective nationwide study. Clin
Nutr ESPEN. 2021 Feb;41:371-376.
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. Ann Am
Thorac Soc. 2021 Mar 25.
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. Surg Neurol Int. 2021 Feb 23;12:69.
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.
Otaka S, Aso S, Matsui H, Fushimi K, Yasunaga H.
Early Versus Late Rib Fixation in Patients With
Traumatic Rib Fractures: A Nationwide Study. Ann
Thorac Surg. 2020 Sep;110(3):988-992.
Otaka S, Aso S, Matsui H, Fushimi K, Yasunaga H.
Effectiveness of surgical fixation for rib fractures inrelation to its timing: a retrospective Japanesenationwide study. Eur J Trauma Emerg Surg. 2020
Nov 18:1-8.

394

Department of Advanced
Cardiology
Project Associate Professor
Katsuhito Fujiu, M.D., Ph.D.

Project Assistant Professor
Hidehiro Kaneko, 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., and Fukuda Denshi Tokyo Central
Sales Co., Ltd.
In conjunction with the department ofcardiovascular medicine, this course develops
leading-edge medical care. It elucidates thepathogenesis of unresolved heart failure andcardiovascular disease and analyzes the pathologicalcondition using cultured cells, experimental animals,
and patient specimens. By clarifying the new disease
pathogenesis mechanism and pathogenesis mechanism,
it
aims
at
elucidatingthefundamental
pathophysiology of cardiovascular disease anddeveloping development prevention methods, newdiagnostic methods, and new therapeutic methods.
In Japan, cardiovascular death is the leading
cause of death in the elderly and is the leading causeof shortening a healthy lifespan. Despite theemergence of various new drugs, new devices, andnew treatments, we have not succeeded in reducing
cardiovascular death for the last 20 years. We havefound that it is important not to study cardiomyocytes
alone, but to examine non-cardiomyocytes to consider
heart disease (Nature 2007, Circulation Research 2005,
Nature Medicine 2017). We also hypothesized thatcooperation between the brain and heart maintains
cardiac homeostasis, and that failure leads to the onsetof cardiovascular disease and cardiovascular death(Nature Medicine 2017). The idea that the brain
regulates the heart is understandable in common sense.
Since ancient times, it has been considered, but
analysis using current molecular biological techniques
has hardly been conducted. We find that the brain
controls the heart, and the heart controls the brain andchanges each other, mainly through animal experiments. Such a molecular biological approach to brainheart linkage will understand new cardiac control
mechanisms and novel therapeutic targets. Besides, asa therapeutic development, we are promoting researchthat will develop new clinical approaches such as drugintervention approaches to non-cardiomyocytes, brain
imaging diagnosis, and brain stimulation therapy.

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.

Research activities
The heart and blood vessels maintain homeostasis incooperation 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 drug

395that 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.

6.

7.

8.

9.

References
1.

2.

3.

4.

5.

Effect of cigarette smoking on carotid arteryatherosclerosis: a community-based cohort study.
Kiriyama H, Kaneko H, Itoh H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yamamichi N, Komuro I. Heart Vessels. 2020;35(1):22-29.
The Efficacy of Lactulose for the Treatment ofHyperammonemic Encephalopathy Due to
Severe Heart Failure. Narita K, Amiya E, Kakuda
N, Kaneko H, Hatano M, Komuro I. Diagnostics(Basel). 2020;10(2):70.
Association Between Waist Circumference andCarotid Intima-Media Thickness in the General
Population. Kamon T, Kaneko H, Itoh H,
Kiriyama H, Mizuno Y, Morita H, Yamamichi N,
Komuro I. Int Heart J. 2020;61(1):103-108.
Association Between Changes in Body Weightand Fat Weight in Middle Age General
Population. Itoh H, Kaneko H, Kiriyama H,
Kamon T, Mizuno Y, Morita H, Yamamichi N,
Komuro I. Int Heart J. 2020;61(1):15-20.
Effect of Metabolically Healthy Obesity on theDevelopment of Carotid Plaque in the General
Population: A Community-Based Cohort Study.
Itoh H, Kaneko H, Kiriyama H, Yoshida Y,

10.

11.

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Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yatomi Y, Yamamichi N, Komuro I. J Atheroscler
Thromb. 2020 ;27(2):155-163.
Beautiful Harmony of the Japanese Precious
Healthcare Legacies for the New Imperial Era.
Kaneko H, Morita H, Komuro I. Circ J. 2020;
84(3):371-373.
Comparison Between Healthcare-Associated andCommunity-Acquired Infective Endocarditis at
Tertiary Care Hospitals in Japan. Kiriyama H,
Daimon M, Nakanishi K, Kaneko H, Nakao T,
Morimoto-Ichikawa R, Miyazaki S, Morita H,
Daida H, Komuro I. Circ J. 2020;84(4):670-676.
Use of Ghost Cytometry to Differentiate Cells
with Similar Gross Morphologic Characteristics.
Adachi H, Kawamura Y, Nakagawa K, Horisaki
R, Sato I, Yamaguchi S, Fujiu K, Waki K, Noji H,
Ota S. Cytometry A. 2020 ;97(4):415-422.
What is the mechanism of irregular pacing
spikes? Pacing failure, sensing failure, orsomething else? A case report. Oguri G, Kojima T,
Fujiu K, Komuro I. Eur Heart J Case Rep. 2020;
4(3):1-4.
Gender-specific association between the bloodpressure category according to the updated
ACC/AHA guidelines for hypertension andcardio-ankle vascular index: a community-based
cohort study. Kamon T, Kaneko H, Itoh H,
Kiriyama H, Mizuno Y, Morita H, Yamamichi N,
Komuro I. J Cardiol. 2020;75(5):578-582.
Human Resistin and Cardiovascular Disease.
Yuxiang L, Fujiu K. Int Heart J. 2020;61(3):421-423.
Spike Sorting Tool for Analysis of Cardiac
Extracellular Signals Recorded by Thin-FilmTransistor Sensor Arrays Anne-Claire Eiler,
Sugita J, Ihida S, Toshiyoshi H, Fujiu K,
Timothée Levi, Agnès Tixier-Mita J of Robotics,
Networking and Artificial Life. 2020 7(1):48 - 51
Serum uric acid level and subclinical left
ventricular dysfunction: a community-based
cohort study. 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. ESC Heart Fail. 2020;7(3):1031-1038.
A long noncoding RNA regulates inflammation

396

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resoution by mouse macrophages through fatty
acid oxidation activation. Nakayama Y, Fujiu K,
Yuki R, Oishi Y, Morioka MS, Isagawa T,
Matsuda J, Oshima T, Matsubara T, Sugita J,
Kudo F, Kaneda A, Endo Y, Nakayama T, Nagai
R, Komuro I, Manabe I. Proc Natl Acad Sci U S
A. 2020;117(25):14365-14375.
Association of arterial stiffness with left atrial
structure and phasic function: a community-based
cohort study. 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 Hypertens. 2020;38(6):1140-1148
Homocysteine as a Key Player in Lifestyle
Management of Arrhythmia. Shimizu Y, Fujiu K.
Int Heart J. 2020;61(4):631-632.
Characteristics and Outcomes of Super-Elderly
Patients (aged ≥90 Years) Hospitalized for Heart
Failure: Analysis of a Nationwide Inpatient
Database. Kaneko H, Itoh H, Yotsumoto H,
Kiriyama H, Kamon T, Fujiu K, Morita K,
Michihata N, Jo T, Morita H, Yasunaga H, andKomuro I. Circ Rep 2020;2(8):393-399.
Carotid intima-media thickness and subclinicalleft heart dysfunction in the general population.
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. Atherosclerosis. 2020;305:42-49.
Rapid Dilatation of False Lumen in a PatientWith Chronic Aortic Dissection Under Suspicionof Anticoagulation Therapy-Induced Recanalization. Yamada S, Hasumi E, Fujiu K, Yamauchi H,
Komuro I. Circ Rep. 2020;2(9):542-543.
Association of body weight gain with subsequentcardiovascular event in non-obese general
population without overt cardiovascular disease.
Kaneko H, Itoh H, Yotsumoto H, Kiriyama H,
Kamon T, Fujiu K, Morita K, Michihata N, Jo T,
MoritaH,
Yasunaga
H,
KomuroI.
Atherosclerosis. 2020;308:39-44.
Association of Cancer with Outcomes in Patients
Hospitalized for 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, and Komuro I. Circ J. 2020;84(10):

22.

23.

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25.

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1771-1778.
Device-Collected Heart Rate Variability Predicts
Ventricular Arrhythmia. Hasumi E, Fujiu K. Int
Heart J. 2020;61(5):861-862.
The Benefits of Antiviral Use of Chloroquine
Versus its Potential Cardiovascular Side Effects.
Shimizu Y, Fujiu K. Int Heart J. 2020;61(5):863-864.
Fluoroless and contrast-free catheter ablation
without a lead apron in routine clinical practice.
Matsubara TJ, Fujiu K, Shimizu Y, Oshima T,
Matsuda J, Matsunaga H, Oguri G, Hasumi E,
Kojima T, Komuro I. Sci Rep. 2020;10(1):17096.
Association of Isolated Diastolic Hypertension
based on the Cut-Off Value in the 2017
ACC/AHA Blood Pressure Guidelines with
Subsequent Cardiovascular Event in General
Population. Kaneko H, Itoh H, Yotsumoto H,
Kiriyama H, Kamon T, Fujiu K, Morita K,
Michihata N, Jo T, Takeda N, Morita H,
Yasunaga H, and Komuro I. J Am Heart Assoc.
2020;9(19):e017963.
The New Target of Vulnerable Plaque. Oshima T,
Fujiu K. Int Heart J. 2020;61(6):1091-1093.
Restfulness from sleep and subsequentcardiovascular disease in the general population.
Kaneko H, Itoh H, Kiriyama H, Kamon T, Fujiu
K, Morita K, Michihata N, Jo T, Takeda N,
Morita H, Yasunaga H, Komuro I. Sci Rep.
2020; (1):19674.
Association of Cardiovascular Health Metrics
with Subsequent Cardiovascular Disease inYoung Adults Kaneko H, Itoh H, Kamon T, Fujiu
K, Morita K, Michihata N, Jo T, Morita H,
Yasunaga H, Komuro I. J Am Coll Cardiol 2020;
76(20):2414-2416.
Serial Change in Clinical Presentations andOutcomes of 5,740 Patients Requiring RepeatedHospital Admissions (Four or More Times) due
to Worsened Heart Failure Itoh H, Kaneko H,
Yotsumoto H, Kiriyama H, Kamon T, Fujiu K,
Morita K, Michihata N, Jo T, Takeda N, Morita H,
Yasunaga H, and Komuro I. Int Heart J. 2020;
61(6):1253-1257.
Safety Monitoring for Obstructive Hypertrophic
Cardiomyopathy During Exercise Nakayama A,
Nakao T, Fujiu K, Daimon M, Morita H, Komuro

397

I. CJC Open. 2020;2(6):732-734
31. Transcatheter Aortic Valve Implantation andSurgical Aortic Valve Replacement for Aortic
Stenosis in Japan. - Analysis of a Nationwide
Inpatient Database -.Kamon T, Kanko 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,
Komuro I. Circ Rep. 2020 ;2(12):753-758.
32. Altered properties of endothelial cells andmesenchymal stem cells underlying thedevelopment of scleroderma-like vasculopathy in
Klf5+/-;Fli1+/- mice. Nakamura K, Taniguchi T,
Hirabayashi M, Yamashita T, Saigusa R, Miura S,
Takahashi T, Toyama T, Ichimura Y, Yoshizaki A,
Trojanowska M, Fujiu K, Nagai R, Sato S, Asano
Y. Arthritis Rheumatol. 2020;72(12):2136-2146.
33. Association between the number of hospital
admissions and in-hospital outcomes in patientswith heart failure. Kaneko H, Itoh H, Yotsumoto
H, Kiriyama H, Kamon T, Fujiu K, Morita K,
Michihata N, Jo T, Morita H, Yasunaga H,
Komuro I. Hypertens Res. 2020; 3(12): 13851391.

398

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399

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 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.

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.

Futatsugi H, Iwabu M, Okada-Iwabu M, Okamoto
K, Amano Y, Morizaki Y, Kadowaki T, Yamauchi
T. Blood Glucose Control Strategy for Type 2
Diabetes Patients With COVID-19. Front
Cardiovasc Med. 7: 593061, 2020
Tanabe H, Fujii Y, Okada-Iwabu M, Iwabu M,
Kano K, Kawana H, Hato M, Nakamura Y, Terada
T, Kimura-Someya T, Shirouzu M, Kawano Y,
Yamamoto M, Aoki J, Yamauchi T, Kadowaki T,
Yokoyama S. Human adiponectin receptor
AdipoR1 assumes closed and open structures.
Commun Biol. 3, 446, 2020
Hosoe J, Miya F, Kadowaki H, Fujiwara T, Suzuki
K, Kato T, Waki H, Sasako T, Aizu K, Yamamura
N, Sasaki F, Kurano M, Hara K, Tanaka M, Ishiura
H, Tsuji S, Honda K, Yoshimura J, Morishita S,
Matsuzawa F, Aikawa S, Boroevich KA, Nangaku
M, Okada Y, Tsunoda T, Shojima N, Yamauchi T,
Kadowaki T: Clinical usefulness of multigene
screening with phenotype-driven bioinformatics
analysis for the diagnosis of patients withmonogenic diabetes or severe insulin resistance.
Diabetes Res. Clin. Pract. 169, 108461, 2020

400

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.

Hara H, Maemura S, Fujiwara T, Takeda N, Ishii
S, Yagi H, Suzuki T, Harada M, Toko H, Kanaya
T, Ijichi H, Moses HL, Takimoto E, Morita H,
Akazawa H, Komuro I. Inhibition of

401

2.

3.

4.

5.

transforming growth factor-β signaling in
myeloid cells ameliorates aortic aneurysmal
formation in Marfan syndrome. PLoS One. 2020
Nov 11; 15(11) :e0239908. doi: 10.1371/journal.
pone.0239908. PMID: 33175881; PMCID: PMC
7657512.
Toko H, Morita H, Katakura M, Hashimoto M,
Ko T, Bujo S, Adachi Y, Ueda K, Murakami H,
Ishizuka M, Guo J, Zhao C, Fujiwara T, Hara H,
Takeda N, Takimoto E, Shido O, Harada M,
Komuro I. Omega-3 fatty acid prevents thedevelopment of heart failure by changing fatty
acid composition in the heart. Sci Rep. 2020 Sep
23;10(1):15553. doi: 10.1038/s41598-020-726860. PMID: 32968201; PMCID: PMC7512019.
Fukuma N, Takimoto E, Ueda K, Liu P, Tajima
M, Otsu Y, Kariya T, Harada M, Toko H, Koga
K, Blanton RM Jr, Karas RH, Komuro I.
Estrogen Receptor-α Non- Nuclear Signaling
Confers Cardioprotection and Is Essential tocGMP-PDE5 Inhibition Efficacy. JACC BasicTransl Sci. 2020 Mar 4;5(3):282-295. doi: 10.
1016/j.jacbts.2019.12.009. PMID: 32215350;
PMCID: PMC7091505.
Ito M, Nomura S, Morita H, Komuro I. Trends
and Limitations in the Assessment of theContractile Properties of Human Induced
Pluripotent Stem Cell-Derived Cardiomyocytes
from Patients With Dilated Cardiomyopathy.
Front Cardiovasc Med. 2020 Sep 3; 7: 154. doi:
10.3389/fcvm.2020.00154. eCollection 2020.
PMID: 33102534
Yamaguchi T, Sumida TS, Nomura S, Satoh M,
Higo T, Ito M, Ko T, Fujita K, Sweet ME, Sanbe
A, Yoshimi K, Manabe I, Sasaoka T, Taylor MRG,
Toko H, Takimoto E, Naito AT, Komuro I.
Cardiac dopamine D1 receptor triggers
ventricular arrhythmia in chronic heart failure.
Nat Commun. 2020 Aug 31; 11(1): 4364. doi:
10.1038/s41467-020-18128-x.

402

Department of Medical andPharmaceutical Community
Healthcare
Project Professor
Hirohisa Imai, M.D., Ph.D.

History and Organization Overview
Appropriate drug treatment has not yet been
implemented in clinical practice. There are many
problems such as polypharmacy, inappropriate drug
selection by doctors, and prescribing habits. Therefore,
effective institutional design and policy planning forthese serious problems have become urgent issues.
In recent years, regional formularies have been
implemented in several districts, and the promotion of"standard drug treatment" has begun to take off inJapan as well. The "Japanese Society of Formulary"
was established in June 2021 with our department of
medical and pharmaceutical community healthcare as
the inauguration body.
In health care today, there needs to be morecooperation among doctors and other medical
professionals in order to provide patients with an
optimal level of care. In particular, if doctors andpharmacists are able to reach a common
understanding of a patient’s illness, this will allow
them to administer an appropriate drug treatment
regimen, to perform continuous patient follow-up, andto evaluate the administered treatment accurately. The
delivery of optimal drug therapy involves multiple
interconnected processes, from investigating whatdrugs should be used to planning the treatment
regimen, assessing treatment compliance andeffectiveness, and managing adverse reactions, andonly a multidisciplinary, team-oriented approach tohealth care will make it possible to provide patientswith efficient, effective drug therapy. Unfortunately,
there are currently few examples of such

“multidisciplinary approaches to delivering optimal
drug therapy.” Japan is a “super-aging” society andthe rapidly increasing number of elderly patients who
are taking multiple medications has become an issueof significant concern. Because optimal drug therapy
delivery cannot be accomplished through thetraditional health care system or through regional
health care systems, the construction of a new healthcare system for the delivery of drug therapy isrequired.
The interfaces between the systems used in the fieldsof medicine and pharmacology, and the working
relationships between doctors and pharmacists, havegaps; these systems function independently of eachother, rendering the design of the overall systeminefficient.
For example, although dispensing limits for patientswith long-term prescriptions have been discussed incancer therapy and primary care settings, notheoretical or empirical research has been conductedto study this issue. Nor have any systems been put inplace to manage drug therapies based on
predetermined protocols for patients with chronic
diseases who are in stable condition. In addition, notenough empirical research has been conducted on thedevelopment of optimal treatment methods (e.g.,
optimal patient selection, efficient treatment
procedures) based on postmarketing surveillance ofexpensive drug products.
Against the aforementioned background, the objectiveof this program is to conduct theoretical and empiricalresearch on the development of new regional health403

care and collaborative systems for doctors (hospitals/
clinics) and pharmacists (both hospital and nonhospital pharmacists) in order to try to construct a newcollaborative system for doctors and pharmacists tooptimize the drug therapies that are provided topatients.
In this program, we will plan theoretical research toformulate measures that will support the constructionof efficient and effective regional medical care andempirical research using large-scale data, and we will
use statistical and epidemiological procedures toanalyze medical record data and prescription drug(including medical history) data as well as data fromour own epidemiological research in order toinvestigate systems for delivering effective drug
therapy through a multidisciplinary approach, startingwith the attending physician and the pharmacist, andfocusing specifically on dispensing limits for patientswith long-term prescriptions, the introduction ofregional formularies, and the introduction ofmultidisciplinary interventions in the treatment ofcancer and cognitive disorders.
This program consists of 1 program professor and 1
assistant program professor. The former is Hirohisa
Imai, a specialist in public health and epidemiology
who also teaches these subjects, and the latter is
Takuya Hirai, Ph.D., a graduate of the University ofTokyo's Graduate School of Public Health and a
specialist in collagen disease. Currently, he has
returned to clinical practice and is retired. The
program also has 2 full-time administrative staff. In
addition, graduate students in the professional degree
course of the School of Public Health have been
involved in this program’s research activities andproviding teaching support.

systems. This program will train the health carespecialists that will be needed for this coming age. In
addition, in order to help train the next generation ofresearchers, this program will be responsible forteaching courses and seminars at the School of
Medicine. the Epidemiology courses and seminars
will focus on pharmacoepidemiological and pharmacoeconomic issues, and provide instruction on how toapply epidemiological approaches to identify
problems and formulate responses in regional healthcare. We will attempt to convey the significance andfundamentals of epidemiology to students with nofield experience by exposing them to common
scenarios in regional health care.
In the School of Public Health (professional degree
course), this program will offer courses in connection
with the School of Medicine in, for example,
Pharmaceutical Epidemiology, Drug Product Delivery
Systems, Adverse Reactions, and the Behavior of
Pharmaceutical Companies. As part of their MPH
degree research, this program has teached graduate
students in the School of Public Health, andperformed interventional research on polypharmacy
patients until now. Graduate students in the latterstages of obtaining their doctorate degrees, who will
be expected to perform their own, independent
research in the future, will receive instruction increating themes for research papers, analyzing data,
the handling of literature references, and other basic
and critical skills, and will also receive guidance whenwriting their dissertations on how to develop a
consistently logical argument throughout theirdissertation as well as on how to properly cite
literature references.

Research
Education
The objective of this program is to develop health carespecialists who can implement medical collaborations
that are suited to a super-aging society. The era when asingle doctor is capable of handling all of the care fora single patient is over. The coming age will see
physicians, pharmacists, nurses, public health andwelfare workers, etc. use a multidisciplinary approach,and collaborate with the government as well, toimplement regional, comprehensive health careThis program will utilize primarily prescription drug
data (including prescribing histories) and medical
record data to conduct theoretical and empiricalresearch focusing on the biostatistical and epidemiological methodologies involved in “the development of
new methods of multidisciplinary collaboration for
optimizing physician-directed drug therapies.”
1.

Research on prescription drug dispensing limits
for patients with long-term prescriptions

4041) “Dispensing limits for patients with long-termprescriptions” refers to the practice of having
patients who have, for example, received a90-day prescription go to the pharmacy every 30
days to receive 30 days’ worth of medicine. The
pharmacist submits a tracking report to theprescribing doctor when the patient picks up his
medicine. This has many benefits in the case ofpatients with chronic conditions, including
making it possible to manage the patient’s drug
therapy appropriately, reducing the physician’s
workload, managing the quantity of drug
remaining, controlling health care costs more
appropriately. This program will conduct
theoretical and empirical research aimed at
establishing a model system that doctors andpharmacists can use in both primary care andoncology to implement dispensing limits forpatients with long-term prescriptions.
2) A pilot study on dispensing limits for patientswith long-term prescriptions is currently
underway (in hypertension, diabetes, dyslipidemia, osteoporosis, breast cancer hormone therapy,
and rheumatism). In the future, this programplans to conduct a larger-scale research study
with the help of the Ministry of Health, Labourand Welfare.
2.

Research on multidisciplinary interventions in
drug therapy in regional health care1) This program will cooperate with regional
metropolitan doctors’ and pharmacists’ associations, national health insurance regional branch
offices, Japan Health Association branch offices,prefectural health and welfare agency pharmaceutical affairs bureaus, and the like to conduct
research on optimal drug therapy interventions
for elderly patients. The patients who should
receive interventions will be identified by apatient selection board comprised of doctors andpharmacists, and said interventions will be
implemented.
2) This program will use prescribing data fromhealth insurance societies to conduct research on
implementing notification interventions for
optimizing drug therapy in the elderly. The
program is conducting research on interventions

that attempt to improve drug therapies by sending
prescribing physicians and compounding
pharmacists written notices informing them of
inappropriate prescriptions. The results of such
notification interventions will be evaluated after
half a year.
3.

Research on the development of methodologies
for implementing regional formularies
1) The cost effectiveness of the use of drug products
has been called into serious question in recent
years, and the efficient use of drug products isbeing required within the framework of regional
comprehensive health care systems. Althoughformularies may be one effective method ofaccomplishing this, “Hospital Formularies” and“Regional Formularies” are very different,
although they may appear alike, because thelatter have many stakeholders, and theimplementation of such formularies is therefore
extremely
difficult.
Althoughregional
formularies have not yet been implemented inJapan, this program is conducting research into
how they can be developed. This program will
investigate, in a quantitative scientific manner,incentives and inducements for promoting datacollection and analysis and the screening and useof listed drug products.
2) This program has started to conduct research toassess the effects of introducing regional
formularies using certain government-approved“Regional Health Care Collaboration Promotion
Foundations.” This program will collect data
provided by prefectural health insurance andJapan Health Association offices on patientcharacteristics,
diseasenames,
medicalinstitutions, drugs, etc. and perform an impact
assessment on the introduction of regional
formularies.

4.

The development of systems for optimizing drug
therapies that utilize artificial intelligence
Adverse reactions have many causes, includinginteractions between different drugs andinteractions with the metabolites of certain drugs,
and the identification and prevention of adverse
reactions requires tremendous effort. Because a405

tremendous amount of work is required toinvestigate the causes of adverse reactions andprevent them from occurring, systems are being
developed that utilize artificial intelligence toidentify safer and more effective drug therapies.
A research team is in the process of collecting
and managing a vast amount of data, and working
to develop innovative interfaces that will allow
doctors andpharmacists to easily make use of
artificial intelligence.

Publication
1. Imai H, Hirai T, Kumazawa R, Nakagawa S,
Yonezawa A, Matsubara K, Nakao H. Prevalenceof and risk factors for adverse events in
Alzheimer’s patients receiving anti-dementia
drugs in at-home care. PloS one. 2020;15(4);e0231226. doi:10.1371
2. Takeuchi Y, Kashiwabara K, Hosoi H, Imai H,
Matsuyama Y. Longitudinal effects of a nationwide lifestyle intervention program on cardiometabolic outcomes in Japan: An observational
cohort study. Preventive medicine. 2020
12;141;106301. pii:S0091-7435(20)30325-X.

406

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
including cutting edge light microscopies, cryo

electron microscopy of molecular resolution, X-ray
crystallography, biophysics, molecular biology andmolecular genetics. We aim to study the structure anddynamics of the molecular motors in vitro and in vivo
at the highest special and temporal resolution and onthese bases try to elucidate functions of molecularmotors in vivo combining molecular genetics.

References1.

Iwata S., Morikawa M., Takei, Y., and N.
Hirokawa. An activity-dependent local transport
regulation via degradation and synthesis of
KIF17 underlying cognitive flexibility. Science
Advances 2020 6: eabc8355
2. Yoshihara S., Jiang X., Morikawa M., 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 compaensating KIF3-based
CRMP2 transport. Cell Rep 35: 108971, April 13,
1-15, 2021
3. 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. in press
2021

407

Department of Molecular
Neurology
Professor
Shoji Tsuji, M.D., Ph.D.

Associate Professor
Jun Mitsui, M.D., Ph.D.

Assistant professor
Takashi Matsukawa, M.D., Ph.D.

Homepagehttps://molecular-nuerology.org/

Introduction and Organization
Department of Molecular Neurology was established on April 1, 2017 to elucidate the molecularmechanisms based on detailed clinical information
and research that integrates comprehensive genome
analysis, furthermore, to develop new therapies that
can intervene in pathophysiological mechanisms ofthe neurological diseases and to conduct new clinical
trials for the neurological diseases.

Clinical activities
We have outpatient clinic specialized in multiple
system atrophy (MSA) cooperating with Departmentof Neurology. We have started a registry for MSA toestablish the natural history of MSA, and, furthermore,
to recruit patients to the clinical trial which we arepreparing. We also take care of patients in theinpatient’s’ ward cooperating with Department of
Neurology. We provide clinical sequencing forpatients with neurological diseases to help clinicaldiagnosis of these patients. We also provide clinicalsequencing on referral basis from other hospitals.

Teaching activities
In under-graduate education, we offer opportunities of research experience on molecular genetics

of neurological disorders during the period of the“free–quarter program”. In the post-graduate
education, we offer programs for graduate students
including molecular genetics, neurobiology andtranslational researches.

Research activities
Multiple system atrophy (MSA) is a progressive
neurodegenerative disease which is characterized byvarious combinations of cerebellar ataxia andparkinsonism in addition to autonomic failure. No
effective therapeutic measures are available. We havebeen conducting extensive researches on MSA
including comprehensive genome analysis on familial
as well as sporadic MSA. We have found that a
homozygous mutation and compound heterozygous
mutations of COQ2 gene are associated with anincreased risk of MSA in multiplex families, andheterozygous mutations of COQ2 gene are associatedwith an increased risk of MSA in patients withsporadic disease (Mitsui J, et al. N Engl J Med. 2013;
369:233-44). Based on these findings, we consideredthat supplementation of coenzyme Q10 to patients with
MSA could benefit patients because COQ2 encodes
the enzyme essential for the biosynthesis of coenzyme
Q10. Recent studies have reported decreased coenzyme
Q10 levels in blood, cerebral spinal fluid, and the
cerebellum even in MSA patients without COQ2

408

mutations. Based on these studies, we started amulticenter-based (13 institutions) phase II clinical
trial (UMIN000031771) to evaluate the clinicalefficacy of a high-dose ubiquinol (reduced form ofcoenzyme Q10) supplementation for suppressing
progression of symptoms of patients with MSA in2013.
To facilitate recruitment of MSA patients into theclinical trial, as well as to establish a detailed natural
history of MSA, we started a registry for MSA. To
standardize the rating of patients based on Unified
Multiple System Atrophy Rating Scale (UMSARS)
among the 13 institutions in the phase II clinical trial,
we translated the original UMSARS into Japanesewith generous help by Dr. Gregor Wenning, theoriginal author of UMSARS. We have also establisheda method for more sensitive evaluation of the
enzymatic activity of COQ2 mutations (Yasuda T, et al.
Neurogenetics. 2019 Mar;20(1):51-5).

5.

References

7.

1.

2.

3.

4.

Porto KJ, Mitsui J, Ishiura H, Kubota A, Luspian
KJ, Eduardo E, Damian L, Toda T, Tsuji S. A
novel multi-exon deletion in the dysferlin gene ofa limb-girdle muscular dystrophy type 2B
Filipino patient. Neurol Clin Neurosci. 2020
Nov 8(6): 419-421. https://doi.org/10.1111/ncn3.
12453
Matsukawa T, Shoji H, Urasaki Y, Ishiura H,
Mitsui J, Oguri S, Tsuji S, Toda T. Novel variantof CSF1R in sporadic case with early-onset
cognitive impairment. Neurol Clin Neurosci.
2020 Nov 8(6): 430-432. https://doi.org/10.1111/
ncn3.12452
Chikada A, Mitsui J, Matsukawa T, Ishiura H,
Toda T, Ogata K, Goto J, Wenning GK, Tsuji S.
Reliability and validity of Japanese version ofUnified Multiple System Atrophy Rating Scale.
Neurol Clin Neurosci.2020 Dec https://doi.org/
10.1111/ncn3.12477
Odake Y, Koh K, Takiyama Y, Ishiura H, Tsuji S,
Yamada M, Yoshita M. Identification of a novel
mutation in ATP13A2 associated with acomplicated form of hereditary spastic paraplegia.
Neurol Genet. 2020 Sep 8;6(5):e514. doi: 10.
1212/NXG.0000000000000514.

6.

8.

9.

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. 2020 Oct
16:jmedgenet-2020-106973.
doi:
10.1136/
jmedgenet-2020-106973.
Pellecchia MT, Stankovic I, Fanciulli A, Krismer
F, Meissner WG, Palma JA, Panicker JN, Seppi K,
Wenning GK; Members of the Movement
Disorder Society Multiple System Atrophy Study
Group. Can Autonomic Testing and Imaging
Contribute to the Early Diagnosis of Multiple
System Atrophy? A Systematic Review andRecommendations by the Movement DisorderSociety Multiple System Atrophy Study Group.
Mov Disord Clin Pract. 2020 Sep 3; 7(7): 750762. doi: 10.1002/mdc3.13052.
Kobayashi R, Naruse H, Koyama S, Kawakatsu S,
Hayashi H, Ishiura H, Mitsui J, Ohta Y, Toda T,
Tsuji S, Otani K. Familial dementia with Lewy
bodies with VPS13C mutations. Parkinsonism
Relat Disord. 2020 Dec;81:31-33. doi: 10.1016/j.
parkreldis.2020.10.008.
Hosoe J, Miya F, Kadowaki H, Fujiwara T,
Suzuki K, Kato T, Waki H, Sasako T, Aizu K,
Yamamura N, Sasaki F, Kurano M, Hara K,
Tanaka M, Ishiura H, Tsuji S, Honda K,
Yoshimura J, Morishita S, Matsuzawa F, Aikawa
SI, Boroevich KA, Nangaku M, Okada Y,
Tsunoda T, Shojima N, Yamauchi T, Kadowaki T.
Clinical usefulness of multigene screening withphenotype-driven bioinformatics analysis for the
diagnosis of patients with monogenic diabetes orsevere insulin resistance. Diabetes Res Clin
Pract. 2020 Nov; 169: 108461. doi: 10.1016/j.
diabres.2020.108461.
Matsukawa T, Yamamoto T, Honda A, Toya T,
Ishiura H, Mitsui J, Tanaka M, Hao A, Shinohara
A, Ogura M, Kataoka K, Seo S, Kumano K,
Hosoi M, Narukawa K, Yasunaga M, Maki H,
Ichikawa M, Nannya Y, Imai Y, Takahashi T,
Takahashi Y, Nagasako Y, Yasaka K, Mano KK,
Matsukawa MK, Miyagawa T, Hamada M,
Sakuishi K, Hayashi T, Iwata A, Terao Y,

409

10.

11.

12.

13.

14.

15.

Shimizu J, Goto J, Mori H, Kunimatsu A, Aoki S,
Hayashi S, Nakamura F, Arai S, Momma K,
Ogata K, Yoshida T, Abe O, Inazawa J, Toda T,
Kurokawa M, Tsuji S. Clinical efficacy of
haematopoietic stem cell transplantation for adultadrenoleukodystrophy. Brain Commun. 2020 Jan
14;2(1):fcz048. doi: 10.1093/braincomms/fcz048.
Nakamura N, Tsunoda K, Mitsutake A, Shibata S,
Mano T, Nagashima Y, Ishiura H, Iwata A, Toda
T, Tsuji S, Sawamura H. Clinical Characteristics
of Neuronal Intranuclear Inclusion DiseaseRelated Retinopathy With CGG Repeat
Expansions in the NOTCH2NLC Gene. Invest
Ophthalmol Vis Sci. 2020 Sep 1;61(11):27. doi:
10.1167/iovs.61.11.27.
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. 2020 Sep 1:1-3. doi:
10.1080/21678421.2020.1813312.
Mitsutake A, Matsukawa T, Porto KJL, Sato T,
Katsumata J, Seki T, Maekawa R, Hideyama T,
Tanaka M, Ishiura H, Toda T, Tsuji S, Shiio Y. A
Japanese family with primary familial brain
calcification
presenting
withparoxysmal
kinesigenic dyskinesia - A comprehensive
mutational analysis. J Neurol Sci. 2020 Nov 15;
418:117091. doi: 10.1016/j.jns.2020.117091.
Ishiura H, Tsuji S. Advances in repeat expansion
diseases and a new concept of repeat
motif-phenotype correlation. Curr Opin Genet
Dev. 2020 Dec;65:176-185. doi: 10.1016/j.gde.
2020.05.029.
Hongo H, Miyawaki S, Imai H, Shimizu M, Yagi
S, Mitsui J, Ishiura H, Yoshimura J, Doi K, Qu W,
Teranishi Y, Okano A, Ono H, Nakatomi H,
Shimizu T, Morishita S, Tsuji S, Saito N.
Comprehensive investigation of RNF213
nonsynonymous variants
associatedwithintracranial artery stenosis. Sci Rep. 2020 Jul 20;
10(1):11942. doi: 10.1038/s41598-020-68888-1.
Yoshida M, Hayashi T, Fujii K, Ishiura H, Tsuji S,
Sakurai Y. Selective impairment of On-reading(Chinese-style pronunciation) in alexia withagraphia for kanji due to subcortical hemorrhage

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in the left posterior middle temporal gyrus.
Neurocase. 2020 Aug;26(4):220-226. doi: 10.
1080/13554794.2020.1788608.
Terao Y, Matsuda SI, Ishiura H, Tsuji S,
Yamamoto T, Fukuda H, Ugawa Y. Do eye
movements "age" earlier in progeria? Clin
Neurophysiol. 2020 Aug;131(8):1835-1836. doi:
10.1016/j.clinph.2020.05.019.
Lim SY, Ishiura H, Ramli N, Shibata S,
Almansour MA, Tan AH, Houlden H, Lang AE,
Tsuji S. Adult-onset neuronal intranuclear
inclusion disease mimicking Fragile X-associatedtremor-ataxia syndrome in ethnic Chinesepatients. Parkinsonism Relat Disord. 2020 May;
74:25-27. doi: 10.1016/j.parkreldis.2020.03.025.
Nakamura-Shindo K, Ono K, Koh K, Ishiura H,
Tsuji S, Takiyama Y, Yamada M. A novel
mutation in the GBA2 gene in a Japanese patientwith SPG46: A case report. eNeurologicalSci.
2020 Apr 2; 19: 100238. doi: 10.1016/j.ensci.
2020.100238.
Kobayashi Y, Shindoh J, Nishioka Y, Inagaki Y,
Mitsui J, Arita J, Hasegawa K. Germline MICA
Polymorphism Is Associated with the Long-Term
Outcomes in Patients Undergoing Hepatectomy
for Colorectal Liver Metastases. J Gastrointest
Surg. 2020 Sep; 24(9): 2137-2139. doi: 10.1007/
s11605-020-04659-7.
Katoh K, Aiba K, Fukushi D, Yoshimura J,
Suzuki Y, Mitsui J, Morishita S, Tsuji S, Yamada
K, Wakamatsu N. Clinical and molecular genetic
characterization of two female patients harboring
the Xq27.3q28 deletion with different ratios of X
chromosome inactivation. Hum Mutat. 2020
Aug;41(8):1447-1460. doi: 10.1002/humu.24058.
Uchino A, Nagai M, Kanazawa N, Ichinoe M,
Yanagisawa N, Adachi K, Nanba E, Ishiura H,
Mitsui J, Tsuji S, Suzuki K, Murayama S,
Nishiyama K. An autopsy case of GM1
gangliosidosis type II in a patient who survived along duration with artificial respiratory support.
Neuropathology. 2020 Aug;40(4):379-388. doi:
10.1111/neup.12651.
Koshi-Mano K, Mano T, Morishima M,
Murayama S, Tamaoka A, Tsuji S, Toda T, Iwata
A. Neuron-specific analysis of histone
modifications with post-mortem brains. Sci Rep.

410

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2020 Feb 28; 10(1): 3767. doi: 10.1038/s41598020-60775-z.
Ishihara S, Okamoto Y, Tanabe H, Yoshimura A,
Higuchi Y, Yuan JH, Hashiguchi A, Ishiura H,
Mitsui J, Suwazono S, Oya Y, Sasaki M,
Nakagawa M, Tsuji S, Ohya Y, Takashima H.
Clinical features of inherited neuropathy with
BSCL2 mutations in Japan. J Peripher Nerv Syst.
2020 Jun;25(2):125-131. doi: 10.1111/jns.12369.
Kurihara M, Sasaki T, Sakuishi K, Terao Y,
Murakawa T, Shinozaki-Ushiku A, Okada S,
Toda T, Tsuji S. Isolated seizure as initialpresentation of GABAA receptor antibodyassociated encephalitis. J Neurol Sci. 2020 Mar
15;410:116666. doi: 10.1016/j.jns.2020.116666.
Nishizawa M, Onodera O, Hirakawa A, Shimizu
Y, Yamada M; Rovatirelin Study Group. Effect ofrovatirelin in patients with cerebellar ataxia: two
randomised double-blind placebo-controlled
phase 3 trials. J Neurol Neurosurg Psychiatry.
2020 Mar; 91(3): 254-262. doi: 10.1136/jnnp2019-322168.
Koh K, Ishiura H, Shimazaki H, Tsutsumiuchi
M, Ichinose Y, Nan H, Hamada S, Ohtsuka T,
Tsuji S, Takiyama Y. VPS13D-related disorders
presenting as a pure and complicated form ofhereditary spastic paraplegia. Mol Genet
Genomic Med. 2020 Mar; 8(3): e1108. doi: 10.
1002/mgg3.1108.
Kurihara M, Ishiura H, Bannai T, Mitsui J,
Yoshimura J, Morishita S, Hayashi T, Shimizu J,
Toda T, Tsuji S. A Novel de novo KIF1A
Mutation in a Patient with Autism, Hyperactivity,
Epilepsy, Sensory Disturbance, and Spastic
Paraplegia. Intern Med. 2020 Mar 15; 59(6):839-842. doi: 10.2169/internalmedicine.3661-19.
Kodama S, Tokushige SI, Sugiyama Y, Sato K,
Otsuka J, Shirota Y, Hamada M, Iwata A, Toda T,
Tsuji S, Terao Y. Rituximab improves not only
back stiffness but also "stiff eyes" in stiff person
syndrome: Implications for immune-mediatedtreatment. J Neurol Sci. 2020 Jan 15; 408:
116506. doi: 10.1016/j.jns.2019.116506.
Enomoto Y, Tsurusaki Y, Yokoi T, Abe-Hatano C,
Ida K, Naruto T, Mitsui J, Tsuji S, Morishita S,
Kurosawa K. CNV analysis using whole exome
sequencing identified biallelic CNVs of VPS13B

in siblings with intellectual disability. Eur J Med
Genet. 2020 Jan; 63(1):103610. doi: 10.1016/j.
ejmg.2018.12.015.

411

Department of
Immunotherapeutics
Project Professor
Kazuhiro Kakimi, M.D., Ph.D.

Project Assistant Professor
Koji Nagaoka, Ph.D.

Project Research Fellow
Yukari Kobayashi

Homepagehttps://immunotherapy-uth.jp/

Introduction and Organization
Since immune checkpoint blockade therapies wereapproved for the treatment of many cancer types,
remarkable clinical responses have been achieved in acertain proportion of patients. Nonetheless, many
patients are unresponsive, and there remain several
tumor types that are refractory to immunotherapy.
Multiple immunosuppressive mechanisms operate in
the tumor microenvironment (TME), and any antitumor immune cells that might be present are often
impaired in the TME.
Thus, effective immunotherapy requires a combination of potent stimulation of anti-tumor immune
responses and, additionally, manipulation of theimmunosuppressive environment to prevent tumor
escape. Therefore, elucidating the mechanisms of
responsiveness or refractoriness and the moleculardeterminants thereof is required to improve cancer
immunotherapy.
The objective of our department is to demonstrate
the feasibility of an immunological data-guided
personalized adaptive approach to immunotherapy,
whereby immunomodulatory strategies are tailored tothe patient’s specific TME.

Teaching activities
Research guidance in molecular immunology isprovided to postgraduate students. Because knowledge

and techniques for evaluation of immune response areimportant for clinicians and medical researchers, we
also provide many opportunities to postgraduate
students to learn how to analyze in vivo immune
responses through experiments using animal models
and by the immunological monitoring of the patientsthemselves in clinical research.

Research activities
1) Evaluation of tumor-immune interaction.
Immunotherapy with immune checkpoint inhibitors(ICIs) has completely changed the therapeutic
landscape for many types of solid tumors. Several
combinations of immunetherapy with chemotherapy,
molecular targeted drugs, or combinations of different
ICIs are now approved for the first-line treatment ofvarious cancers. However, not all types of cancer
respond equally well to ICIs, and even in responsive
cancers, only a subset of patients experiences durable
responses and favorable long-term outcomes. This isbecause primary and acquired resistance occurs in aconsiderable proportion of patients across different
cancer types.
Therefore, it is crucial to establish reliable predictive
biomarkers to distinguish ICI responders from
non-responders, who may suffer unnecessary costs
and toxicities, and to identify candidates for rational
combination therapies. Currently, tumor mutationalburden and PD-L1 expression are the two major412

variables used as biomarkers that have been validated
in phase III clinical trials. Additionally, several otherfactors associated with response or resistance to ICIs
across cancer types have been proposed as biomarkers,
based on molecular profiling of cancers treated withdifferent immunotherapies. These include an
immune-inflamed phenotype, expression of T cellsignaling pathway genes such as IFNγ, microsatellite
instability, somatic copy-number alterations, HLA
class I diversity, T cell repertoire clonality change,
WNT-β-catenin signaling, TGFβ expression and evencommensal microbiota.
However, as single biomarkers, none of the above issufficient to identify individual patients who will
likely benefit from immunotherapy. Unlike conventional cancer therapies, immunotherapies, including
ICIs, do not directly target tumor cells; instead, theyaffect tumor cells through the patient’s immune
system or the tumor microenvironment (TME).
Therefore, the different components that affecttumor-immune interactions need to be taken into
account when developing predictive biomarkers for
immunotherapy. Comprehensive analysis of multiple
different functional pathways and molecular networks
that reveal integrated mechanisms of tumor-immune
interactions are crucial for this purpose. General andlocal cancer immunity status in each patient needs tobe taken into consideration.
To this end, Blank et al. proposed the concept of thecancer immunogram that integrates multiparameterbiomarkers to visualize the immunological status of anindividual patient. We have applied this concept tolung cancer patients and developed an immunogram
reflecting the cancer-immunity cycle. Since then, van
Dijk et al. have reported an immunogram informative
specifically for urothelial cancer patients. Althoughimmunegrams may be useful for visualizing thelandscape of the tumor microenvironment and thecompromised steps of anti-tumor immunity in eachpatient, both Blank et al. and van Dijk et al. had only
theorized that they could be useful to patients but had
not tested the concept in clinical practice. In contrast,
we analyzed real-world lung cancer patient data to
generate immunograms with potential applications for
personalized immunotherapy. We utilized RNA-Seq

data from the TCGA cohort as a standard and set up ascoring scale to quantify parameters incorporated in
the immunogram. We propose a novel versatilescoring method for constructing such individual
immunograms.
2) To develop combinatorial and personalized
immunotherapy.
Immune profiling, including bulk transcriptome
assays with microarrays or bulk RNA-Seq as well as
fluorescence-based flow cytometry, contributes
valuable insights into the mechanisms behindtumor-immune cell interactions and can uncovermechanisms and biomarkers for prediction oftherapeutic responses. Recently, high-dimensional
technologies such as scRNA-Seq and cytometry bytime of flight (CyTOF) are being increasingly
employed for immune profiling in cancer in order todetect rare immune subsets and dissect phenotypic andfunctional heterogeneity. Using these new technologies, deep immunephenotyping at the single-celllevel is possible in the individual patient. Deepphenotyping of the TME of each patient will be auseful guide to potential individual target molecules orcells and to determining the therapeutic strategies tobe adapted for each patient.
The future of immunotherapy will be combinatorial
and personalized treatments adapted to each patient’s
cancer-immune interactions in the TME. Clearly,
instigating this type of personalized therapy will bechallenging for many reasons, not the least of which
will be the high cost and labor-intensive nature.
However, it is to be expected that technical advances
will overcome some of these difficulties. Fortunately,
the cost of NGS is decreasing every year, and thedevelopment of a cost-effective targeted scRNA-Seq
platform using our original VFAC will hopefully
contribute to this.
To demonstrate the feasibility of an immunological
data-guided personalized adaptive approach to
immunotherapy,
wherebyimmunomodulatory
strategies are tailored to the patient’s specific TME,
we utilized tumor-bearing mice model. The TME ofgrowing tumors was immunologically assessed andthe animals were treated based on those results. Using

413

scRNA-Seq, but not bulk RNA-Seq, it was possible todetermine the molecules in the tumors that wereinvolved in generating an immunosuppressive
microenvironment. Tumors currently considered
non-responsive to immune checkpoint therapy might
be convertible to responders by elucidating andregulating the complicated network of cancer cells andimmune cells in the individual patient TME.

5)

List of Publications
1) Sato Y, Mori K, Hirano K, Yagi K, Kobayashi Y,
Nagaoka K, Hosoi A, Matsushita H, Kakimi K,
Seto Y. Adoptive γδT-cell transfer alone or
combined with chemotherapy for the treatment ofadvanced esophageal cancer. Cytotherapy. 2021
May;23(5):423-432. doi: 10.1016/j.jcyt.2021.02.
002. Epub 2021 Mar 26. PMID:33781711.
2) 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; PMCID: PMC7880746.
3) Yabuno A, Matsushita H, Hamano T, Tan TZ,
Shintani D, Fujieda N, Tan DSP, Huang RY,
Fujiwara K, Kakimi K, Hasegawa K.
Identification of serum cytokine clusters
associated with outcomes in ovarian clear cell
carcinoma. Sci Rep. 2020 Oct 28;10(1):18503.
doi:
10.1038/s41598-020-75536-1.
PMID:
33116254; PMCID:PMC7595156.
4) Sato Y, Wada I, Odaira K, Hosoi A, Kobayashi Y,
Nagaoka K, Karasaki T, Matsushita H, Yagi K,
Yamashita H, Fujita M, Watanabe S, Kamatani T,
Miya F, Mineno J, Nakagawa H, Tsunoda T,
Takahashi S, Seto Y, Kakimi K. Integrative
immunogenomic analysis of gastric cancer
dictates novel immunological classification andthe functional status of tumor-infiltrating cells.
Clin Transl Immunology. 2020 Oct 17;9(10):

6)

7)

2)

3)

e1194. doi: 10.1002/cti2.1194. PMID:33101677;
PMCID: PMC7568758.
Nagaoka K, Shirai M, Taniguchi K, Hosoi A, Sun
C, Kobayashi Y, Maejima K, Fujita M, Nakagawa
H, Nomura S, Kakimi K. Deep immunephenotyping at the single-cell level identifies a
combination of anti-IL-17 and checkpoint
blockade as an effective treatment in a preclinicalmodel of data-guided personalized immunetherapy. J Immunother Cancer. 2020 Oct;8(2):e001358. doi:10.1136/jitc-2020-001358. PMID:
33093158; PMCID: PMC7583806.
Kakimi K, Matsushita H, Masuzawa K, Karasaki
T, Kobayashi Y, Nagaoka K, Hosoi A, Ikemura S,
Kitano K, Kawada I, Manabe T, Takehara T,
Ebisudani T, Nagayama K, Nakamura Y, Suzuki R,
Yasuda H, Sato M, Soejima K, Nakajima J.
Adoptive transfer of zoledronate-expanded
autologous Vγ9Vδ2 T-cells in patients withtreatment-refractory non-small-cell lung cancer: amulticenter, open-label, single-arm, phase 2 study.
J Immunother Cancer. 2020 Sep;8(2):e001185.
doi:10.1136/jitc-2020-001185. PMID: 32948652;
PMCID: PMC7511646.
Kobayashi Y, Kushihara Y, Saito N, Yamaguchi S,
Kakimi K. A novel scoring method based on
RNA-Seq immunograms describing individual
cancer-immunity interactions. Cancer Sci. 2020 1)
2020/7/23. AACR2020 VIRTUAL ANNUALMEEINGII Virtual Minisymposium. Kazuhiro Kakimi.
Autologous γδ T cell therapy for treatmentrefractory non-small-cell lung cancer: An
open-label, single-arm, multicenter, phase II study
2020/7/23. AACR2020 VIRTUAL ANNUALMEEING
II 、 Poster Presentation. Yasuyoshi Sato, Ikuo
Wada, Akihiro Hosoi, Yukari Kobayashi, Koji
Nagaoka, Takahiro Karasaki, Hirokazu Matsushita,
Koichi Yagi, Hiroharu Yamashita, Shunji
Takahashi, Yasuyuki Seto, Kazuhiro Kakimi.
Novel immunological classification of gastriccancer by integrative analysis,
2020/7/23. AACR2020 VIRTUAL ANNUALMEEING
II 、 Poster Presentation. Masataka Shirai, Koji
Nagaoka, Kiyomi Taniguchi, Changbo Sun,
Akihiro Hosoi, Kazuhiro Kakimi. Single-cell
RNA-Seq identified an immunosuppressive IL-17
producing tumor-infiltrating T cells in murine

414

gastric tumor model,
4) 2020/7/23. AACR2020 VIRTUAL ANNUALMEEING
II、Poster Presentation. Koji Nagaoka, Takayuki
Kanaseki, Changbo Sun, Akihiro Hosoi, Serina
Tokita, Kazuhiro Maejima, Masashi Fujita,
HidewakiNakagawa,
Toshihiko
Torigoe,Kazuhiro Kakimi. To identify neoantigens
relevant to anti-tumor activity is challenging evenwith NGS-based prediction combined with MHC
ligandome profiling,5) 2020/8/17-19. Keystone Symposia: eSymposia.
Koji Nagaoka, Masataka Shirai, Kiyomi
Taniguchi, Akihiro Hosoi, Changbo Sun, Yukari
Kobayashi and Kazuhiro Kakimi. Deep-immunophenotyping at the single-cell level identifies a
combination of anti-IL-17 and checkpoint
blockade as an effective treatment in a preclinicalmodel of data-guided personalized immunetherapy. Nov; 111(11):4031-4040. doi: 10.1111/
cas.14621. Epub 2020 Sep 9. PMID: 32810311;
PMCID: PMC7648030.
8) Matsushita H, Hasegawa K, Oda K, Yamamoto S,
Asada K, Karasaki T, Yabuno A, Nishijima A,
Nejo T, Kobayashi Y, Sato S, Ikeda Y, Miyai M,
Takahashi Y, Yamaguchi R, Fujiwara K, Aburatani
H, Kakimi K. Neoantigen load and HLA-class I
expression identify a subgroup of tumors with aT-cell-inflamed
phenotype
andfavorable
prognosis in homologous recombination-proficient high-grade serous ovarian carcinoma. J
Immunother Cancer. 2020 May;8(1):e000375.
doi:10.1136/jitc-2019-000375. PMID: 32461346;
PMCID: PMC7254153.
9) Sugie T, Sato E, Miyashita M, Yamaguchi R,
Sakatani T, Kozuka Y, Moritani S, Suzuki E,
Kakimi K, Mikami Y, Moriya T. Multispectral
quantitative immunohistochemical analysis oftumor-infiltrating lymphocytes in relation toprogrammed death-ligand 1 expression in
triple-negative breast cancer. Breast Cancer. 2020
Jul;27(4):519-526. doi: 10.1007/s12282-02001110-2. Epub 2020 May 23. PMID: 32447649.
10) Ma L, Sakamoto Y, Kanai A, Otsuka H, Takahashi
A, Kakimi K, Imai T, Shimokawa T.
Characterization of a Novel Murine Colon
Carcinoma Subline with High-Metastatic Activity
Established by In Vivo Selection Method. Int J

Mol Sci. 2020 Apr 18; 21(8): 2829. doi: 10.3390/
ijms21082829. PMID: 32325684; PMCID:
PMC7215277.
11) Kobayashi Y, Yamada D, Kawai T, Sato Y,
Teshima T, Yamada Y, Nakamura M, Suzuki M,
Matsumoto A, Nakagawa T, Hosoi A, Nagaoka K,
Karasaki T, Matsushita H, Kume H, Kakimi K.
Different immunological effects of the moleculartargeted agents sunitinib, everolimus andtemsirolimus in patients with renal cell carcinoma.
Int J Oncol. 2020 Apr; 56(4): 999-1013. doi: 10.
3892/ijo.2020.4975. Epub 2020 Feb 4. PMID:
32319571.

Presentation at International
conference
1)

2)

3)

4)

2020/7/23.
AACR2020
VIRTUAL
ANNUALMEEING II Virtual Minisymposium.
Kazuhiro Kakimi. Autologous γδ T cell therapy
for treatment-refractory non-small-cell lungcancer: An open-label, single-arm, multicenter,
phase II study
2020/7/23.
AACR2020
VIRTUAL
ANNUALMEEING II 、 Poster Presentation.
Yasuyoshi Sato, Ikuo Wada, Akihiro Hosoi,
Yukari Kobayashi, Koji Nagaoka, Takahiro
Karasaki, Hirokazu Matsushita, Koichi Yagi,
Hiroharu Yamashita, Shunji Takahashi, Yasuyuki
Seto, Kazuhiro Kakimi. Novel immunologicalclassification of gastric cancer by integrative
analysis,
2020/7/23.
AACR2020
VIRTUAL
ANNUALMEEING II 、 Poster Presentation.
Masataka Shirai, Koji Nagaoka, Kiyomi
Taniguchi, Changbo Sun, Akihiro Hosoi,
Kazuhiro
Kakimi.
Single-cell
RNA-Seq
identified
animmunosuppressive
IL-17
producing tumor-infiltrating T cells in murine
gastric tumor model,
2020/7/23.
AACR2020
VIRTUAL
ANNUALMEEING II、Poster Presentation. Koji
Nagaoka, Takayuki Kanaseki, Changbo Sun,
Akihiro Hosoi, Serina Tokita, Kazuhiro Maejima,
Masashi Fujita, Hidewaki Nakagawa, Toshihiko
Torigoe, Kazuhiro Kakimi. To identify
neoantigens relevant to anti-tumor activity ischallenging even with NGS-based prediction

415

5)

combined with MHC ligandome profiling,
2020/8/17-19. Keystone Symposia: eSymposia.
Koji Nagaoka, Masataka Shirai, Kiyomi
Taniguchi, Akihiro Hosoi, Changbo Sun, Yukari
Kobayashi and Kazuhiro Kakimi. Deep-immunophenotyping at the single-cell level
identifies a combination of anti-IL-17 andcheckpoint blockade as an effective treatment ina preclinical model of data-guided personalized
immunotherapy.

416

Department of Ubiquitous
Preventive Medicine
Associate Professor
Yuichi Ikeda, M.D., Ph.D.

Assistant Professor
Toshiyuki Ko, M.D., Ph.D.

Introduction and Organization

Research Activities

As an official department in the Graduate School of
Medicine of the University of Tokyo, the Departmentof Ubiquitous Preventive Medicine was established inAugust 1st, 2007, with a donation from three pharmaceutical companies, Toa-Eiyo Ltd., Shionogi & Co.,
Ltd. and NEC Corporation to the University. Its
predecessor is the Clinical Bio-Informatics Research
Unit, which was established in 2002 as a governmentfunded program (Bio-Informatics Training Programsupported by the Ministry of Education, Culture, Sports,
Science and Technology [MEXT] through Special
Coordination Funds for Promoting Science andTechnology).
When the Clinical Bio-Informatics
Research Unit completed its program tenure in 2007,
its academic services were succeeded by our department and the Department of Clinical Epidemiology and
Systems, both affiliated with the Department of
Cardiovascular Medicine in the Graduate School of
Medicine of the University of Tokyo.
Our department provides clinical as well as
academic support for the Department of Epidemiology
and Preventive Medicine, which was established in2007 within the University of Tokyo Hospital. In
collaboration with our department, the Department ofClinical Epidemiology and Systems also support the
management of the Department of Epidemiology andPreventive Medicine.

Our goal is to create diagnostic and therapeutic basis
for prevention and early detection of cardiovasculardiseases by utilizing advanced techniques ofbiochemistry and molecular pharmacology.
Weespecially focus on the discovery of bioactive
molecules and diagnostic biomarkers in order topromote translational research, which connects basic
scientific findings to tangible clinical application.
One of our achievements is the establishment of anovel technique for detecting post-translational
modification and degradation of B-type natriuretic
peptide, one of the most important biomarkers in
cardiovascular pathologies such as ischemic heartdisease and heart failure. This unique technique wasdeveloped in collaboration with Shimadzu Corporation.
We have already confirmed and published its utility inclinical practice (Clin Chem, in press), further, issued
press-release from the University of Tokyo Hospital.
In addition to the development of diagnostic
techniques, we have also established several screening
systems towards the discovery of bioactive substancesthat are involved in the pathogenesis of cardiovasculardiseases. Utilizing these newly developed systems,
we will screen tissue extracts and a small-moleculecompound library to identify novel bioactive molecules.
In this way, Ubiquitous Preventive Medicine is anapplied science, based on which a comprehensive
system is to be developed in an effort to promote
preventive medicine for health promotion.

417

Clinical activities
The Department of Ubiquitous Preventive Medicine
is involved in the management of the Department of
Epidemiology and Preventive Medicine in the
University of Tokyo Hospital and provides clinical aswell as academic support for the department.

Teaching activities
The Department of Ubiquitous Preventive Medicine
offers education and research supervision to graduate
students and post-doctoral fellows in the affiliate
Department of Cardiovascular Medicine.

Publications
1.

2.

3.

4.

Saito A, Amiya E, Hatano M, Shiraishi Y, Nitta D,
Minatsuki S, Maki H, Hosoya Y, Tsuji M, Bujo C,
Nawata K, Kinoshita O, Kimura M, Endo M,
Kagami Y, Nemoto M, Ikeda Y, Morita H, Ono M,
Komuro I. Controlling nutritional status score as apredictive marker for patients with implantable
left ventricular assist device. ASAIO J. 2020:
66(2):166-172.
Ko T, Higashitani M, Uemura Y, Utsunomiya M,
Yamaguchi T, Matsui A, Ozaki S, Tobita K,
Kodama T, Morita H, Komuro I. Clinical outcome
and diverse risk factors for different therapeutictarget locations of peripheral artery disease. J
Atheroscler Thromb. 2020;27:769-779.
Yamaguchi T, Sumida TS, Nomura S, Satoh M,
Higo T, Ito M, Ko T, Fujita K, Sweet ME, Sanbe
A, Yoshimi K, Manabe I, Sasaoka T, Taylor MRG,
Toko H, Takimoto E, Naito AT, Komuro I. Cardiac
dopamine D1 receptor triggers ventriculararrhythmia in chronic heart failure. Nat Commun.
2020;11:4364. doi: 10.1038/s41467-020-18128-x.
Toko H, Morita H, Katakura M, Hashimoto M, Ko
T, Bujo S, Adachi Y, Ueda K, Murakami H,
Ishizuka M, Guo J, Zhao C, Fujiwara T, Hara H,
Takeda N, Takimoto E, Shido O, Harada M,
Komuro I. Omega-3 fatty acid prevents thedevelopment of heart failure by changing fatty
acid composition in the heart. Sci Rep. 2020;
10:15553.doi:10.1038/s41598-020-72686-0.

418Department of Clinical Trial DataManagement
Project Assistant Professor
Tempei Miyaji, M.Sc.

Project Researcher
Takuhiro Yamaguchi, Ph.D.

Registered Researcher
Satoru Fukimbara, Ph.D.
Hideki Suganami, Ph.D.
Yukikazu Hayashi, M.Sc.
Kenta Kachi, M.Sc

Project Academic Support Staff
Miyuki Kurosaki
Kumiko Seike
Mari Goto

Homepage

http://ctdm.umin.jp/

Introduction and Organization
Why we discuss Clinical Data Management (CDM)?
The reason why the concept of CDM is important has
not been fully discussed and educated in Japan. Our
department was established to answer this question.
The Department of Clinical Trial Data Management
was established in 2007 and carried out educationaland research activities on CDM in collaboration withThe Department of Biostatistics, The ClinicalResearch Support Center and Department of HealthCommunication in University of Tokyo.
As compared to the situation of CDM in the UnitedStates and Europe, technical aspects (data collection,
entry, check…) have been mainly focused in Japan but
the essence of CDM is to ensure quality of clinicaldata to appropriate level for fair and scientificevaluation. This has not been recognized in manyeducational activities. CDM should be defined as atechnical system to conduct clinical trials scientifically,
ethically and efficiently and to draw correctconclusion and also as a research discipline withtheory and practice that applies statistics, quality
control and clinical knowledge. It can optimize thewhole clinical trial process, keep the level of data
quality appropriately and calculate the trial cost.
One of our missions is to promote researches on CDM
aimed at improving the quality of clinical trials. The
other is to provide training for data managers with the
new education system which can look around all theclinical trial process to adapt rapid change of medical
environment and recent increase of e-clinical trials in
the world.

Teaching activities
1. Development of systematic educational programsof CDM and holding of seminars, which include;

419









Design of clinical trials
CDM
Risk-based Monitoring
Patient-reported Outcome
Mobile Helath
Safety information and PMS
Translational research methodology

2. Acceptance of clinical trial staffs from other sites,that is, conducting an on-the-job training (OJT)
3. Support to clinical researchers, especially those in
the University of Tokyo Hospital, in collaboration
with the Clinical Research Support Center and theDepartment of Clinical Epidemiology and Systems;
 Consultation works on medical statistics andresearch methodology
 Functioning as a data center and stuffs
participate in projects as biostatisticians or
clinical data managers.

3.

4.

Research activities
In addition to activities described above, we areconducting the research on methodology of Riskbased monitoring, mobile Health (mHealth) anddeveloping ePRO in collaboration with otheruniversities, pharmaceutical industries, CRO andvenders.
We are also supporting several clinical studies which
are conducted in the University of Tokyo Hospital.
Moreover, we also have collaborative works outsideof University of Tokyo Hospital for several clinicalresearches.

5.

References
1.

2.

Nagaoka H, Momo K, Hamano J, Miyaji T,
Oyamada S, Kawaguchi T, Homma M, Yamaguchi
T, Morita T, Kizawa Y. Effects of an Indomethacin
Oral Spray on Pain Due to Oral Mucositis inCancer Patients Treated With Radiotherapy andChemotherapy: A Double-Blind, Randomized,
Placebo-Controlled Trial (JORTC-PAL04). J Pain
Symptom Manage. 2021 Jan 28:S0885-3924(21)00144-5.
Saiga M, Hosoya Y, Utsunomiya H, Kuramoto Y,
Watanabe S, Tomita K, Aihara Y, Muto M,
Hikosaka M, Kawaguchi T, Miyaji T, Yamaguchi T,

6.

Zenda S, Goto A, Sakuraba M, Kusano T, Miyabe
K, Kuroki T, Yano T, Taminato M, Sekido M,
Tsunoda Y, Satake T, Doihara H, Kimata Y.
Protocol for a multicentre, prospective, cohort study
to investigate patient satisfaction and quality of life
after immediate breast reconstruction in Japan: the
SAQLA study. BMJ Open. 2021 Feb 15;11(2):e042099.
Minatogawa H, Izawa N, Kawaguchi T, Miyaji T,
Shimomura K, Honda K, Iihara H, Ohno Y, Inada Y,
Arioka H, Morita H, Hida N, Sugawara M, Katada
C, Nawata S, Ishida H, Tsuboya A, Tsuda T,
Yamaguchi T, Nakajima T. Study protocol for
SPARED trial: Randomized noninferiority phase III
trial comparing dexamethasone on day 1 withdexamethasone on day 1-4 combined withneurokinin-1 receptor antagonist, palonosetron, andolanzapine (5 mg) in patients receiving cisplatinbased chemotherapy. BMJ Open 2020;10:e041737.
Fujisawa D, Umemura S, Okizaki A, Satomi E,
Yamaguchi T, Miyaji T, Mashiko T, Kobayashi N,
Kinoshita H, Mori M, Morita T, Uchitomi Y, Goto
K, Ohe Y, Matsumoto Y. A nurse-led,
screening-triggered early specialized palliative careintervention program for patients with advanced
lung cancer: study protocol for a multicenter
randomized controlled trial. BMJ Open 2020;
0:e037759.doi:10.1136/bmjopen-2020-037759
Zenda S, Ryu A, Takashima A, Arai M, Takagi Y,
Miyaji T, Mashiko T, Shimizu Y, Yamazaki N,
Morizane C, Yamaguchi T, Kawaguchi T, Hanai A,
Uchitomi Y, Oshiba F. Hydrocolloid dressing as aprophylactic use for hand-foot skin reaction
induced by multitargeted kinase inhibitors: protocolof a phase 3 randomised self-controlled study. BMJ
Open. 2020 Oct 6;10(10):e038276.
Fujimori M, Sato A, Jinno S, Okusaka T,
Yamaguchi T, Ikeda M, Ueno M, Ozaka M,
Takayama Y, Miyaji T, Majima Y, Uchitomi Y. An
integrated communication support program foroncologists, caregivers, and patients with rapidly
progressing advanced cancer to promote patientcentered communication: J-SUPPORT 1904 study
protocol for a randomized controlled trial. BMJ
Open 2020;10:e036745. doi: 10.1136/bmjopen2019-036745

420

7.

Miyaji T, Kawaguchi T, Azuma K, Suzuki S, Sano
Y, Akatsu M, Torii A, Kamimura T, Ozawa Y,
Tsuchida A, Eriguchi D, Hashiguchi M, Nishino M,
Nishi M, Inadome Y, Yamazaki T, Kiuchi T,
Yamaguchi T: Patient-generated health datacollection using a wearable activity tracker incancer patients-a feasibility study. Support Care
Cancer (2020).
8. Tanaka R, Kaburaki T, Yoshida A, Takamoto M,
Miyaji T, Yamaguchi T: Fluorescein Angiography
Scoring
SystemUsing
Ultra-Wide-Field
Fluorescein
Angiography
VersusStandard
Fluorescein Angiography in Patients with Sarcoid
Uveitis. Ocul Immunol Inflamm. 2020 Mar 12, 1-5.
doi: 10.1080/09273948.2020.1737141. [Epub aheadof print] PMID: 32162984
9. Hashimoto H, Yamaguchi T, Abe M: A new
standard prophylaxis for emesis caused bycisplatin? - Authors' reply. Lancet Oncol. 2020 Mar,21(3):e129. doi: 10.1016/S1470-2045(20)30100-5.
PMID: 32135113
10. Tagami K, Kawaguchi T, Miura T, Yamaguchi T,
Matsumoto Y, Watanabe YS, Uehara Y, Okizaki A,
Inoue A, Morita T, Kinoshita H: The association
between health-related quality of life andachievement of personalized symptom goal.
Support Care Cancer. 2020 Jan 22, doi:
10.1007/s00520-020-05316-0. [Epub ahead ofprint] PMID: 31970517
11. Hirota S, Yamaguchi T: Timing of Pediatric DrugApproval and Clinical Evidence Submitted toRegulatory Authorities: International Comparison
Among Japan, the United States, and the European
Union. Clin Pharmacol Ther. 2019 Dec 23, doi:
10.1002/cpt.1757. [Epub ahead of print]
PMID:31933395
12. Hashimoto H, Abe M, Tokuyama O, Mizutani H,
Uchitomi Y, Yamaguchi T, Hoshina Y, Sakata Y,
Takahashi TY, Nakashima K, Nakao M, Takei D,
Zenda S, Mizukami K, Iwasa S, Sakurai M,
Yamamoto N, Ohe Y: Olanzapine 5 mg plus
standard antiemetic therapy for the prevention ofchemotherapy-induced nausea and vomiting(J-FORCE): a multicentre, randomised, doubleblind, placebo-controlled, phase 3 trial. Lancet
Oncol. 2020 Feb, 21(2):242-249. doi: 10.1016/

S1470-2045(19)30678-3. Epub 2019 Dec 11.
PMID:31838011

Social Cooperation Program422

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, ouractivities 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
to academic 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 andMedical Examination of the University of Tokyo
Hospital and the Division of Health Sciences andNursing of the University of Tokyo. In addition, thisprogram aimed to disseminate 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) andMari 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423

research and educational environment that fosters
young leaders in nursing research.

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 carenursing, for undergraduates, master’s and Ph.D.
students within the Department of GerontologicalNursing/Wound Care management.
The primary master thesis in 2020 was titled“ Changes in the blood vessel and subcutaneous
tissue of peripheral intravenous catheter placementsites: An observational study using ultrasonography”
We were in charge of lectures on nursing
translational research at the seminar hosted by GNRC
for post-doctoral fellows and other researchers. (The
8th Introduction seminar to Nursing Science andEngineering)

We offer lectures and consultations on researchmatters and provide guidance on article writing topromote nursing research in the clinical setting. We
are planning and running an annual symposium known
as “UTokyo nursing research” in order to promotejoint research with the Departments of Nursing andMedical Examination and School of Health Science at
the University of Tokyo Hospital.
2. Research fields and themes in 2020
 Understanding the mechanisms that lead toperipheral intravenous catheter failures: PIV-CF
 Evaluation of a new intravenous catheter toprevent PIV-CF Development of a thermo-film for the early
detection of extravasation
 Development of a training program for thetechnical improvement 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 innursing will be determined using multidisciplinary
studies and research. Regarding our scientificapproach, epidemiologic surveys and genetic research
will be conducted, followed by evaluation oftechnologies/devices developed in collaboration withcompanies, endeavoring to provide epoch-making
technologies that meet clinical needs utilizing the
Nursing Translational Research system.
Several research projects are also ongoing 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 arebeing conducted in collaboration with nurses at the
University of Tokyo Hospital.

2.

3.

4.

5.

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. 2020
Dec 2;9(1):57-60.
Abe-Doi M, Murayama R, Tanabe H, Komiyama
C, Sanada H. Evaluation of a thermosensitive
liquid crystal film for catheterization site
assessment immediately following chemotherapy
administration: an observational study. Eur J
Oncol Nurs. 2020 Oct; 48:101802.
Oe M, Koike N, Tobe H, Ohashi Y, Kuramochi E,
Ikeda M, Suzuki R, Yamauchi T, Murayama R,
Sanada H. Difficulties of self-monitoring blood
glucose in the aged with diabetes: An analysis
based on observations of self-monitoring blood
glucose. J Nur Sci Eng. 2020;7:141-148.
Abe-Doi M,Murayama R, Tanabe H, Kamiyama
E, Komiyama C, Matsui Y, Sanada H. Usability,
feasibility, and safety test of a new
thermosensitive liquid crystal film for the early
detection of extravasation in clinical practice: A
pilot study. J Nur Sci Eng. 2020; 7: 89-98.
Tanabe H Kawasaki M, Ueda T, Yokota T, Zushi

424

6.

7.

8.

Y, Murayama R, Abe-Doi M, Sanada H. A shortbevel needle with a very thin tip improves veinpuncture performance of peripheral intravenous
catheters: an experimental study. J Vasc Access.
2020 Nov;21(6):969-976.
Kanno C, Murayama R, Abe-Doi M, Takahashi T,
Shintani Y, Nogami J, Komiyama C, Sanada H.
Developmentofanalgorithm
using
ultrasonography-assisted peripheral intravenous
catheter placement for reducing catheter failure.
Drug Discov Ther. 2020;14(1):27-34.
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. Jpn J Nurs Sci. 2020 Jul;
17(3):e12329.
Takahashi T, Murayama R, Abe-Doi M,
Miyahara-Kaneko M, Kanno C, Nakamura M,
Mizuno M, Komiyama C, Sanada H. Preventing
peripheral intravenous catheter failure by
reducing mechanical irritation. Sci Rep. 2020 Jan
31;10(1):1550.

425

Department of
Imaging Nursing Science
Project Associate Professor
Nao Tamai, Ph.D

Project Lecturer
Masaru Matsumoto, Ph.D

Project Assistant Professor
Yuka Miura, Ph.D

Collaborative Researchers
Mayumi Handa and Mikihiko Karube

Homepage

http://www.imagingnursing.m.u-tokyo.ac.jp/index.html

Organization history and overview
The Department of Imaging Nursing Science wasfounded as part of the Corporate Sponsored Research
Programs offered by the Graduate School of Medicine,
The University of Tokyo, in April 2017. It aims torealize “a safe, secure, and comfortable medical careexperience” through visualized nursing technology.
The department conducts translational researchthrough surveys on actual nursing care conditions
based on imaging technology and propose nursing
techniques and their evaluation, with the goal ofdeveloping care systems and applying these in clinicalsettings.
Specific plans include developing (1) an ultrasoundtechnology support system for nursing care, (2) aremote support system using imaging technology toassist nursing care, and (3) innovative technologies
using new imaging techniques in nursing.
This Social Cooperation Program was establishedwith the cooperation of FUJIFILM Corp. and with the
Department of Gerontological Nursing / Wound CareManagement as partner departments aiming to findsolutions to these challenges and to further the
progress in nursing technologies. It aspires to establish
imaging nursing technologies in clinical nursing

settings in Japan, as a forerunner in shifting towards a
globally unprecedented super-aging society, and to
become the first transmitter of new discoveries to theworld.
Department members are Project Associate
Professor Nao Tamai, Project Lecturer Masaru
Matsumoto, Project Assistant Professor Yuka Mirura,and Visiting Researchers Mayumi Handa and
Mikihiko Karube (FUJIFILM Corp.). The Project
Associate Professor concurrently served as a member
at a visualized nursing field of Division of Care
Innovation, the Graduate School of Medicine, Global
Nursing Research Center and now strives to establish
and disseminate imaging nursing skills in nursing
research.

Education
In 2020, we provided the following lectures forundergraduate and postgraduate students.
a) Bioengineering Nursing (S2 in 4th yr.)b) Practicum in Human Health Support (W in 2ndyr.)c) Gerontological Nursing Practice (A2 in 4th yr.)d) Special Lecture in Gerontological Nursing I (S1)e) Special Lecture in Wound Care Nursing I (S2)426f) Special Lecture in Wound Care Nursing II (A)We have provided cooperation and guidance toundergraduate students in the Department of Health
Science and graduate students in the Department ofGerontological Nursing and Wound Care Management
for their research plans through seminars and practicaltraining.
Through external lectures and workshops toincrease awareness, we have held lectures on skin andelimination care at levels equivalent to curricula for
Certified Nurses in Wound, Ostomy and Continence
Nursing course at the Nurse Training Center of the
Kyoto Tachibana University. We have also held
lectures on training for nurse-designated procedures in
the Nursing Training School of the Japanese Nursing
Association.
At the nursing science and engineering introductory
seminar, hosted by the Global Nursing ResearchCenter of the Graduate School of Medicine, we
lectured to many nursing researchers and clinicalnurses at a webinar on imaging nursing skills,
especially those which were challenged in clinicalsettings.

Research
This course seeks to develop nursing assessment
skills using ultrasonography and to promote research
in imaging nursing that directly contributes to clinicalsettings. We are developing a versatile portableultrasound device that is ultralight-weight, produceshigh image quality, and operates on a wide range of
frequencies. Furthermore, a nursing assessment
coaching software is being developed using imaging
analysis, which does not require special techniques, tosupport assessment by nurses.
Specifically, we undertook research and development on the following topics:
1) Supporting swallowing care: Improvement ofpharyngeal-residual-observation
methodofpyriform sinus.
2) Supporting urination care: Standardization of
bladder-urine-volume-measurement method in thestanding and sitting position using ultrasonicdevice and examination of a method to identify
urinary tract infection in older adults.
3) Supporting defecation care: Clinical implementa-tion of an educational program on evaluation ofstool retention using ultrasonic equipment,
construction and evaluation of ICT system,
development of stool retention evaluation method
for ultrasonic movies by AI.
4) Supporting pressure injury care: development ofeducational programs using ultrasonic devices anddevelopment of methods for detecting deep tissue
injuries by AI.
With these research activities, we have received thefollowing awards:
・第 8 回看護理工学会 学会賞（2020 年 10 月）.
Morphological characteristics of skin tears toestimate the etiology-related external forces thatcause skin tears in an elderly population. Koyano Y,
Nakagami G, Tamai N, Sugama J, Sanada H.
Journal of Nursing Science and Engineering.
2020;7:68-78.
・第 40 回日本看護科学学会学術集会 JANS40 大会賞（2020 年 12 月）. 末梢静脈点滴トラブルを防ぐ為の超音波画像を用いた AI によるケア
リコメンデーションシステムの開発. 高橋 聡
明, 村山陵子, 仲上豪二朗, 阿部麻里, 松本 勝,
真田弘美. 第 40 回日本看護科学学会学術集会
抄録集. 2020;61.

References
1. 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.
Journal of Nursing Science and Engineering.
2020;8:143–150.
2. Tamai N, Kuwata M, Urai T, Ushiro T, Yamashita
Y, Minematsu T, Dai M, Nakai A, Weijie K,
Kataoka Y, Nitta S, Noro S, Sanada H. Effect ofan education program on the prevention of skintears for nurses in a Japanese long-term care
hospital: a pre-post study. Journal of JapaneseSociety of Wound, Ostomy, and ContinenceManagement. 2020;24(4):379–387.
3. 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.

427

4.

5.

6.

7.

8.

9.

Diagnostic accuracy of ultrasound examination in
detecting aspiration and pharyngeal residue inpatients with dysphagia: A systematic review andmeta-analysis. Japan Journal of Nursing Science.
2020;18(2):e12396.
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. Journal of Tissue
Viability. 2020;30(1):28–35.
Matsumoto M, Yoshida M, Miura Y, Sato N,
Okawa Y, Yamada M, Otaki J, Nakagami G,
Sugama J, Okada S, Ohta H, Sanada H.
Feasibility of the constipation point-of-careultrasound educational program in observing fecal
retention in the colorectum: a descriptive study.
Japan Journal of Nursing Science. 2020;18(1):e12385.
Tamai N, Minematsu T, Ikeda M, Mugita Y,
Sanada H. Effects of improved hypoallergenic
fabrics in medical wigs in breast cancer patientswithchemotherapy-induced
alopecia:A
randomized clinical trial. BMJ Supportive &Palliative Care. 2020.
Matsumoto M, Yoshida M, Yabunaka K,
Nakagami G, Miura Y, Fujimaki S, Okawa Y,
Sugama J, Okada S, Ohta H, Sanada H. Safety
and efficacy of a defecation care algorithm basedon ultrasonographic bowel observation in
Japanese home-care settings: a single-case,multiple-baseline study. Geriatrics & Gerontology
International. 2020;20(3):187–194.
Matsumoto M, Yabunaka K, Yoshida M,
Nakagami G, Miura Y, Okawa Y, Sugama J,
Okada S, Ohta H, Sanada H. Improvement ofconstipation symptoms in an older adult patient bydefecation care based on using a hand-held
ultrasound device in home care settings: a casereport. Journal of Wound, Ostomy and Continence
Nursing. 2020;47(1):75–78.
Koyano Y, Nakagami G, Tamai N, Sugama J,
Sanada H. Morphological characteristics of skintears to estimate the etiology-related external
forces that cause skin tears in an elderly
population. Journal of Nursing Science andEngineering. 2020;7:68–78.

10. Matsumoto M, Tsutaoka T, Nakagami G, Tanaka
S, Yoshida M, Miura Y, Sugama J, Okada S, Ohta
H, Sanada H. Deep learning-based classificationof rectal fecal retention and property using
ultrasound images in older adult patients. Japan
Journal of Nursing Science. 2020;17(4):e12340.
11. Ikeda M, Kanai H, Osaka M, Tamai N, Takemura
Y, Sanada H. Implementing appearance-care
program research for breast cancer patients into
routine clinical practice. Open Journal of Nursing.
2020;10(3).
12. Ikeda M, Tamai N, Kanai H, Osaka M, Sanada H,
Kamibeppu K. Effects of the appearance careprogram for breast cancer patients receiving
chemotherapy: A Mixed method study. Cancer
Reports. 2020;3(3):e1242.
13. Yoshida M, Miura Y, Okada S, Yamada M,
Kagaya H, Saitoh E, Kamakura Y, Okawa Y,
Matsuyama Y, Sanada H. Effectiveness of
Swallowing Care on Safe Oral Intake Using
Ultrasound-Based Observation of Residues in the
Epiglottis
Valley:A Pragmatic,
QuasiExperimental Study. Healthcare (Basel). 2020;8(1):50.
14. Yoshida M, Miura Y, Yabunaka K, Sato N,
Matsumoto M, Yamada M, Ohtaki J, Kagaya H,
Kamakura Y, Saitoh E, Sanada H. Efficacy of an
education program for nurses that concerns theuse of point-of-care ultrasound to monitor for
aspiration and pharyngeal post-swallow residue: A
prospective, descriptive study. Nurse Education in
Practice. 2020;44:102749.
15. Miura Y, Nakagami G, Tohara H, Ogawa N,
Sanada H. Association between jaw-opening
strength and geniohyoid muscle thickness andecho intensity measured by ultrasound. Medical
Ultrasonography. 2020;22(3):299–304.
16. Tamai N, Minematsu T, Maeda T, Yabunaka K,
Sanada H. The relationship between skinultrasound images and muscle damage using skinblotting in wheelchair basketball athletes. Spinal
Cord. 2020;58:1022–1029.
17. Tsunemi Y, Nakagami G, Takehara K, Tamai N,
Kitamura A, Mugita Y, Oe M, Kishida M, Sanada
H. Effects of skin care education for care staff atelderly care facilities on skin conditions of theresidents. Journal of Dermatology. 2020;47:327–33.

428

Department of Healthcare Quality
Assessment
Project Professor
Hiroaki Miyata, Ph.D.

Project Associate Professor
Hiraku Kumamaru, M.D., Sc.D.

Project Assistant Professor
Naoaki Ichihara, M.D., Ph.D., M.P.H.

Project Researcher
Shun Kosaka, M.D., Ph.D.

Adjunct Researcher
Norimichi Hirahara, Ph.D.
Hiroyuki Yamamoto, M.D., Ph.D., M.P.H.
Arata Takahashi, HIM, M.S.
Eriko Fukuchi, M.S.

Registered Researcher
Hideki Endo, M.D.
Chieko Fujimura.
Shiori Nishimura, M.S.
Satoshi Shoji, MD
Mitsuaki Sawano, MD, PhD
Hisateru Tachimori, PhD
Shimada Kouki, Ph.D.
Shiyori Usune

Clerical Staff
Urara Isozum/i, M.S.

Clerical Staff (Secretary)
Takayo Nakamura.

Homepage

http://hqa.umin.jp/

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

429high 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 approximately 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
more than 5,300 hospitals and clinics are participatingin 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.
Clinical databases like NCD are the core componentsof quality improvement initiative in many health careservices such as in the field of thoracic surgery.
HQA supports NCD’s systematic data collection, data
management, data analyses, and the 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 thequality improvement activities in many healthcare
fields.
Increasing number of clinical researches,
conducted in collaboration with the professionalsocieties, has come out based on detailed analyses of430

various registry data collected by NCD. Also, in
collaboration with Pharmaceuticals and Medical
Devices Agency as well as device manufacturers, newregistries have worked on academia-governmentindustry collaboration projects using NCD registrydata. One example is the research project based on theregistry for transcatheter valve therapy which also
supportedthemanufacturers’
post-marketingsurveillance activities. HQA has also been involved ininternational research collaborations with major
registries abroad, including American College ofSurgeon’s NSQIP, Asian Cardiac Database and The
Society of Thoracic Surgeons National Database,aiming to participate in quality improvement activities
in different regions of the world.

Select Publications
1.

2.

3.

4.

5.

6.

Okamura A, Yamamoto H, Watanabe M, Miyata
H, Kanaji S, Kamiya K, et al. Association
between Preoperative HbA1c Levels andComplications after Esophagectomy: Analysis of
15 801 Esophagectomies from the National
Clinical Database in Japan. Ann Surg. 2020; doi:
10.1097/SLA.0000000000004547 Epub.
Okita Y, Kumamaru H, Motomura N, Miyata H,
Takamoto S. Current status of open surgery foracute type A aortic dissection in Japan. J Thorac
Cardiovasc Surg. S0022-5223(20)33045-2. 2020;
Epub 2020 Nov 17.
Kofunato Y, Takahashi A, Gotoh M, Kakeji Y,
Seto Y, Konno H, et al. Geriatric Risk Prediction
Models for Major Gastroenterological Surgery
using the National Clinical Database in Japan: A
Multicenter Prospective Cohort Study. Ann Surg.
2020; Epub Oct 15.
Saito A, Kumamaru H, Miyata H, Motomura N.
Device use for proximal anastomosis on
ascending aorta in off-pump coronary artery
bypass grafting. Ann Thorac Surg. 2020;
111:1909-1915.
Watanabe M, Tachimori Y, Oyama T, Toh Y,
Matsubara H, Ueno M, et al. Comprehensive
registry of esophageal cancer in Japan, 2013.
Esophagus. 2020; 18: 1-24
Iwatsuki M, Yamamoto H, Miyata H, Kakeji Y,
Yoshida K, Konno H, et al. Association of

7.

8.

9.

10.

11.

12.

13.

surgeon and hospital volume with postoperative
mortality after total gastrectomy for gastriccancer: data from 71,307 Japanese patientscollected from a nationwide web-based data entry
system. Gastric Cancer. 2020; 24(2): 526-534
Hirahara N, Miyata H, Kato N, Hirata Y,
Murakami A, Motomura N. Development ofBayesian Mortality Categories for Congenital
Cardiac Surgery in Japan. Ann Thorac Surg.
S0003-4975(20)31485-5 2020; Epub Sep 16.
Yamashita YI, Yamamoto H, Miyata H, Kakeji Y,
Kitagawa Y, Yamaue H, et al. Risk Factors forBile Leakage: Latest Analysis of 10,102
Hepatectomies for Hepatocellular Carcinoma
from the Japanese National Clinical Database. J
Hepatobiliary Pancreat Sci. 2021; 28: 556-562
Hirata Y, Shimizu H, Kumamaru H, Takamoto S,
Motomura N, Miyata H, et al. Congenital Heart
Disease After the Fukushima Nuclear Accident:
The Japan Cardiovascular Surgery Database
Study. J Am Heart Assoc. 2020 Jul 7; 9(13):e014787
Kohsaka S, Kumamaru H, Inohara T, Amano T,
Akasaka T, Miyata H, et al. Outcome of
Percutaneous Coronary Intervention in Relation
to the Institutional Volume of Coronary Artery
Bypass Surgery. J Clin Med. 9(5) 2020 Apr 27.
Izumisawa Y, Endo H, Ichihara N, Takahashi A,
Nawata K, Shiraishi H, et al. Association
between prehospital transfer distance and surgicalmortality in emergency thoracic aortic surgery. J
Thorac Cardiovasc Surg. S0022-5223(20)307091. 2020 Mar 23
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. 2020; doi:
10.1097/SLA.0000000000003799. Epub Mar 20.
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. 2020; doi: 10.
1097/SLA.0000000000003804. Epub Jan 21.

431

Department of Tissue Stem Cells
and Life Dentistry
Project Professor
Makoto Komura, M.D., Ph.D.

Project Lecturer (Jan, 2021-)
Yukio Asano, D.V.M., Ph.D.

Project Assistant Professor (April, 2020-December, 2020)
Ryoko Inaki, D.D.S., Ph.D.

Homepage http://plaza.umin.ac.jp/~tsc-lds/manage.html
Introduction and Organization

Teaching activities

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 ( bio sheet / bio tube)
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 the correlation 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 AssistantProfessor (April-December, 2020) and now assisted bya Project Lecturer (January, 2021-).

We shared the appeal of basic research toundergraduates through laboratory tours.
With the cooperation of Department of PediatricSurgery, we are preparing to give lectures to master andPh.D. students in the upcoming year.
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.
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432

・ Factor examination of regeneration model Development of dental pulp stem cell culture
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:

Ohno M, Fuchimoto Y, Higuchi M, Yamaoka T,
Komura M, Umezawa A, Hsu HC, Enosawa S,
Kuroda T. Long-term observation of airway
reconstruction using decellularized tracheal
allografts in micro-miniature pigs at growing
stage. Regen Ther. 2020; 15:64-69.
Komura M, Komura H, Ishimaru T, Konishi K,
Komuro H, Hoshi K, Takato T.
Tracheal
cartilage growth promotion by intra-tracheal
administration of basic FGF. Pediatr Surg Int.
2020; 36:33-41.

433

Department of Skincare Science
Project Associate Professor
Takeo Minematsu, Ph.D.

Project Lecturer
Misako Dai, R.N., Ph.D.

Homepage http://skincarescience.m.u-tokyo.ac.jp/index-e.html
Introduction and Organization
The Department of Skincare Science was established in
the Graduate School of Medicine with funding from
Saraya Co., Ltd. on February 1st, 2017. The global aim
of our department is to develop new nursing
technologies to evaluate and improve the physiologicalcondition of vulnerable skin due to aging and disease.
The department is currently headed by a Project
Associate Professor and assisted by a Project Lecturer.

Teaching activities
In 2019, we gave the following lectures toundergraduate, master and Ph.D. students:a) Nursing Science and Engineering (S2 in 4th yr.)b) Gerontological Nursing I (S1 in graduate students)c) Wound Care Management I (S2 in graduate
students)d) Wound Care Management II (S2 in graduate
students)
We supervised graduate students within the
Department of Skincare Science and the Department ofGerontological Nursing/Wound Care Management on
individual research projects, research planning andtraining work.
In 2020, Ph.D. and master’s courses involved thefollowing research themes:
Ph.D.: “Development of the measurement of taurine
concentration by the skin blotting: A non-invasive
identifying method for chronic dehydration ofvulnerable older people in home care setting”
Master’s: “Identification of microRNAs responsive toshare loading in rat skin”
We gave lectures on the suitability of physiologicaland molecular biological approaches based on
analytical and critical thinking to nursing researchers,
nurses, and graduate students in the 8th Nursing Scienceand Engineering Seminar, which was held by the
Global Nursing Research Center, Graduate School of
Medicine, The University of Tokyo.

Research activities
The skin is the only organ that can be directly seen andtouched physically on a daily basis. Any abnormalities
to the skin cause pain and itching, which significantly
impair patients' Quality of Life (QoL). Therefore, ourresearch focuses on skin assessment and skincare to
maintain skin integrity and promote a healthy life forpatients.
In particular, we are working to establish anddisseminate the research methodology of “biologicalnursing” which aims to biologically elucidate thecauses and developmental mechanisms of disorderedskin conditions and discomforts, and to identify newcare targets.
Skin blotting and wound blotting represent our careinnovations through biological nursing studies. These
are simple and non-invasive technologies to assess thephysiological status of the skin and wounds. Since
February 2017, we have been closely working with
Saraya Co., Ltd., to develop new nursing technologies
to apply wound blotting in clinical settings. After its
development in 2018, this new product has been
applied in many facilities. In addition to this effort, wehave also contributed to the 2020 Tokyo Paralympic

434Games through pressure ulcer care for wheelchairathletes.
2.
The following are the research topics of ourdepartment in 2020:
 Development of non-invasive skin assessment
using the skin blotting to:・ Identify chronic dehydration
・ Distinguish Category I pressure injuries
・ Identify deep tissue damage on the buttocks ofwheelchair athletes
・ Predict skin tear development
 Development of wound assessment using woundblotting and investigation of its practicalapplications to:・ Identify latent wound infection
・ Improve biofilm detection
 Pressure injury care in wheelchair athletes
・ Development of wheelchair cushions for dailyliving and performance・ Prevention of pressure injury on buttocks byvibration
 Lymphoedema care・ Identification of ultrasonographic features ofsubcutaneous tissue related to cellulitis
recurrence・ Identification of biomarkers related to cellulitis
recurrence Scalp care of patients who have undergone anticancer drug therapy
・ Structural and physiological alterations in scalp
due to anti-cancer drug therapy
・ Effectiveness of medical wigs made from novel
materials
Our research has been internationally recognized in
the form of several awards, including:・ Bronze Award of IAUD International Design Award．
2020/12/18.
・ International Lymphoedema Framework Japan 10th
Anniversary Award. 2020/11/26.

References1.

Tamai N, Minematsu T, Sanada H. Changes in
scalp epidermal thickness using in vivo
reflectance confocal microscopy in breast cancer

3.

4.

5.

6.

7.

8.

patients undergoing chemotherapy: A case series.
J Nurs Sci Engineer. 8: 143-150. 2021
Tamai N, Minematsu T, Ikeda M, Mugita Y,
Sanada H. Effects of improved hypoallergenic
fabrics in medical wigs in breast cancer patientswithchemotherapy-induced
alopecia:A
randomized clinical trial. BMJ Supportive &pallative Care. E-pub ahead of print.2021. doi:
10.1136/bmjspcare-2020-002309
Arisandi D, Ogai K, Urai T, Aoki M, Minematsu
T, Okamoto S, Sanada H, Nakatani T, Sugama J.
Development of recurrent pressure ulcers, risk
factors in older patients: a prospective
observational study. Journal of Wound Care. 29(Sup4): S14-S24. 2020. doi:10.12968/jowc.2020.
29.Sup4.S14
Tsuruoka K, Oe M, Minematsu T, Tomida S,
Ohashi Y, Shimojima Y, Mori Y, Nitta S, Qin Q,
Abe M, Yamauchi T, Sanada H. Skincharacteristics associated with foot callus inpeople with diabetes: A cross-sectional study
focused on Desmocollin1 in corneocytes. J Tissue
Viability. 29(4): 291-296. 2020. https://doi.org/10.
1016/j.jtv.2020.05.003
Mugita Y, Nakagami G, Minematsu T, Kitamura A,
Sanada H. Combination of urease inhibitor andantiseptic inhibits urea decomposition-induced
ammonia production by Proteus mirabilis. Int
Wound J. 17(6): 1558-1565. 2020. Doi: 10.1111/
iwj.13422.
Tamai N, Minematsu T, Maeda T, Yabunaka K,
Sanada H. The relationship between skinultrasound images and muscle damage using skinblotting in wheelchair basketball athletes. Spinal
Cord. 58: 1022-1029. 2020. doi: 10.1038/s41393020-0442-6
Dai M, Minematsu T, Nakagami G, Sugama J,
Sanada H. Awareness and attitudes oflymphoedema patients toward compression
stockings in the summer: a cross-sectionalquestionnaire survey. Journal of Lymphoedema.
15: 49-53. 2020.
Sari WD,Minematsu T, Yoshida M, NoguchiWatanabe M, Tomida S, Kitamura A, Abe M,
Sanada H. Validity of skin blot examination foralbumin and nerve growth factor β to detectitching of the skin in Indonesian older adults. J435

Tissue Viability. 2020. E-pub ahead of print.
9. Kunimitsu M, Nakagami G, Kitamura A,
Minematsu T, Koudounas S, Ogai K, Sugama J,
Takada C, Sanada H. Temporal changes in thediversity and composition of the bed microbiotaof patinets with pressure ulcers. J Jpn WOCN.
24(4): 366-378. 2020. doi: https://doi.org/10.
32201/jpnwocm.24.4_366
10. Tamai N, Kuwata M, Urai T, Ushiro T, Yamashita
Y, Minematsu T, Dai M, Nakai A, Weijie K,
Kataoka Y, Nitta S, Noro S, Sanada H. Effect ofan education program on the prevention of skintears for nurses in a Japanese long-term care
hospital: A pre-post study. J Jpn WOCN. 24(4):379-387. 2020. doi: https://doi.org/10.32201/
jpnwocm.24.4_379

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 three 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 2018, 6.5 million people
have been certified as being in need for long-term carein Japan. However, factors and diseases leading toconditions requiring long-term care remain largely
unknown. In order to identify factors predicting
conditions requiring long-term care, we obtained andhave analyzed anonymized data of Comprehensive
Survey of Living Conditions, a nationwide survey
containing household situation and health-related
questions, from Ministry of Health, Labor andWelfare.
2) Research on discontinuation of physician visit inpatients with diabetes

437

Discontinuation of diabetes care is associated withincreased rate of complications and mortality. One of
the limitations in the previous studies is selection bias,
as the patients mostly voluntarily participated in thestudies so were more motivated than the averagepatients. In order to identify predictors of
discontinuation in patients with diabetes in real-world
data, we have analyzed the JMDC database incollaboration with the Department of Clinical
Epidemiology and Health Economics (Professor
Hideo Yasunaga).
3) Research on diabetes and cancer
Patients with diabetes have higher risks of developing
such diseases as cardiovascular diseases, cerebrovascular diseases, kidney diseases and cancer. While
improved glycemic controls is associated with areduced risk for vascular diseases and kidney diseases,
association between glycemic control and cancer risk
is unclear. In order to investigate this issue, we are
analyzing data of patients with diabetes in a medical
information database of the University of Tokyo
Hospital, in collaboration 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.

References
1.

2.

3.

Ikeda Kurakawa K, Okada A, Jo T, Ono S,
Bessho K, Michihata N, Matsui H, Yamaguchi S,
et al. Effects of Prophylactic Antibiotics on
Length of Stay and Total Costs for PediatricAcute Pancreatitis: A Nationwide Database Studyin Japan. Pancreas. 2020;49(10):1321-6.
Okada A, Yamana H, Yamaguchi S, Ikeda
Kurakawa K, Matsui H, Fushimi K, et al.
Outcomes of lactulose plus branched-chainamino acid infusion and lactulose alone forhepatic encephalopathy: A retrospective cohort
study using a national inpatient database. Hepatol
Res. 2020;50(6):693-703.
Adachi H, Kawamura Y, Nakagawa K, Horisaki
R, Sato I, Yamaguchi S, et al. Use of Ghost
Cytometry to Differentiate Cells with Similar
Gross Morphologic Characteristics. Cytometry A.

2020;97(4):415-22.
4. Hirano R, Yamaguchi S, Waki K, Kimura Y, Chin
K, Nannya Y, et al. Willingness of Patients
Prescribed Medications for Lifestyle-RelatedDiseases to Use Personal Health Records:
Questionnaire Study. J Med Internet Res. 2020;22(5):e13866.
5. Aoe M, Okada A, Usui T, Manaka K, Nangaku M,
Makita N. Comparison between the clinicalcharacteristics of patients with adrenal
incidentalomas and those with hypertensionassociated adrenal tumors in a single center inJapan. Endocr J. 2020;67(6):645-54.
6. Yamana H, Ono S, Okada A, Jo T, Yasunaga H.
Association
betweenmandatory
healthexamination attendance and diabetes treatment
initiation among employees being treated for
hypertension. J Occup Health. 2020; 62(1):e12183.
7． Higashihara T, Okada A, Nakamura Y, Saigusa H,
Homma S, et al. Proliferative Glomerulonephritis
with Monoclonal Immunoglobulin Deposits
without Conspicuous Mesangial Proliferation,
Complicated with Squamous Cell Lung
Carcinoma. Intern Med. 2020;59(4):557-562.

438

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
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.
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.

Education
Department of Innovative Dementia Prevention was

involved in the education through research activities ofgraduate students of the Graduate School of Medicine
and the School of Pharmaceutical Sciences, as well as
medical student belonging to the Medical Scientist
Training Program. In addition, TH has given a lecture
on “Special Course for Clinical Pharmacy” 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
strategies against AD. However, to quantitatively

439

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 Aβoligomer species in the soluble fractions of brains of
APP transgenic mice and AD brains (Hashimoto T, Soc
for Neuroscience meeting 2017). 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. In 2017, wehave found a significant decrease in Aβ deposition in
the brains of human apoE3 KI/APP transgenic mice. In
2018, we have also found that apoE3 reduced thedeposition of Aβ compared with murine apoE using invivo seeding technique. We also found that the Aβlevels in the interstitial fluids of human apoE3 KI/APPtransgenic mice are similar to those in APP transgenic
mice by in vivo microdialysis 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 ofAD 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

440

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 Alzheimer's disease (AD),especially the effects on amyloid pathogenesis, wehave been conducting analyses using APP Tg mice (A7strain), a mouse model of Alzheimer's disease. In APP
Tg mice, which were fed a high-fat diet (HFD) from 3
months of age and developed a diabetic-like condition,
there was a decrease in brain responsiveness to insulin
stimulation in addition to systemic insulin resistance.
In this mouse, the amount of Aβ in the brain increased
significantly with age compared to the normal dietgroup, and the accumulation of amyloid plaques was
also accelerated at 15 months of age. In vivo kinetic
analysis showed that this might be partly due to adecrease in Aβ clearance in the brain caused by HFD
feeding.
In APP Tg mice lacking IRS-2, which plays animportant role in signal transduction as a substrate forinsulin and IGF-1 receptors, amyloid accumulation in
the brain was markedly suppressed, despite the fact thatthe mice exhibit systemic insulin resistance anddevelop diabetes. 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 with metabolic overload,
rather than decreased insulin signaling, may be
responsible for accelerated amyloid accumulation(Wakabayashi et al., Mol Neurodegener 2019).
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. We are now
focusing on ER stress as a molecular mechanism bywhich HFD feeding promotes the formation of amyloid
plaques, and are conducting in vivo studies.
In addition, the mechanism by which IRS-2 deficiency
has a protective 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.

References
1.

2.

3.

Tomoko Wakabayashi: Transmembrane Collagens
in Neuromuscular Development and Disorders.
Frontiers in Molecular Neuroscience, doi:
10.3389/fnmol.2020.635375
Tadafumi Hashimoto, Daisuke Fujii, Yasushi
Naka, Mayu Kashiwagi-Hakozaki, Yuko Matsuo,
Yusuke Matsuura, Tomoko Wakabayashi, Takeshi
Iwatsubo: Collagenous Alzheimer amyloid plaquecomponent impacts on the compaction ofamyloid-β plaques. Acta Neuropathologica
Communications, 8, 212, 2020
Koji Matsukawa, Michail S Kukharsky, SeiKyoung Park, Sangeun Park, Naruaki Watanabe,
Takeshi Iwatsubo, Tadafumi Hashimoto, Susan W
Liebman, Tatyana A Shelkovnikova: Long noncoding RNA NEAT1_1 ameliorates TDP-43
toxicity in in vivo models of TDP-43
proteinopathy. RNA Biology, doi: 10.1080/
15476286.2020.1860580

441

Department of Health Services
Research
Project Associate Professor
Taisuke Jo, M.D.,Ph.D.

Project Assistant Professor
Nobuaki Michihata, M.D., PhD.

Project Assistant Professor
Hayato Yamana, 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 maintenance of health services particularlyin the aging society in Japan. Education and trainingof personnel to cultivate human resources such as
researchers and analysts in HSR is another importantmission 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.

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 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
quality of health care and analysis of heath economics,
finance and allocation of medical resources. Utilizing
large databases, the members of HSR were working toaddress the following issue.
1) Clinical and epidemiological research questions related to various disease, including respiratory disease.
2) Outcomes and cost effectiveness in both western
medicine and eastern medicine in Japan.
3) Impact of super aging society on population
dynamics and demand of health services.
4) Efficient distribution of medical staffs, medical
institutions and armamentarium.
The followings are the examples of studies

442

conducted in 2020.
1) High-dose versus low-dose intravenous immuneglobulin for treatment of children with Kawasaki
disease weighing 25 kg or more
Little is known whether 2 g/kg IVIG is necessary for
older children with Kawasaki Disease (KD), because
they could have more complications and financial
burden. The purpose of this study was to compare
outcomes between high and low-dose IVIG in KD
children with higher body weight (25 kg or more),using a national inpatient database in Japan from 2010
to 2017.
We identified those receiving 2 g/kg and 1g/kg IVIG
as an initial treatment. Outcomes included the
proportions of coronary artery abnormalities (CAA)
formation, IVIG resistance, adverse effects, length ofstay, and medical costs. A propensity-score matching
analysis was conducted to compare the outcomes
between the groups.
We identified 1332 patients with KD and created 4:1
propensity-score matched pairs between high andlow-dose IVIG groups. There were no significant
differences in the proportions of CAA (5.3% vs. 4.1%;
p=0.587), IVIG resistance and length of stay. Medical
costs were significantly higher in the high-dose groupthan low-dose group (p<0.001).
No significant difference was shown between thehigh and low-dose IVIG groups in the proportions ofoutcomes, while medical costs were higher in thehigh-dose group. Further studies are needed toascertain the appropriate IVIG dose in older patientswith KD.
2) Association between mandatory health examination
attendance and diabetes treatment initiation among
employees being treated for hypertension
It is unclear whether mandatory health examination
is effective for employees who are already being
treated for chronic diseases. We focused on patients
being treated for hypertension and evaluated theassociation
betweenemployer-based
healthexamination attendance and diabetes treatment
initiation.
Using a database that stores health insurance claims
and health examination results of subscribers enrolled
in society-managed health insurance plans in Japan,
we identified employees aged 40–59 years who werebeing treated for hypertension when starting diabetes

treatment from April 2012 to December 2016. A
case-crossover analysis was conducted using 90, 180,
and 270 days prior to diabetes treatment initiation as
reference points and 90 days after the mandatory
health examination as the exposure period. We
conducted a subgroup analysis by hemoglobin A1c(HbA1c) level and frequency of outpatient blood
glucose testing before the mandatory healthexamination.
We identified 1464 individuals starting treatment fordiabetes while on antihypertensive drugs. The overallodds ratio for starting diabetes treatment within 90
days of the health examination was 1.89 (95%
confidence interval: 1.70–2.10). The subgroup
analysis showed that this odds ratio increased as
HbA1c level increased and as blood glucose testing
frequency decreased.
Among employees starting treatment for diabetes
while being treated for hypertension, employer-based
mandatory health examination attendance wasassociated with initiation of diabetes treatment. The
health examinations may be functioning as acomplement to screening in outpatient settings.
3) Inhaled corticosteroid withdrawal may improveoutcomes in elderly patients hospitalized for COPD
exacerbation: A nationwide database study
Inhaled corticosteroids (ICS) is used foradvanced-stage COPD. However, in patients with
COPD exacerbation, withdrawal of ICS can often be
unavoidable. This study aimed to evaluate theassociation between ICS withdrawal and outcomes inelderly patients with COPD exacerbation.
We conducted a retrospective cohort study using
Japanese Diagnosis Procedure Combination inpatientand outpatient database from July 2010 to March 2016.
We identified patients aged ≥65 years who were
hospitalizedfor
COPD
exacerbation.
Re-hospitalization for COPD exacerbation or death,frequency of antimicrobials or anti-flu medicine
prescribed within one year after discharge, andfrequency of oral corticosteroids prescription after
discharge were compared between patients withwithdrawal and continuation (control) group of ICS,
using propensity score analyses.
Among 23,047 eligible patients, the numbers of
those with ICS withdrawal and continuation were 971
and 2,764, respectively. Hazard ratios (95%443

confidence intervals) of re-hospitalization for COPD
exacerbation or death for the ICS withdrawal group(with reference to the control group) was 0.68 (0.54 to0.84) in the 1-to-2 propensity score matching and 0.71
(0.56 to 0.90) in the stabilized inverse probability oftreatment weighting. Frequency of antimicrobials or
anti-flu medicine prescription within one year was
significantly less in the ICS withdrawal group than in
the control group, whereas frequency of oralcorticosteroids prescription within 30 days as well as
within one year was not significantly different
between the two groups.
In elderly patients, ICS withdrawal after COPD
exacerbation was significantly associated with
reduction in re-hospitalization or death. ICS
withdrawal may be a feasible treatment option inelderly patients with COPD exacerbation.
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. Ota K, Sasabuchi Y, Matsui H, Jo T, Fushimi K,
Yasunaga H. Age distribution and seasonality inacute eosinophilic pneumonia: analysis using anational inpatient database. BMC Pulm Med.
2019;19(1):38.
2. Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H.
Early Enteral Nutrition in Patients Undergoing
Sustained
Neuromuscular
Blockade:A
Propensity-Matched Analysis Using a Nationwide
Inpatient Database. Crit Care Med. 2019;47(8):1072-80.
3. Ohbe H, Isogai S, Nakajima M, Jo T, Matsui H,
Fushimi K, et al. Physician-manned prehospitalemergency care in tertiary emergency centers inJapan. Acute Med Surg. 2019;6(2):165-72.
4. Ohbe H, Isogai S, Jo T, Matsui H, Fushimi K,
Yasunaga H. Extracorporeal membrane oxygenation improves outcomes of accidental hypothermia without vital signs: A nationwide observational study. Resuscitation. 2019;144:27-32.
5. Ohbe H, Isogai S, Jo T, Matsui H, Fushimi K,
Yasunaga H. Treatment with Antithrombin or
Thrombomodulin and Mortality from Heatstroke-

Induced Disseminated Intravascular Coagulation:
A Nationwide Observational Study. Semin
Thromb Hemost. 2019;45(8):760-6.
6. Mouri H, Jo T, Michihata N, Matsui H, Fushimi
K, Yasunaga H. Continuous Neuromuscular
Blockade and Mortality in Subjects With
Exacerbation of Idiopathic Interstitial Pneumonias.
Respir Care. 2019;64(1):34-9.
7. Michihata N, Shigemi D, Sasabuchi Y, Matsui H,
Jo T, Yasunaga H. Safety and effectiveness ofJapanese herbal Kampo medicines for treatmentof hyperemesis gravidarum. Int J Gynaecol Obstet.
2019;145(2):182-6.
8. Kumazawa R, Jo T, Matsui H, Fushimi K,
Yasunaga H. Association between AngiotensinConverting Enzyme Inhibitors and Post-Stroke
Aspiration Pneumonia. J Stroke Cerebrovasc Dis.
2019;28(12):104444.
9. Jo T, Michihata N, Yamana H, Sasabuchi Y,
Matsui H, Urushiyama H, et al. Reduction in
exacerbation of COPD in patients of advanced age
using the Japanese Kampo medicine Dai-kenchuto: a retrospective cohort study. Int J Chron
Obstruct Pulmon Dis. 2019;14:129-39.
10. Hiraishi Y, Jo T, Michihata N, Hasegawa W,
Sakamoto Y, Urushiyama H, et al. Hospital
Volume and Mortality following Diagnostic
Bronchoscopy in Lung Cancer Patients: Data
from a National Inpatient Database in Japan.
Respiration. 2019;97(3):264-72.
11. Goto T, Jo T, Matsui H, Fushimi K, Hayashi H,
Yasunaga H. Machine Learning-Based Prediction
Models for 30-Day Readmission after Hospitalization for Chronic Obstructive Pulmonary Disease.
COPD. 2019;16(5-6):338-43.
12. Minami T, Mph, Yamana H, Ph DM, Shigemi D,
Mph, et al. Artificial colloids versus humanalbumin for the treatment of ovarian hyperstimulation syndrome: A retrospective cohort
study. Int J Reprod Biomed. 2019;17(10):709-16.
13. Takano A, Ono S, Yamana H, Matsui H,
Matsumoto T, Yasunaga H, et al. Factors
associated with long-term prescription of
benzodiazepine: a retrospective cohort study
using a health insurance database in Japan. BMJ
Open. 2019;9(7):e029641.
14. Shinkawa H, Yasunaga H, Hasegawa K, Matsui H,

444

Michihata N, Fushimi K, et al. Mortality andmorbidity after pancreatoduodenectomy inpatients undergoing hemodialysis: Analysis usinga national inpatient database. Surgery. 2019;
165(4):747-50.
15. Okubo Y, Miyairi I, Michihata N, Morisaki N,
Kinoshita N, Urayama KY, et al. Recent
Prescription Patterns for Children With Acute
Infectious Diarrhea. J Pediatr Gastroenterol Nutr.
2019;68(1):13-6.
16. Okubo Y, Hayakawa I, Nariai H, Michihata N,
Matsui H, Fushimi K, et al. Recent practicepatterns in diagnostic procedures anticonvulsants,
and antibiotics for children hospitalized withfebrile seizure. Seizure. 2019;67:52-6.
17. Morita K, Matsui H, Michihata N, Fushimi K,
Yasunaga H. Association of Early Systemic
Corticosteroid Therapy with Mortality in Patientswith Stevens-Johnson Syndrome or Toxic
Epidermal Necrolysis: A Retrospective Cohort
Study Using a Nationwide Claims Database. Am J
Clin Dermatol. 2019;20(4):579-92.
18. Ishimaru T, Fujiogi M, Michihata N, Matsui H,
Fushimi K, Kawashima H, et al. Impact ofcongenital heart disease on outcomes after
primary repair of esophageal atresia: a retrospective observational study using a nationwide
database in Japan. Pediatr Surg Int. 2019;35(10):1077-83.
19. Ikawa F, Michihata N, Akiyama Y, Iihara K,
Matano F, Morita A, et al. Treatment Risk for
Elderly Patients with Unruptured Cerebral
Aneurysm from a Nationwide Database in Japan.
World Neurosurg. 2019;132:e89-e98.
20. Ikawa F, Hidaka T, Yoshiyama M, Ohba H,
Matsuda S, Ozono I, et al. Characteristics ofCerebral Aneurysms in Japan. Neurol Med Chir
(Tokyo). 2019;59(11):399-406.
21. Fujiogi M, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Fujishiro J. Outcomes following
laparoscopic versus open surgery for pediatricinguinal hernia repair: Analysis using a national
inpatient database in Japan. J Pediatr Surg. 2019;54(3):577-81.
22. Fujiogi M, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Fujishiro J. Early Outcomes of
Laparoscopic Versus Open Surgery for Urachal

Remnant Resection in Children: A Retrospective
Analysis Using a Nationwide Inpatient Databasein Japan. J Laparoendosc Adv Surg Tech A. 2019;29(8):1067-72.

445

Division of Chronic Kidney Disease(CKD) Pathophysiology
Division Chief (Professor)
Reiko Inagi, Ph.D.

Assistant Professor
Tsuyoshi Inoue, M.D., Ph.D.

Postdoctoral fellow
Hiroshi Maekawa, M.D., Ph.D. (Division of Nephrology and Endocrinology)
Sho Hasegawa, M.D., Ph.D. JSPS Research Fellowship for Young Scientists (DC2)

PhD Students
Rie Fujii, M.D. (Division of Nephrology and Endocrinology)
Rie Uni, M.D. (Division of Nephrology and Endocrinology)
Haruki Ouchi, M.D. (Division of Nephrology and Endocrinology)

Visiting Researcher
Kenichiro Yoshioka, M.Pharm. (Kyowa Kirin Co., Ltd.)Lab Technician
Ikumi Okuaki, B.S.
Rieko Matsuda, 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.

446

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
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
CKD
6) Elucidating the neuro-immune axis in kidney
injury7) Role of ADP-ribosyl cyclase (Bst1, CD38) inrenal injury

Research Funds (PI) Japan Society for the Promotion of Science, Grantsin-Aid for Scientific Research
18H02727 (to Reiko Inagi, Mechanisms oforganelle cross talk disorder and failure of organ
homeostasis in aging and disease),
18H06192 (to Tsuyoshi Inoue, The mechanism of
immune cell activation in the cholinergic
anti-inflammatory pathway)
20K17243 (to Hiroshi Maekawa, The elucidationof pathophysiology of cGAS-STING pathway in
AKI-to-CKD transition)
 Japan Agency for Medical Research andDevelopment (AMED)PRIME 19gm6210013h0001 (to Tsuyoshi Inoue,
Elucidation of cell interaction mechanism insuppression of chronic kidney disease progression
through nervous and immune systems
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 (toTsuyoshi Inoue, Suppressive mechanism ofatherosclerosis progression by vagus nerve
stimulation) The Kidney Foundation, Japan, Grant for
pathophysiological research conference in chronic
kidney disease (to Tsuyoshi Inoue, Elucidation oferythropoietin production regulation mechanism byvagus nerve)

447

 Takeda Science Foundation, Medical Research
Grant (to Tsuyoshi Inoue, Elucidation of new
anti-inflammatory
and
organ
protection
mechanisms controlled by autonomic nervous
system) Mochida Memorial Foundation for Medical andPharmaceutical Research, Research Grant (toTsuyoshi Inoue, Elucidation of the mechanism ofmacrophageanti-inflammatory
effectbysympathetic and parasympathetic stimulation)
 Astellas Foundation for Research on Metabolic
Disorders, Research Grant (to Tsuyoshi Inoue,
Anti-inflammatory mechanism of macrophages byautonomic nerve stimulation)
 Suzuken Memorial Foundation, Research Grant (toTsuyoshi Inoue, Study on therapeutic effect ofautonomic nerve stimulation in kidney disease)

2.

3.

4.

AwardsDr. Hiroshi Maekawa received the Young
Investigator Award at the 63nd Conference of JapaneseSociety of Nephrology.

5.

Dr. Sho Hasegawa received the CKD Frontier Awardat the 9th Chronic Kidney Disease Frontier.
Dr. Sho Hasegawa received the Young InvestigatorAward at the 18th Annual Meeting of Asian PacificCongress of Nephrology.

6.

Dr. Sho Hasegawa received the Advances in Research
Conference Trainee Support Grant of American
Society of Nehprology.
Dr. Sho Hasegawa received the CKD Frontier Awardat the 10th Chronic Kidney Disease Frontier.
Dr. Sho Hasegawa received the Young InvestigatorAward at the 24th Annual Meeting of the Society ofCardiovascular Endocrinology and Metabolism

References1.

Takemura K, Nishi H, Inagi R. Mitochondrial
Dysfunction in Kidney Disease and Uremic
Sarcopenia.
Front Physiol. 2020 Sep 4;11:565023. doi:7.

10.3389/fphys.2020.565023. PMID: 33013483;
PMCID: PMC7500155.
Inagi R. The Implication of Organelle Cross Talk
in AKI.
Nephron. 2020;144(12):634-637. doi: 10.1159/
000508639. PMID: 32702704.
Chikamori M, Kimura H, Inagi R, Zhou J,
Nangaku M, Fujii T. Intracellular calcium
response of primary cilia of tubular cells tomodulated shear stress under oxidative stress.
Biomicrofluidics. 2020 Jul 2;14(4):044102. doi:
10.1063/5.0010737. PMID: 32665806; PMCID:
PMC7334031.
Nishi H, Takemura K, Higashihara T, Inagi R.
Uremic Sarcopenia: Clinical Evidence and Basic
Experimental Approach.
Nutrients. 2020 Jun 18;12(6):1814. doi: 10.
3390/nu12061814. PMID: 32570738; PMCID:
PMC7353433.
Uni R, Inoue T, Nakamura Y, Fukaya D,
Hasegawa S, Wu CH, Fujii R, Surattichaiyakul B,
Peerapanyasut W, Ozeki A, Akimitsu N, Wada Y,
Nangaku M, Inagi R. Vagus nerve stimulationeven after injury ameliorates cisplatin-induced
nephropathy
via
reducing
macrophage
infiltration.
Sci Rep. 2020 Jun 11;10(1):9472. doi:
10.1038/s41598-020-66295-0. PMID: 32528023;
PMCID: PMC7290038.
Inagi R. Organelle stress and glycation in kidneydisease.
Glycoconj J. 2021 Jun;38(3): 341-346. doi:
10.1007/s10719-021-09989-5. Epub 2021 Mar
11. PMID: 33709200.
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: ASN.2020121723.
doi:
10.1681/ASN.2020121723.
PMID:
33875568.

448

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 one technical assistants.

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,449

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.

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
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)

450

7.

8.

9.

10.

11.

12.

13.

14.

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)
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)
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)
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

15.

16.

17.

18.

19.

20.

21.

docosahexaenoic acid during spermatogenesis. J
Biol Chem, 292, 12065-12076 (2017)
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)
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)
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)
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.
Kita Y, Yoshida K, Tokuoka MS, Hamano F,
Yamazaki M, Sakimura K, Kano M, Shimizu T.
Fever is mediated by conversion of endocannabinoid 2-arachidonoylglycerol to prostaglandin E2.
PLoS ONE, 10, e0133663 (2015)
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)
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)

451

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, ALCARE Co., Ltd. and Fujifilm
Corporation, and in close collaboration withdepartmentsof
Orthopaedic
Surgery
andRehabilitation 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.

clinical features, laboratory and radiographic findings,
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 to2.

3.

Horii C, Asai Y, Iidaka T, Muraki S, Oka H,
Tsutsui S, Hashizume H, Yamada H, Yoshida M,
Kawaguchi H, Nakamura K, Akune T, Oshima Y,
Tanaka S, Yoshimura N: The incidence and risk
factors for adjacent vertebral fractures incommunity-dwelling people with prevalentvertebral fracture: the 3rd and 4th survey of the
ROAD study. Arch Osteoporos 15(1): 74, 2020.
Iidaka T, Muraki S, Oka H, Horii C, Kawaguchi
H, Nakamura K, Akune T, Tanaka S, Yoshimura
N: Incidence rate and risk factors forradiographic osteoarthritis in Japanese men andwomen. A 10-year follow-up of the ROAD study.
Osteoarthritis Cartilage 28(2): 182-188, 2020.
Matsui T, Hara K, Kayama T, Iwata M, Shitara N,
Hojo S, Endo Y, Fukuoka H, Yoshimura N,
Kawaguchi H: Cervical muscle diseases are

452

4.

5.

6.

7.

8.

9.

associated with indefinite and various symptoms
in the whole body. Eur Spine J 29(5): 1013-1021,
2020.
Ishimoto Y, Jamaludin A, Cooper C, WalkerBone K, Yamada H, Hashizume H, Oka H,
Tanaka S, Yoshimura N, Yoshida M, Urban J,
Kadir T, Fairbank J: Could automated machinelearned MRI grading and epidemiological studies
of lumbar spinal stenosis? Validation within the
Wakayama Spine Study. BMC Musculoskelet
Disord 21(1): 158, 2020.
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 Res 24(1): 37-48, 2021.
Murakami K, Nagata K, Hashizume H, Oka H,
Muraki S, Ishimoto Y, Yoshida M, Tanaka S,
Minamide A, Nakagawa Y, Yoshimura N,
Yamada H: Prevalence of cervical anterior andposterior spondylolisthesis and its association
with degenerative cervical myelopathy in a
general population. Sci Rep 26;10(1): 10455,
2020.
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, 2020 (online).
Makizako H, Nishita Y, Seungwon J, Otsuka R,
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,
Opne Access, 2020 (online).
Leyland KM, Gates LS, Sanchez-Santos MT,
Nevitt MC, Felson D, Jones G, Jordan JM, Judge
A, Prieto-Alhambra D, Yoshimura N, Newton JL,
Callahan LF, Cooper C, Batt ME, Lin J, Liu Q,
Cleveland RJ, Collins GS, Arden NK, PCCOA
Steering Committee: Knee osteoarthritis andtime-to all-cause mortality in six communitybased cohorts: an international meta-analysis ofindividual participant-level data. Aging Clin Exp
Res 33(3): 529-545, 2021.
10. 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 (online).

University Hospital
Clinical Divisions

University Hospital
Central Clinical Facilities

455

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 2020, 205,277 outpatient blood
sampling were performed in this section. Furthermore,
239,098 urine samples were examined.
The 2nd Section
This section deals with clinical biochemistry andimmuno-serology tests. In 2020, 5,077,465 serum

enzyme tests (such as AST and ALT), and 512,042
immunological tests were performed.
The 3rd Section
This section deals with laboratory hematology and
DM-related tests, and gene analysis tests. In 2020,
1,087,307 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 2020, 37,979 ECG, 16,273
pulmonary function tests, and 9,068 EEG were
performed.
The 5th Section
This section deals with ultrasonography. In 2020,
10,123 echocardiography tests, 11,960 abdominal
echography tests, and 9,068 other ultrasonography
tests were performed.

456

Teaching activities
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.

2.

3.

4.

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-19-associated biomarkers, iv) platelet biology,
development of laboratory diagnosis in thrombosisand hemostasis, 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,andix)
promotionof
medical-science-engineering cooperation.

5.

6.

References
Original article:
1. Endo, Y., Araoka, H., Baba, M., Okada, C., Kimura,M., Higurashi, Y., Sato, T., Yatomi, Y., Moriya, K.,
and Yoneyama, A. Matrix-assisted laser desorption

7.

ionization-time of flight mass spectrometry can beused to identify Helicobacter cinaedi. Diagn.
Microbiol. Infect. Dis. 96: 114964, 2020.
Fujisawa, M., Yasumoto, A., Kato, H., Sugawara,
Y., Yoshida, Y., Yatomi, Y., and Nangaku, M. The
role of anti-complement factor H antibodies in thedevelopment of atypical haemolytic uremic
syndrome: a possible contribution to abnormality ofplatelet function. Br. J. Haematol. 189: 182-186,
2020.
Fukuhara, S., Yasukawa, K., Sato, M., Ikeda, H.,
Inoguchi, Y., Etoh, T., Masakado, M., Umeda, F.,
Yatomi, Y., Yamauchi, T., and Inoguchi, T.
Clinical usefulness of human serum nonmercaptalbumin to mercaptalbumin ratio as a biomarker for
diabetic complications and disability in activities ofdaily living in elderly patients with diabetes.
Metabolism. 103: 153995, 2020.
Hirano, M., Kimura, K., Ishigaki, T., Nojima. M.,
Daimon, M., Morita, H., Takenaka, K., Xu, B.,
Sawada, N., Hirokawa, M., Komuro, I., Morisaki,T., Yotsuyanagi, H., Kawamata, T., Yokoyama, K.,
Konuma, T., Kato, S., Yasui, H.., Nagamura-Inoue,
T., Uchimaru, K., Takahash i, S., Imai, Y., and Tojo,
A. High prevalence of left ventricular noncompaction and its impact on chemotherapy-related
cardiac dysfunction in patients with hematologicaldiseases. Circ. J. 84: 1957-1964, 2020.
Hirokawa, M., Daimon, M., Kozuma, K., Shinozaki,T., Kimura, K., Nakao, T., Nakanishi, K., Sawada,N., Ishiwata, J., Yoshida, Y., Kato, T.S., Mizuno,Y., Morita, H., Yatomi, Y., and Komuro, I. Are
there gender differences in the association between
body mass index and left ventricular diastolic
function? A clinical observational study in theJapanese general population. Echocardiography.
37: 1749-1756, 2020.
Igarashi, N., Honjo, M., Yamagishi, R., Kurano, M.,
Yatomi, Y., Igarashi, K., Kaburaki, T., and Aihara,
M. Involvement of autotaxin in the pathophysiology of elevated intraocular pressure in
Posner-Schlossman syndrome. Sci. Rep.10: 6265,
2020.
Itoh, H., Kaneko, H., Kiriyama, H., Yoshida, Y.,
Nakanishi, K., Mizuno, Y., Daimon, M., Morita, H.,
Yatomi, Y., Yamamichi, N., and Komuro I. Effectof Metabolically Healthy Obesity on the

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13.

Development of Carotid Plaque in the General
Population: A Community-Based Cohort Study. J.
Atheroscler. Thromb. 27: 155-163, 2020.
Izumi, C., Eishi, K., Ashihara, K., Arita, T., Otsuji,Y., Kunihara, T., Komiya, T., Shibata, T., Seo, Y.,
Daimon, M., Takanashi, S., Tanaka, H., Nakatani,S., Ninami, H., Nishi, H., Hayashida, K., Yaku, H.,
Yamaguchi, J., Yamamoto, K., Watanabe, H., Abe,Y., Amaki, M., Amano, M., Obase, K., Tabata, M.
Miura, T., Miyake, M., Murata, M., Watanabe, N.,
Akasaka, T., Okita, Y., Kimura, T., Sawa, S.,
Yoshida, K. On behalf of the Japanese Circulation
Society Joint Working Group. JCS/JSCS/JATS/
JSVS 2020 guidelines on the management ofvalvular heart disease. Circ. J. 84: 2037-2119,
2020.
Kageyama, Y., Uranbileg, B., Kusumoto, Y., Sakai,E., Ikeda, H., Kurano, M., Yatomi, Y. Suppressionof sphingosine 1-phosphate lyase retards the liver
regeneration in mice after partial hepatectomy.
BioSci. Rep. 40: BSR20200592, 2020.
Kanoh, H., Nitta, T., Go, S., Inamori, K.I., Veillon,
L., Nihei, W., Fujii, M., Kabayama, K., Shimoyama,
A., Fukase, K., Ohto, U., Shimizu, T., Watanabe, T.,
Shindo, H., Aoki, S., Sato, K., Nagasaki,
M.,Yatomi, Y., Komura, N., Ando, H., Ishida, H.,
Kiso, M., Natori, Y., Yoshimura, Y., Zonca, A.,
Cattaneo, A., Letizia, M., Ciampa, M., Mauri, L.,
Prinetti, A., Sonnino, S., Suzuki, A., and Inokuchi,
J.I. Homeostatic and pathogenic roles of GM3
ganglioside molecular species in TLR4 signaling inobesity. EMBO J. 39: e101732, 2020.
Kiriyama, H., Daimon, M., Nakanishi, K., Kaneko,
H., Nakao, T., Morimoto-Ichikawa, R., Miyazaki,
H., Morita, H., Daida, H., and Komuro I.
Comparison between Healthcare-associated andCommunity-acquired Infective Endocarditis at
Tertiary Care Hospitals in Japan. Circ. J., 84:
670-676, 2020.
Kiriyama, H., Kodera, S., Minatsuki, S., Kaneko,
H., Kikuchi, H., Kiyosue, A., Toko, H., Daimon,
M., Ando, J., Morita, H., and Komuro I.
Short-Term and Long-Term Efficacy ofDrug-Coated Balloon for In-Stent Restenosis in
Hemodialysis Patients with Coronary Artery
Disease. Int. Heart J. 60: 1070-1076, 2020.
Kiriyama, H., Kaneko, H., Itoh, H., Yoshida, Y.,

14.

15.

16.

17.

18.

19.

20.

Nakanishi, K., Mizuno, Y., Daimon, M., Morita, H.,
Yamamichi, N., and Komuro, I. Effect of cigarettesmoking on carotid artery atherosclerosis: acommunity-based cohort study. Heart Vessels. 35:
22-29, 2020.
Kobayashi, Y., Suzuki, R., Yasukawa, K., Oba, K.,
Yamauchi, T., Yatomi, Y., and Kadowaki T.
Oxidized albumin in blood reflects the severity ofmultiple vascular complications in diabetes mellitus.
Metabol. Open 6: 100032, 2020.
Kurano, M., Tsukamoto, K., Hara, M., Tsuneyama,K., Nishikawa, T., Ikeda, H., and Yatomi, Y.
Modulation of sphingosine 1-phosphate byhepatobiliary cholesterol handling. FASEB J. 34:
14655-14670, 2020.
Kurano, M., Tsukamoto, K., Shimizu, T., Kassai,
H., Nakao, K., Aiba, A., Hara, M., and Yatomi, Y.
Protection Against Insulin Resistance by
Apolipoprotein
M/Sphingosine
1-Phosphate.
Diabetes. 69: 867-881, 2020.
Mikami, Y., Jo, T., Matsuzaki, H., Ishimori, T.,
Saito, M., Sakamoto, Y., Yamauchi, Y., Takai, D.,
Yatomi, Y., and Nagase, T. Preoperativeintervention with long-acting bronchodilators forthe reduction of postoperative pulmonary
complications in untreated patients with obstructive
lung disease. Clin. Respir. J. 14: 92-101, 2020.
Miyoshi, T., Addetia, K., Citro, R., Daimon, M.,
Desale, S., Fajardo, P.G., 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., Blitz, A., Lang, R.M.,
Asch, F.M., and WASE Investigators. Leftventricular diastolic function in healthy adultindividuals: Results of the world alliance societiesof echocardiography (WASE) normal values study.
J. Am. Soc. Echocardiogr. 33: 1223-1233, 2020.
Morita, Y., Kurano, M., Sakai, E., Nishikawa, T.,
Nishikawa, M., Sawabe, M., Aoki, J., and Yatomi,
Y. Analysis of Urinary Sphingolipids using
LC-MS/MS in Diabetic Nephropathy. J. Diabetes
Investig. 11: 441-449, 2020.
Morita, Y., Kurano, M., Tanaka, M., Hisasue, T.,
Sato, M., Ono, Y., Sato, T., Shukuya, K., andYatomi, Y. Midstream urine sampling is necessary

458

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24.

25.

26.

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for accurate measurement of the urinary level ofneutrophil gelatinase-associated lipocalin in healthy
female subjects. Clin. Biochem. 79: 70-74, 2020.
Morita, Y., Kurano, M., Morita, E., Shimamoto, S.,
Igarashi, K., Sawabe, M., Aoki, J., and Yatomi, Y.
Urinary autotaxin concentrations are associatedwith kidney injury. Clin. Chim. Acta. 509: 156-165,
2020.
Nagai, K., Uranbileg, B., Chen, Z., Fujioka, A.,
Yamazaki, T., Matsmoto, Y., Tsukamoto, H., Ikeda,
H., Yatomi, Y., Chiba, H., Hui, S.P., Nakazawa, T.,
Saito, R., Koshiba, S., Aoki, J., Saigusa, D., andTomioka, Y. Identification of novel biomarkers ofhepatocellular carcinoma by high‐definition mass
spectrometry:
Ultrahigh‐performanceliquidchromatography quadrupole time‐of‐flight mass
spectrometry and desorption electrospray ionization
mass spectrometry imaging. Rapid Commun Mass
Spectrom., 34(Suppl 1): e8551. 2020.
Nakanishi, K., Daimon, M., Yoshida, Y., Ishiwata,J., Sawada, N., Hirokawa, M., Kaneko, H., Nakao,T., Mizuno, Y., Morita, M., Di, Tullio, M.R.,
Homma, S., and Komuro, I. Serum uric acid levelas a potential marker of subclinical left ventricular
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460

Surgical Center
Professor (Director)
Kazuhiko Fukatsu M.D., Ph.D.

Lecturer
Mitsuaki Muroya, M.D., Ph.D
Satoshi Murakoshi, M.D., Ph.D.
Yuhei Saito, 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 and 9,945 (under the circumstance of Covid-19
pandemic) operations were performed in 2006, 2007,2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016,2017, 2018, 2019 and 2020 fiscal year, respectively.
The number of operations in 2019 fiscal year counts forapproximately 1.8 times comparing to that in 2001.
These days more and more patients undergo
endoscopic surgery such as laparoscopy/thoracoscopy

461

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 wall 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 complicatedand long operations such as transplant surgery, open-462

heart 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

463

Department of Clinical Radiology
Professor (department manager)
Osamu Abe, M.D., Ph.D.

Lecturer (vice manager)
Jiro Sato, M.D.

Assistant Professor
Masaki Katsura, M.D., Ph.D.

Chief Technologist (vice manager)
Hideyuki Iwanaga, R.T.

Homepagehttps://www.h.u-tokyo.ac.jp/patient/depts/houshasenbu/

Introduction and Organization
In the Department of Clinical Radiology, clinicalservices on Diagnostic Radiology (imaging andintervention), Radiation Oncology (radiotherapy),
Nuclear Medicine, and the Radiation Safety Control
System are provided in cooperation with radiology
technologists and nurses. Present constituent members
are three medical doctors, 75 radiological technicians,
and one technical official of the radiation control. In
addition, the Department of Radiology staff members(teachers, graduate school students, medical staff, andclinical trainees) join this. In addition, the doctors ofother departments and the nurses cooperate and arealso engaged in clinical radiology activities.
Department of Clinical Radiology is actively
participating in the following projects. 1) PACS: We
have recently developed a radiology information
system (RIS) networking with a hospital information
system(HIS)
andpicturearchivingandcommunicating system (PACS). The PACS of thewhole hospital (the film-less imaging system) wasestablished in 2003. The new reporting system wasinstalled in 2012. 2) Radiation Safety Control:
stimulated by the need for evaluating the individualaccumulated exposure dose by medical radiation, we
have started a working group to solve this problem.
We aim to provide the accumulated exposure dose

data on RIS. 3) Researches on new radiology
techniques: Ongoing collaborative researches are as
follows: image-guided radiation therapy, clinical PET,
multi-detector row CT, 3-Tesla MRI, flat panel
detector, postmortem imaging, and artificial
intelligence.

Clinical activities
1) Diagnostic Radiology:
The diagnostic radiology section is responsible forall the clinical examinations of CT, MRI, andangiography including interventional radiology. All ofthese examinations are performed under the requests
of clinicians. Over two hundred CT examinations are
conducted using six multi-detector-row CT scanners
each day. Interventional procedures such as
percutaneous biopsy and abscess drainage are alsodone by CT guidance. About eighty MR examinations
are done using two of 1.5-Tesla and five of 3-Teslascanners every day. Diagnostic and interventional
procedures are performed using six angiographic units,
including a hybrid operating room. Image Computing& Analysis Laboratory provides processing of volume
image data into clinical 3D images and analysis ofimaging data.
2) Nuclear medicine:464

The section of nuclear medicine is responsible forall the radionuclide imaging examinations, including
conventional scintigraphy such as bone, kidney,
thyroid scans, single-photon emission computerized
tomography (SPECT), and positron emission
tomography (PET) scans. Scanning is performed on
the first basement floor in the Central Clinic Building
1. Blood flow, metabolism, and receptor functions aremeasuredtounderstandnormalandpathophysiological states, using a variety ofpositron-emitter radiotracers with 18F. Whole-body
18
F-fluorodeoxyglucose-PET (FDG-PET) for thestaging of malignancy plays a vital role in the clinicalmanagement of the patients. These nuclear imaging
procedures are performed and reported by radiologists
and cardiologists.
3) Radiation Oncology:
The radiation therapy is performed using threelinear accelerators: an intracavitary irradiation device(RALS), a brachytherapy device, and a gamma knife
for radiosurgery. The network system connecting theseradiotherapy pieces of equipment, CT/MR devices,and treatment planning systems was alreadyconstructed. Each year, over 700 new patients receive
radiation therapy in the Radiation Oncology section.
Highly accurate 3D radiation therapy is the mostoutstanding feature. We have developed a new linear
accelerator with C-arm and multi-leaf collimatorsystems, mainly for non-coplanar radiation therapy inmany patients, especially with brain tumors or headand neck tumors. In addition, the linear accelerator
system with cone-beam CT technology has been
introduced to our hospital, which enables
image-guided radiation therapy.
4) Radiation safety control:
The educational training and registration of theradiation-engaging persons are controlled according to
the University of Tokyo Hospital Ionizing Radiation
Injury Prevention Rules.
In conclusion, the department of clinical radiology
is a service section to all clinical departments. The
leading supporter as a doctor is a radiologist. However,the cooperation with the radiation diagnosis andtreatment engaging persons of other clinicaldepartments, technicians and nurses must be
reinforced. We want to make still more effort toachieve the cooperation and improve clinical activities
in the department of clinical radiology.

References
See the corresponding part of the Department ofRadiology.

Number of examinations in 2020
Inpatient

Outpatient

Total

Radiography(plain)Radiography(enhanced)

83,44464,254

147,698

3,819

1,368

5,187

Angiography

3,133

12

3,145

Computed
tomography
Magnetic
resonance
imaging
Nuclearmedicine

13,76334,74448,507

4,633

14,813

19,446

1,479

2,358

3,837

Radiotherapy

5,448

8,503

13,951Bone mineraldensitometry

325

2,406

2,731

465

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, 79 pharmacy staffs,
and 8 graduate students and 8 undergraduate students
from the faculty of pharmaceutical sciences (as ofMarch 1st, 2021).

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 (2,654
items), out-patient medicines, anesthetics, muscle
relaxation drugs, psychotropic drugs, poison
medicines.

4665) 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 2020)
Number of items on in-hospital formulary: 2,654
Number of prescriptions (ps.) filled or preparation(pp.) (annual)out-patients:
320,766 ps.
(outside :287,512 ps.)(inside :33,254 ps.)out-patient chemotherapy:
11,983 ps.

in-patients :231,367 ps.
injection drugs:
184,428 ps.
IVH:
3,213 pp.
chemotherapy:
10,225 pp.
TDM consultations (annual) :18,973 pp.
Numbers of hospital pharmaceutical cares (annual):
20,234 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467

hospital is one of the most important curriculums. In
2017, 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
2020, 11 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. 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-(1) Akashi A, Nakayama A, Kamatani Y, Higashino T,
Shimizu S, Kawamura Y, Imoto M, Naito M,
Hishida A, Kawaguchi M, Takao M, Matsuo M,
Takada T, Ichida K, Ooyama H, Shinomiya N,
Matsuo H. A common variant of LDL receptor
related protein 2 (LRP2) gene is associated withgout susceptibility: A meta-analysis in a Japanese
population. Hum Cell. 2020;33:303-07.
(2) Fujikawa H, Sakamoto Y, Masuda N, Oniki K,
Kamei S, Nohara H, Nakashima R, Maruta K,
Kawakami T, Eto Y, Takahashi N, Takeo T,
Nakagata N, Watanabe H, Otake K, Ogata Y,
Tomioka NH, Hosoyamada M, Takada T,
Ueno-Shuto K, Suico MA, Kai H, Saruwatari J,
Shuto T. Higher blood uric acid in female humans
and mice as a protective factor against
pathophysiological decline of lung function.
Antioxidants (Basel). 2020;9:387.
(3) Higashino T, Morimoto K, Nakaoka H, Toyoda Y,
Kawamura Y, Shimizu S, Nakamura T, Hosomichi
K, Nakayama A, Ooyama K, Ooyama H, Shimizu T,
Ueno M, Ito T, Tamura T, Naito M, Nakashima H,
Kawaguchi M, Takao M, Kawai Y, Osada N, Ichida
K, Yamamoto K, Suzuki H, Shinomiya N, Inoue I,
Takada T, Matsuo H. Dysfunctional missense
variant of OAT10/SLC22A13 decreases gout risk
and serum uric acid levels. Ann Rheum Dis.

468

(4)

(5)

(6)

(7)

(8)

(9)

2020;79:164-66.
Kawamura Y, Toyoda Y, Ohnishi T, Hisatomi R,
Higashino T, Nakayama A, Shimizu S, Yanagi M,
Kamimaki I, Fujimaru R, Suzuki H, Shinomiya N,
Takada T, Matsuo H. Identification of adysfunctional
splicing
mutation
inthe
SLC22A12/URAT1
gene
causingrenalhypouricaemia type 1: A report on two families.
Rheumatology (Oxford). 2020;59:3988-90.
Mitsuboshi S, Yamaguchi R, Uchida H, Kamoshida
S, Hashi H. Inappropriate sales of hypochlorousacid solution in Japan: An online investigation.
Infect Control Hosp Epidemiol. 2020:1-2.
Nakashima A, Ichida K, Ohkido I, Yokoyama K,
Matsuo H, Ohashi Y, Takada T, Nakayama A,
Suzuki H, Shinomiya N, Urashima M, Yokoo T.
Dysfunctional ABCG2 gene polymorphisms areassociated with serum uric acid levels and all-cause
mortality in hemodialysis patients. Hum Cell. 2020;
33:559-68.
Nakayama A, Nakatochi M, Kawamura Y,
Yamamoto K, Nakaoka H, Shimizu S, Higashino T,
Koyama T, Hishida A, Kuriki K, Watanabe M,
Shimizu T, Ooyama K, Ooyama H, Nagase M,
Hidaka Y, Matsui D, Tamura T, Nishiyama T,
Shimanoe C, Katsuura-Kamano S, Takashima N,
Shirai Y, Kawaguchi M, Takao M, Sugiyama R,
Takada Y, Nakamura T, Nakashima H, Tsunoda M,
Danjoh I, Hozawa A, Hosomichi K, Toyoda Y,
Kubota Y, Takada T, Suzuki H, Stiburkova B, Major
TJ, Merriman TR, Kuriyama N, Mikami H,
Takezaki T, Matsuo K, Suzuki S, Hosoya T,
Kamatani Y, Kubo M, Ichida K, Wakai K, Inoue I,
OkadaY,ShinomiyaN,
MatsuoH.
Subtype-specific gout susceptibility loci andenrichment of selection pressure on ABCG2 and
ALDH2 identified by subtype genome-wide
meta-analyses of clinically defined gout patients.
Ann Rheum Dis. 2020;79:657-65.
Okamoto K, Asano S, Yamamoto T, Toyono T,
Yamaguchi R, Okada Y, Okugawa S, Suzuki H,
Moriya K, Aihara M. Poor penetration of cefcapene
into aqueous humor after oral administration of
cefcapene pivoxil to patients undergoing cataract
surgery. J Infect Chemother. 2020;26:312-15.
Oriyama T, Yamamoto T, Nara K, Kawano Y,
Nakajima K, Suzuki H, Aoyama T. Prediction of thepermeability of antineoplastic agents through nitrile
medical gloves by zone classification based on their
physicochemical properties. J Pharm Health Care
Sci. 2020;6:23.
(10) Panthee N, Ono M, Yamamoto T, Ikemura M,
Tanaka T, Itoda Y, Suzuki H. Evaluation of spinal
cord protective threshold of serum memantine, an
NMDA receptor antagonist, in a rabbit model ofparaplegia. Indian J Thorac Cardiovasc Surg.
2020;36:598-607.
(11) Saito H, Toyoda Y, Hirata H, Ota-Kontani A,
Tsuchiya Y, Takada T, Suzuki H. Soy isoflavone
genistein inhibits an axillary osmidrosis risk factor
ABCC11: In vitro screening and fractional
approach for ABCC11-inhibitory activities in plant
extracts and dietary flavonoids. Nutrients. 2020;
12:2452.
(12) Saito H, Toyoda Y, Takada T, Hirata H, Ota-Kontani
A, Miyata H, Kobayashi N, Tsuchiya Y, Suzuki H.
Omega-3 polyunsaturated fatty acids inhibit thefunction of human URAT1, a renal urate
re-absorber. Nutrients. 2020;12:1601.
(13) Takada T, Nishimura T. Preface. Drug Metab
Pharmacokinet. 2020;35:1.
(14) Toyoda Y, Takada T, Miyata H, Matsuo H, Kassai H,
Nakao K, Nakatochi M, Kawamura Y, Shimizu S,
Shinomiya N, Ichida K, Hosoyamada M, Aiba A,
Suzuki H. Identification of GLUT12/SLC2A12 as aurate transporter that regulates the blood urate levelin hyperuricemia model mice. Proc Natl Acad Sci
U S A. 2020;117:18175-77.
(15) Toyoda Y, Takada T, Saito H, Hirata H,
Ota-Kontani A, Kobayashi N, Tsuchiya Y, Suzuki H.
Inhibitory effect of citrus flavonoids on the in vitrotransport activity of human urate transporter 1(URAT1/SLC22A12), a renal re-absorber of urate.
NPJ Sci Food. 2020;4:3.
(16) Toyoda Y, Takada T, Suzuki H. Febuxostat inhibitedaxillary osmidrosis risk factor ATP-binding cassettetransporter C11 in vitro. J Dermatol. 2020;47:
1198-99.
(17) Watanabe K, Kage H, Nagoshi S, Toyama K, Ohno
Y, Shinozaki-Ushiku A, Nakazaki K, Suzuki H,
Kurokawa M, Nagase T. Dual EGFR and ABL
tyrosine kinase inhibitor treatment in a patient withconcomitant EGFR-mutated lung adenocarcinoma
and BCR-ABL1-positive CML. Case Rep Oncol

469

Med. 2020;2020:4201727.
(18) Yamanashi Y, Takada T, Yamamoto H, Suzuki H.
NPC1L1 facilitates sphingomyelin absorption andregulates diet-induced production of VLDL/LDLassociated S1P. Nutrients. 2020;12:2641.

470

Rehabilitation Center
Professor
Nobuhiko Haga, M.D.

Associate Professor
Toru Ogata, M.D.

Lecturer

Sayaka Fujiwara, M.D.

Research Associate
Yasuaki Karasawa, M.D., Kentaro Morita, M.D.,
Haruhi Inokuchi, 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 fivefull-time 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
work for 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 to other departments in the University ofTokyo Hospital were included in our department.
From 2009, a speech therapist added to ourdepartment, and now three therapists 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
departments of the university hospital. We always takecharge of 250-300 patients corresponding about
25-30% of the whole number of inpatients. We also
see 15 people per day at the outpatient rehabilitation
setting. The numerical ratio of outpatient is being
reduced in order to give priority to the clinical service

471

corresponding to needs expansion of service toinpatients.

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 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 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 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

References
1.

2.

3.

4.

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 andankle 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

472

8.

9.

10.

11.

12.

13.

baseline phenotypes from the International
Fibrodysplasia Ossificans Progressiva (FOP)
Association Global Registry. Bone 134: 115274,
2020
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 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: Predictionof pathogenicity of missense variants byindividual modeling for each amino acidsubstitution. 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 importanceof 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 of life in patients with malignant glioma:
Impact of symptoms and implications forrehabilitation. 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 inJapan. Pediatr Int 62: 3-13, 2020

473

Central Supply Service
Professor
Kazuhiko Fukatsu, M.D., Ph.D.

Assistant Professor
Satoshi Murakoshi, M.D, Ph.D.

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, 8 staff members, and 26 members from external
staff sources are the main members of this division.

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

474

Division of Diagnostic Pathology
Director (Professor)
Tetsuo Ushiku, M.D., Ph.D.

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)
Yoko Tateishi, M.D., Ph.D. (Lecturer)

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

Research Associate
Naoko Yamauchi, M.D., Ph.D. (Hospital Lecturer),
Mariko Tanaka, M.D., Ph.D. (Hospital Lecturer),
Hirofumi Rokutan, M.D., Ph.D., Munetoshi Hinata, M.D., Ph.D.
Sho Yamazawa, M.D., Ph.D., Naohiro Makise, M.D., Ph.D.
Akiko Iwasaki, M.D., Ph.D.,

Project Research Associate
Ruri Saito, M.D., Ph.D. ("Tsunagu"- Fukushima-Kanto Pathology- Forensic Pathology
Cooperation Program)

Homepage http://pathol.umin.ac.jp/
Introduction and Organization
Department of Pathology and Diagnostic Pathology
and Division of Diagnostic Pathology of the
University of Tokyo Hospital have been organized tofunction as a unit to perform pathology practice(autopsy, surgical pathology, cytology, molecular
testing, etc.) at the University of Tokyo Hospital aswell as education and research 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
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

475

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 2020
fiscal year consisted of 15,450 surgical cases, 14,154
cytology, 933 intraoperative histologic diagnosis, 371
intraoperative cytology, 44 autopsy cases (autopsy rate,
15.4%). Limited hospital activity due to COVID-19
pandemic resulted in the decrease of the number of
specimens.
The following surgical pathology conferences are
regularly held; thoracic organs (Drs. ShinozakiUshiku and Hinata in charge), liver and pancreatobiliary tract (Drs. Yamauchi,Tanaka and Rokutan),liver metastasis (Dr. Abe), and female genital tracts(Drs. Ikemura and Iwasaki), breast (Dr. Ikemura),
hematology (Dr. Shinozaki-Ushiku), bone and soft
tissues (Drs. Ushiku and Makise), kidney (Drs. Abe
and Hinata), and skin (Dr. Tanaka).
We provide FFPE specimens suitable formultiplex genomic testing. We also joinclinicopathologic and genomic conference which isheld every week to present histology of the cases andjoin the discussion.
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 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 Division of Diagnostic Pathology accepted
six junior residents (total 12 months) in 2020 for theirsecond-year program.

Research activities
We are working on the pathologic research
projects of neoplastic diseases based on observation
obtained from pathologic diagnosis as well as
discussion with clinicians 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.

476

References(Only case reports are provided here. Originalarticles are included in the section of “Department
Pathology and Diagnostic Pathology”)
1.

2.

3.

4.

5.

6.

7.

Nakayama A, Yokota A, Suzuki Y, Iizuka T,
Fukawa T, Ushiku T, Takazawa Y, Fujii T.
Primary alveolar soft part sarcoma of the rectum
resected by endoscopic submucosal dissection: A
case report. Pathol Int. 2020-6;70(8):581-586.
Miyama Y, Makise N, Miyakawa J, Kume H,
Fukayama M, Ushiku T. An autopsy case of
prostatic rhabdomyosarcoma with DICER1
hotspot mutation. Pathology International.
2020-10;Epub ahead of print.
Shinozaki-Ushiku A, Kohsaka S, Kage H, Oda K,
Miyagawa K, Nakajima J, Aburatani H, Mano H,
Ushiku T. Genomic profiling of multiple primarycancers including synchronous lung adenocarcinoma and bilateral malignant mesotheliomas: Identification of a novel BAP1
germline variant. Pathol Int. 2020-10;70(10):775-780.
Shinozaki-Ushiku A, Ishikawa S, Komura D,
Seto Y, Aburatani H, Ushiku T. The first case ofgastric carcinoma with NTRK rearrangement:
identification of a novel ATP1B-NTRK1 fusion.
Gastric Cancer. 2020-9;23(5):944-947.
Enomoto Y, Namba Y, Hoshika Y, Komemushi
Y, Mitani K, Kume H, Kobayashi E, Miyama Y,
Homma Y, Ushiku T, Seyama K. A case of
Birt-Hogg-Dubé syndrome implying reduced or
no wild-type folliculin without mutated protein ispathogenic. Eur J Med Genet. 2020-4;63(4):103820.
Ito Y, Takaoka K, Toyama K, Taoka K,
Wakabayashi Y, Shinozaki-Ushiku A, Okazaki A,
Chikamatsu K, Mitarai S, Ushiku T, Kurokawa
M. The First Case of Concomitant Mycobacterium Genavense Lymphadenitis and EBVPositive Lymphoproliferative Disorder. Mediterr
J Hematol Infect Dis. 2020-7;12(1):e2020035.
Kato T, Hiraishi Y, Kaseda K, Suzuki S, Tanaka
G, Yamauchi Y, Yasui M, Shinozaki-Ushiku A,
Ushiku T, Yamaji O, O’Neal WK, Nagase T A
79-Year-Old Man With Progressive Dyspnea andMultiple Pulmonary Nodules. Chest. 2020-8;

8.

9.

10.

11.

12.

13.

14.

15.

158(2):e79-e84.
Kobayashi H, Shin M, Makise N, ShinozakiUshiku A, Ikegami M, Taniguchi Y, Shinoda Y,
Kohsaka S, Ushiku T, Oda K, Miyagawa K,
Aburatani H, Mano H, Tanaka S. Genetic TestingDistinguishes Multiple Chondroid Chordomas
withNeuraxial Bone Metastases
fromMulticentric Tumors. Case Rep Genet. 2020-11;
eCollection 2020.
Morimoto A, Fujioka Y, Ushiku T, Kurokawa M.
Monomorphic Epitheliotropic Intestinal T-cell
Lymphoma Invades Brain. Intern Med. 2021-3;
60(5):815-816.
Muroyama Y, Tamiya H, Tanaka G, Tanaka W,
Huang AC, Oldridge DA, Matsusaka K,
Takazawa Y, Jo T, Ushiku T, Nagase T.
Alpha-Fetoprotein-Producing Lung Hepatoid
Adenocarcinoma with Brain Metastasis Treatedwith S-1. Case Rep Oncol. 2020-12;13(3):15521559.
Nagao S, Tsuji Y, Sakaguchi Y, Ushiku T, Koike
K. Inflammatory fibroid polyp mimicking an
early gastric cancer. Gastrointest Endosc. 2020-7;
92(1):217-218.
Nishikawa T, Ushiku T, Emoto S, Murono K,
Kaneko M, Sonoda H, Sasaki K, Shuno Y,
Tanaka T, Hata K, Kawai K, Nozawa H, Ishihara
S. Anal canal adenocarcinoma with pagetoidspread and inguinal lymph node metastasis
treated with preoperative chemoradiotherapy: A
case report. Mol Clin Oncol. 2020-6;12(6):529532.
Sasaki K, Fukui R, Hata K, Nozawa H, Ushiku T,
Aburatani H, Mano H, Ishihara S. Clinical
Diagnosis of a Double Primary Sigmoid Colon
Cancer and Metastatic Tumour Using a
Gene-Targeted Panel Test: A Case Report. ANZJ Surg. 2020-11;90(11):E139-E140.
Kurihara M, Sasaki T, Sakuishi K, Terao Y,
Murakawa T, Shinozaki-Ushiku A, Okada S,
Toda T, Tsuji S. Isolated seizure as initialpresentation of GABAA receptor antibodyassociated encephalitis. J Neurol Sci 2020-3;410:
116666.
Aizawa H, Karasaki T, Nagayama K, ShinozakiUshiku A, Aburatani H, Mano H, Nakajima J.
ClinicalApplicationof
Next-generation

477

Sequencing for the Diagnosis of Lung Squamous
Cell Carcinoma: Is It Primary or Secondary?
Intern Med 2020;59(10):1299-1302.
16. Ando M, Kobayashi H, Shinozaki-Ushiku A,
Chikuda H, Matsubayashi Y, Yoshida M, Saito Y,
Kohsaka S, Oda K, Miyagawa K, Aburatani H,
Mano H, Yamasoba T. Spinal solitary fibroustumor of the neck: Next-generation sequencingbased analysis of genomic aberrations. Auris
Nasus Larynx. 2020;47(6):1058-1063.
17. Yoshihara R, Komai T, Nagafuchi Y, Tsuchida Y,
Shoda H, Tanaka M, Ushiku T, Fujio K.
Eosinophilic cholangitis with eosinophilic
granulomatosis with polyangiitis: A case reportand review of the literature. Allergol Int 2020-1;
69(1):154-156.

478

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 andpromote corneal transplantation and to perform
clinical and basic research in the corneal diseases andcorneal transplantation. The section is composed oftwo 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).
Contact lens clinic for keratoconus and postkeratoplasty eyes and keratoconus clinic for providing
corneal crosslinking surgery, which is a brand-new
treatment to halt keratoconus progression, were heldin the afternoon of Thursday. At the corneal service,
we determine indication for corneal transplantationand follow up patients after the surgery. Total 61
corneal surgeries including keratoplasty were

performed in 2020. In addition to the full-thickness
corneal transplantation (penetrating keratoplasty), we
have successfully 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 ofcorneal 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
statistically investigated in various kinds of479

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 foryoung 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 the delivery of
nucleic acid based drug in corneal neovascularizationor corneal dystrophy, genetic analysis and genome
editing for corneal dystrophy.

References
1:

2:

3:

Ono T, Kawasaki Y, Chen LW, Toyono T,
Shirakawa R, Yoshida J, Aihara M, Miyai T. Sci
Rep. 2020 Sep 10; 10(1):14880. doi: 10.1038/
s41598-020-71818-w.
Yoshida J, Toyono T, Shirakawa R, Miyai T, Usui
T. Sci Rep. 2020 Oct 29; 10(1):18594. doi:
10.1038/s41598-020-75412-y.
Omoto T, Toyono T, Inoue T, Shirakawa R,
Yoshida J, Miyai T, Yamagami S, Usui T. Cornea.
2020 May; 39(5):573-577. doi: 10.1097/ICO.
0000000000002211.

480

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 2020, 25 patients (including 1 children) received
autologous HSCT and 39 patients (including 8
children) 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.

481

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.
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.

References1.

2.

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.

3.

4.

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 hematopoietic cells. In the area of pediatric oncology, we
continue the studies on molecular mechanisms ofpediatric malignancies such as neuroblastoma,
rhabdomyosarcoma, and infant leukemia.

5.

6.

Sekiguchi M, Seki M, Kawai T, Yoshida K,
Yoshida M, Isobe T, Hoshino N, Shirai R, Tanaka
M, Souzaki R, Watanabe K, Arakawa Y, Nannya
Y, Suzuki H, Fujii Y, Kataoka K, Shiraishi Y,
Chiba K, Tanaka H, Shimamura T, Sato Y,
Sato-Otsubo A, Kimura S, Kubota Y, Hiwatari M,
Koh K, Hayashi Y, Kanamori Y, Kasahara M,
Kohashi K, Kato M, Yoshioka T, Matsumoto K,
Oka A, Taguchi T, Sanada M, Tanaka Y, Miyano
S, Hata K, Ogawa S, Takita J. Integrated
multiomics analysis of hepatoblastoma unravels
its heterogeneity and provides novel druggabletargets. NPJ Precis Oncol 4(20), 2020.
Irikura T, Mitani Y, Seki M, Takita J, Hiwatari M.
Cold agglutinin disease in an infant: remission
after intravenous immunoglobulin. Pediatr Int
62(10): 1214-1216, 2020.
Amano K, Takasugi N, Kubota Y, Mitani Y,
Sekiguchi M, Watanabe K, Fujimura J, Oka A,
Takita J, Hiwatari M.
CBFA2T3-GLIS2positive acute megakaryoblastic leukemia in apatient with Down syndrome. Pediatr Blood
Cancer 67(2): e28055, 2020.
Kubota Y, Seki M, Kawai T, Isobe T, Yoshida M,
Sekiguchi M, Kimura S, Watanabe K,
Sato-Otsubo A, Yoshida K, Suzuki H, Kataoka K,
Fujii Y, Shiraishi Y, Chiba K, Tanaka H, Hiwatari
M, Oka A, Hayashi Y, Miyano S, Ogawa S, Hata
K, Tanaka Y, Takita J. Comprehensive genetic
analysis of pediatric germ cell tumors identifies
potential drug targets. Commun Biol 3(1), 2020
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(3):281-289, 2020.
Kato S, Kubota Y, Watanabe K, Hogetsu K,
Arakawa Y, Koh K, Takita J, Hiwatari M.
Tandem high-dose chemotherapy with autologous
stem cell rescue for stage M high-risk
neuroblastoma: Experience using melphalan/etoposide/carboplatin and busulfan/melphalan
regimens. Pediatr Transplant 24(7): e13772,
2020.

482

7.

8.

9.

Yokoyama Y, MaieK, Fukuda T, Uchida N,
Mukae J, Sawa M, Kubo K, Kurokawa M,
Nakamae H, Ichinohe T, Yoshiko Atsuta Y, andChiba S. A high CD34+cell dose is associatedwith better disease-freesurvival in patients with
low-risk diseases undergoing peripheralblood
stem cell transplantation from HLA-matched
related donors. Bone Marrow Transplantation
55(9): 1726-1735, 2020.
Matsukawa T, Yamamoto T, Honda A, Toya T,
Ishiura H, Mitsui J, Tanaka M, Hao A, Shinohara
A, Ogura M, Kataoka K, Seo S, Kumano K,
Hosoi M, Narukawa K, Yasunaga M, Maki H,
Ichikawa M, Nannya Y, Imai Y, Takahashi T,
Takahashi Y, Nagasako Y, Yasaka K, Mano K,
Matsukawa M, Miyagawa T, Hamada M,
Sakuishi K, Hayashi T, Iwata A, Terao Y,
Shimizu J, Goto J, Mori H, Kunimatsu A, Aoki S,
Hayashi S, Nakamura F, Arai S, Momma K,
Ogata K, Yoshida T, Abe O, Inazawa J, Toda T,
Kurokawa M, Tsuji S. Clinical efficacy of
haematopoietic stem cell transplantation for adultadrenoleukodystrophy. Brain Commun 2(1):fcz048, 2020.
Ito Y, Hino T, Honda A, Kurokawa M.
Fluoroquinolones for BK viral complication after
transplantation: Meta-analysis. Transpl Infect Dis
22(6): e13433, 2020.

483

Department of Endoscopy andEndoscopic Surgery
Associate Professor
Yousuke Nakai, M.D., Ph.D.

Associate
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, 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 by appropriate PPE (personal
protective equipment) and the social distance in theendoscopy 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.

484

Table 1. Endoscopic examinations in the Department of Endoscopy and Endoscopic Surgery
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
EGD*

10963

11376

11840

11740

11874

11944

11490

Colonoscopy

5208

5688

6000

6043

6394

6814

5921

Bronchoscopy

197

196

169

218

228

362

ERCP

1072

956

912

1035

946

630

698

763

766

Enteroscopy

282

282

375

Laryngoscopy

108

83

Colposcopy

378

Total

18838

EUS

**

†

11699

11226

（2177） （2501）

8.906

5530

5675

（109）

（329）

350

316

395

300

1206

1137

1057

1314

1302

882

1084

1023

923

1059

711

396

310

86

304

138

151

74

128

102

105

125

114

92

102

42

365

404

327

295

417

430

414

392

333

19644

20591

20627

21034

22038

20769

20169

20314

16226

4,548

*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.

Sato T, Kogure H, Nakai Y, Ishigaki K, Hakuta R,
Saito K, Saito T, Takahara N, Hamada T, Mizuno
S, Yamada A, Tada M, Isayama H, Koike K.
Double-balloon endoscopy-assisted treatment of
hepaticojejunostomy anastomotic strictures andpredictive factors for treatment success. Surg
Endosc. 2020;34(4):1612-1620.
Sato T, Kogure H, Nakai Y, Ishigaki K, Hakuta R,
Saito K, Saito T, Takahara N, Hamada T, Mizuno
S, Tada M, Isayama H, Koike K. A prospective
study of fully covered metal stents for different
types of refractory benign biliary strictures.
Endoscopy. 2020 May;52(5):368-376.
Nakai Y, Sato T, Hakuta R, Ishigaki K, Saito K,
Saito T, Takahara N, Hamada T, Mizuno S,
Kogure H, Tada M, Isayama H, Koike K.
Management of Difficult Bile Duct Stones by5.

6.

Large Balloon, Cholangioscopy, Enteroscopy andEndosonography. Gut Liver. 202014(3):297-305.
Nakai Y, Isayama H, Wang HP, Rerknimitr R,
Khor C, Yasuda I, Kogure H, Moon JH, Lau J,
Lakhtakia S, Ratanachu-Ek T, Seo DW, Lee DK,
Makmun D, Dy F, Liao WC, Draganov PV,
Almadi M, Irisawa A, Katanuma A, Kitano M,
Ryozawa S, Fujisawa T, Wallace MB, Itoi T,
Devereaux B. International consensus statements
for endoscopic management of distal biliary
stricture. J Gastroenterol Hepatol. 2020;35(6):967-979.
Nakai Y, Sato T, Hakuta R, Ishigaki K, Saito K,
Saito T, Takahara N, Hamada T, Mizuno S,
Kogure H, Nogchi K, Ito Y, Isayama H, Koike K.
Long-term outcomes of a long, partially covered
metal stent for EUS-guided hepaticogastrostomy
in patients with malignant biliary obstruction.
Gastrointest Endosc. 2020;92(3):623-631.
Kogure H, Kawahata S, Mukai T, Doi S, Iwashita
T, Ban T, Ito Y, Kawakami H, Hayashi T,
Sasahira N, Kubota K, Togawa O, Kato H, Okabe
Y, Matsubara S, Yagioka H, Saito T, Nakai Y,
Isayama H. Multicenter randomized trial ofendoscopic papillary large balloon dilation
without sphincterotomy versus endoscopic
sphincterotomy for removal of bile duct stones:
MARVELOUS trial. Endoscopy. 2020;52(9):736744.

485

7.

8.

9.

10.

11.

12.

13.

Hakuta R, Kogure H, Nakai Y, Hamada T, Sato T,
Suzuki Y, Inokuma A, Kanai S, Nakamura T,
Noguchi K, Ishigaki K, Saito K, Saito T,
Takahara N, Mizuno S, Yamada A, Tada M,
Koike K. Feasibility of balloon endoscopeassisted endoscopic retrograde cholangiopancreatography for the elderly. Endosc Int Open.
2020;8(9):E1202-E1211.
Matsubara S, Isayama H, Nakai Y, Kawakubo K,
Yamamoto N, Saito K, Saito T, Takahara N,
Mizuno S, Kogure H, Ishizawa T, Arita J,
Hasegawa K, Koike K. Endoscopic ultrasoundguided gallbladder drainage with a combinedinternal and external drainage tubes for acutecholecystitis. J Gastroenterol Hepatol. 2020;35(10):1821-1827.
Hakuta R, Nakai Y, Hamada T, Suzuki Y,
Inokuma A, Oyama H, Kanai S, Nakamura T,
Sato T, Ishigaki K, Saito K, Saito T, Takahara N,
Mizuno S, Kogure H, Tada M, Koike K. Regularstatin use and incidence of postendoscopic
retrograde cholangiopancreatography pancreatitis.
J Clin Gastroenterol. 2020;54(10):905-910.
Nakai Y, Chang KJ. EUS-guided fine-needle
injection for pancreatic cancer: back to the future.
Gastrointest Endosc. 2020;92(5):1053-1054.
Ishigaki K, Nakai Y, Oyama H, Kanai S, Suzuki
T, Nakamura T, Sato T, Hakuta R, Saito K, Saito
T, Takahara N, Hamada T, Mizuno S, Kogure H,
Tada M, Isayama H, Koike K. Endoscopic
Ultrasound-Guided Tissue Acquisition by
22-Gauge Franseen and Standard Needles for
Solid Pancreatic Lesions. Gut Liver. 2020;14(6):817-825.
Noguchi K, Nakai Y, Mizuno S, Hirano K, Kanai
S, Suzuki Y, Inokuma A, Sato T, Hakuta R,
Ishigaki K, Saito K, Saito T, Hamada T, Takahara
N, Kogure H, Isayama H, Koike K. Role ofEndoscopic ultrasonography-guided fine needle
aspiration/biopsy in the diagnosis of autoimmune
pancreatitis. Diagnostics (Basel). 2020;10(11):954.
Ishigaki K, Hamada T, Nakai Y, Isayama H, Sato
T, Hakuta R, Saito K, Saito T, Takahara N,
Mizuno S, Kogure H, Ito Y, Yagioka H,
Matsubara S, Akiyama D, Mohri D, Tada M,
Koike K. Retrospective Comparative study of

14.

15.

16.

17.

18.

19.

side-by-side and stent-in-stent metal stentplacement for hilar malignant biliary obstruction.
Dig Dis Sci. 2020;65(12):3710-3718.
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 multicenter
study of partially covered metal stents in patients
receivingneoadjuvant
chemotherapy
forresectable and borderline resectable pancreaticcancer: 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 pancreatic diseases
in patients with surgically altered anatomy:
clinical outcomes of combination of doubleballoon endoscopy- and endoscopic ultrasoundguided interventions. Dig Endosc. 2021;33(3):441-450.

486

20. 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.

487

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

488

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.

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.
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.
Kotani A, Oda Y, Hirakawa Y, Nakamura M,

Hamasaki Y, Nangaku M. Peritoneal Dialysisrelated Peritonitis Caused by Streptococcus oralis.
Intern Med. 2021 May 22.
4. 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.
5. 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.
6. Matsuura R, Doi K, Hamasaki Y, Nangaku M.
RRT Selection for AKI Patients With Critical
Illness. Semin Nephrol. 2020 Sep;40(5):498-505.
7. 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.
8. 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.
9. Komaru Y, Doi K, Nangaku M. Urinary
Neutrophil Gelatinase-Associated Lipocalin in
Critically Ill Patients With Coronavirus Disease2019. Crit Care Explor. 2020 Aug 20;2(8):e0181.
10. 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.
11. 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.
12. Matsuura R, Komaru Y, Miyamoto Y, Yoshida T,
Yoshimoto K, Hamasaki Y, Nangaku M, Doi K.

489

13.

14.

15.

16.

17.

18.

19.

20.

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.
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.
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.
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.

21. 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.
22. 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.
23. 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.
24. 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.
25. 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).
26. 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).
27. 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).
28. Matsuura R, Doi K, Komaru Y, Miyamoto Y,
Yoshida T, Isegawa T, Yoshimoto K, Yamashita T,

490

29.

30.

31.

32.

33.

34.

35.

36.

Noiri E, Nangaku M. Endogenous Erythropoietin
and Hepatic Dysfunction in Acute Kidney Injury
Requiring Renal Replacement Therapy. Nephron.
142, 10-16(2019).
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).
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).
Nakamura Y, Kurata Y, Hamasaki Y, Nangaku M.
Extraperitoneal Placement of a Peritoneal Dialysis
Catheter. Intern Med. 58, 147-148 (2019).
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).
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)
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)
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)
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)

491

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., 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

492

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.

493

Research Activities
Please refer to Department of Health Communication
for information about research activities.

References
Please refer to Department of Health Communication.

494

Department of Clinical Research
GovernanceDirector & Project Professor
Hideaki Ui, Ph.D.

Research Associate
Kazuyoshi Ichihashi, Ph.D.

Homepage

http://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 Clinical
Quality & Compliance. These offices mutually
cooperate to promote and strengthen governancefunctions 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 Quality &Compliance are as follows: (1) auditing of clinicalresearches and clinical trials, (2) giving guidance andadvice on the reliability of clinical trials, (3)performing trend-analysis of audit findings andcompliance issues, report and make recommendations
to the hospital director to become a high reliability
organization,(4) providing support for the
preparation of GCP inspections by regulatory495

authorities, and integrated management of findings,(5) integrated management of outsourced auditing,(6) integrated management of audit results of the
University of Tokyo Hospital, (7) collecting
information for corrective action and preventive
action after audits and investigations, (8) collecting
and analyzing regulatory information on reliability ofclinicalresearch/trials,
andproviding
education/training, and (9) the secretariat of the
Auditing Working Group of Core Centers’ Network
for Translational and Clinical Research, Project ofTranslational and Clinical Research Core Centers,
TR-SPRINT (AMED).
The Department of Clinical Research Governanceconsists of a director (full-time post from August,2015), a Research Associate/URA in the Office ofStrategic Planning and Promotion, and 7 staffs (4auditors
and3
temporarystaffs(auditor/audit-assistant/support staff)) in the Office ofClinical Quality & Compliance as of March 2019. The
Office of Research Integrity and Promotion. has no
additional member, and the director serves as it.

Activities
The Office of Strategic Planning and Promotion has
undertaken the following activities in fiscal year 2018.
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,Labour and Welfare.
2) Others: investigations of research paper publication
activities, co-operating the “Forum for Developmentof Seeds for Advanced Medicine”, etc.
The Office of Clinical Quality Assurance &Compliance has undertaken the following activities infiscal year 2018.
1) Audit activities: (1) As regards to trials/researches
conducted by the University of Tokyo Hospital, theoffice conducted 4 audits for investigator-initiatedclinical trials, 3 audits for Specified ClinicalResearches, and 2 audits for other trials. (2) One audit
for investigator-initiated clinical trial conducted atother university hospital which lead by the UniversityofTokyo
Hospital.
(3)
One
audit
for
investigator-initiated clinical trial conducted at otheruniversity hospital. (4) provided assistance in the
preparation of audit SOPs and audit plan, etc. for othersome clinical trials and researches.
2) Support for surveys/investigations: Regarding TR
Core Centers surveys by AMED, and ClinicalResearch Core Hospital investigations, the Officeattended to explain the system and structure of quality
assurance, etc.
3) 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.
4) Advisory: provided advice on compliance andreliability related matters to the Central Coordinating
Unit, Site Coordinating unit, and prepares advisory
records.
5) TR program: In June/2017, the University of Tokyo
Hospital was appointed as the secretariat of new
initiative, Audit Working Group of AMED describedabove. The Working Group consists of one to threeauditors from each Center. The secretariat conducted
three meetings with all members (May 5th, November
6th, and March 12th), one Training for auditors (March5th), and 24 times meetings in total on three themes (1)Auditors education and training, (2) Collect issues inauditing and solve them, and (3) Optimal conduct ofaudit & quality assurance, at each sub-working group.
6) Networking: (1) As a part of UCHT Allianceactivity, monitoring took place among the eight
member universities in the Kanto Koshinetsu region toevaluate the implementation system. (2) Participatedin the study to evaluate the reliability as a part of the
National University Hospital Clinical Research
Promotion Initiative (NUH-CRPI). (3) Participated in
the Japan Society of Quality Assurance (JSQA).

496

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

Assistant professor
Yosuke Eriguchi, M.D., Ph.D., Ayaka Ishii-Takahashi, M.D., Ph.D.

Homepage

http://kokoro.umin.jp/

Introduction and Organization
The Department of Child Psychiatry was establishedin April 2005 as the clinical counterpart to the Clinical
Education Center of Mental Development, both ofwhich are funded by the special grant for faculty
development. The major aim of the Clinical Education
Center is to train mental health specialists in various
fields with a fundamental grounding in childpsychiatry and neurosciences. Much of the services
provided are based on the 38 years of experience inintervention and treatment for developmentallydisabled children established in the former childpsychiatry division of Department of Neuropsychiatry.
Our department uses a multidisciplinary approach byworking in collaboration not only with the Departmentof Neuropsychiatry, Department of Pediatrics andGraduate School of Education in the University ofTokyo but also several other educational and/or
clinical facilities on mental development or developmental disorders. The Department of Child Psychiatry
complemented the Clinical Education Center by
providing fieldwork for clinical training and offeredclinical 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 2020, 7 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 &adolescent Obsessive-Compulsive Disorders (OCD).
Number of new patients in 2020 was 173, which
was about two-thirds of the number of new patientslast year. This decrease seemed to be affected by the
restriction on outpatient care due to the spread of
COVID-19 infection. More than 70% of the newpatients consisted of patients with ASD, ADHD or tic
disorders. Out of 173 patients, children of elementary
school age were 64, and children of junior high school
age were 34. In other words, children of elementaryor junior high school age were more than half of thepatients. Number of preschool children was 62,
suggesting our response to ongoing needs for early

497

diagnosis and intervention.
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. For general psychiatrists including
senior residents of the Department of Neuropsychiatry,
an inpatient program of assessment aboutdevelopmental 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.
Effectiveness of a program of group cognitive
behavior therapy for adults with high-functioning

498

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.

3.

4.

5.

Neuropsychological research
Neuropsychological data on ASD, ADHD andTourette syndrome are being collected. Analysis of therelations among neuropsychological findings and theclinical evaluation are being conducted.
6.
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.

2.

Kano Y, Fujio M, Kaji N, Matsuda N, Nonaka M,
Kono T. Changes in Sensory Phenomena, Tics,
Obsessive-Compulsive Symptoms, and Global
Functioning of Tourette Syndrome: A Follow-Up
After Four Years. Front Psychiatry, 11: 619,
2020.
Matsuda N, Nonaka M, Kono T, Fujio M,

7.

Nobuyoshi M, Kano Y. Premonitory Awareness
Facilitates Tic Suppression: Subscales of thePremonitory Urge for Tics Scale and a New
Self-Report Questionnaire for Tic-AssociatedSensations. Front Psychiatry, 11: 592, 2020.
Yassin W, Nakatani H, Zhu Y, Kojima M, Owada
K, Kuwabara H, Gonoi W, Aoki Y, Takao H,
Natsubori T, Iwashiro N, Kasai K, Kano Y, Abe O,
Yamasue H, Koike S. Machine-learningclassification using neuroimaging data in
schizophrenia, autism, ultra-high risk and firstepisode psychosis. Transl Psychiatry, 10(1): 278,
2020.
Koshiyama D, Okada N, Ando S, Koike S,
Yahata N, Morita K, Sawada K, Morita S,
Kawakami S, Kanata S, Fujikawa S, Sugimoto N,
Toriyama R, Masaoka M, Araki T, Kano Y, Endo
K, Yamasaki S, Nishida A, Hiraiwa-Hasegawa M,
Kasai K. Association between duration ofbreastfeeding based on maternal reports anddorsal and ventral striatum and medial orbital
gyrus volumes in early adolescence. Neuroimage,
220: 117083, 2020.
Okada N, Yahata N, 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, Edden RAE, Sawa A,
Kasai K. Neurometabolic underpinning of theintergenerational transmission of prosociality.
Neuroimage, 218: 116965, 2020.
Okada N, Yahata N, 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, Kasai K. Smaller anterior
subgenual cingulate volume mediates the effectof girls' early sexual maturation on negative
psychobehavioral outcome. Neuroimage, 209:
116478, 2020.
Yamasaki M, Makino T, Khor SS, Toyoda H,
Miyagawa T, Liu X, Kuwabara H, Kano Y,
Shimada T, Sugiyama T, Nishida H, Sugaya N,
Tochigi M, Otowa T, Okazaki Y, Kaiya H,
Kawamura Y, Miyashita A, Kuwano R, Kasai K,
Tanii H, Sasaki T, Honda M, Tokunaga K.
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Kaneko Y, Omori M, Kaido T, Kano Y, Iwasaki
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61(1): 33-39, 2021.
Eriguchi Y, Aoki N, Kano Y, Kasai K. Rotational
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Yamasue H. Oxytocin-induced increase in
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symptoms. Mol Autism, 12(1):15, 2021.
Yamasue H, Okada T, Munesue T, Kuroda M,
Fujioka T, Uno Y, Matsumoto K, Kuwabara H,
Mori D, Okamoto Y, Yoshimura Y, Kawakubo Y,
Arioka Y, Kojima M, Yuhi T, Owada K, Yassin W,
Kushima I, Benner S, Ogawa N, Eriguchi Y,
Kawano N, Uemura Y, Yamamoto M, Kano Y,
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14. Oshima F, William M, Takahashi N,
Tsuchiyagaito A, Kuwabara H, Shiina A, Seto M,
Hongo M, Iwama Y, Hirano Y, Sutoh C, Taguchi
K, Yoshida T, Kawasaki Y, Ozawa Y, Masuya J,
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500

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 theadvancementoftissuetransplantationandtransplantation medicine is our important mission. In
this line 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

501

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.

502Center 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.,
Yoshiko Mizuno, M.D., Ph.D. (Department of Biostatistics and Bioinformatics)

Homepage:

http://www.h.u-tokyo.ac.jp/patient/depts/kenshin/index.html
https://www.todai-yobouigaku.com/

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503

Department are administered in collaboration withthree Central Clinical Facilities (Clinical Laboratory
Center, Radiological Center, and Department ofEndoscopy and Endoscopic Surgery) and six Clinical
Divisions (Gastroenterology, Breast and Endocrine
Surgery, Gynecologic Surgery, Ophthalmology and
Vision Collection, Neurology, and Geriatric Medicine).
The staff of the Center for Epidemiology andPreventive Medicine is composed of ten physicians(eight regular physicians and one physician from therelated departments). Three of the regular physiciansalso perform upper gastrointestinal endoscopy andcolonoscopy. Our department also has nine nurses, fiveassistant clerks, and one medical clerk.

Clinical activities
In addition to basic examinations, we provide nine
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, and 9) estimation of gastric cancer
risk. While meeting the needs of examinees, we haveincreased the number of the optional examinations. We
have provided pancreatic cancer screening from
September 2020.
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
In the fiscal year (FY) 2020 (from April1,2020 toMarch 31, 2021) , our center was suspended from April
20 to May 31, 2020 due to coronavirus. Respiratory
function test has been cancelled from March 31,2020
and gastrointestinal endoscopy has been cancelled from
April 9 to June 8, 2020.
The total number of examinees (who had basic
examinations and optional examinations) in the FY
2020 was 6963 including 2557 in basic examinations,431 in complete cardiovascular examinations, 542 incomplete cerebrovascular examinations, 57 in check up
for dementia, 287 in colorectal cancer screening, 524
in uterine cancer screening, 665 in breast cancer
screening, 564 in lung cancer screening, 1028 in tumor
marker diagnosis, 203 in estimation of gastric cancer
risk, and 17 in upper gastrointestinal endoscopy (later).
Although check up for dementia was discontinued in
December 2018, we restarted this examination in June2020.
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
2020, we issued 1192 letters of referral to otherdepartments in our hospital and 36 to other hospitals.

504

We have expanded our public relations efforts and15,000 brochures were delivered during the FY 2020.
We also prepared posters which were placed within
our hospital and on the campus of the University ofTokyo as well. We have established our original
website (https://www.todai-yobouigaku.com/) 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. 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. Serum uric acid level and subclinicalleft ventricular dysfunction: a community-based
cohort study. ESC Heart Fail. 2020 Jun;7(3):10311038.
2. Sakaguchi Y, Tsuji Y, Shinozaki T, Ohki D,
Mizutani H, Minatsuki C, Niimi K, Yamamichi N,
Koike K. Steroid injection and polyglycolic acidshielding to prevent stricture after esophageal
endoscopic submucosal dissection: a retrospective
comparative analysis (with video). Gastrointest
Endosc. 2020 Dec;92(6):1176-1186.
3. Kamon T, Kaneko H, Itoh H, Kiriyama H, Mizuno
Y, Morita H, Yamamichi N, Komuro I. Genderspecific association between the blood pressure
category according to the updated ACC/AHA
guidelines for hypertension and cardio-ankle
vascular index: a community-based cohort study.
J Cardiol. 2020 May;75(5):578-582.
4. Shimamoto T, Yamamichi N, Gondo K, Takahashi
Y, Takeuchi C, Wada R, Mitsushima T, Koike K.
The association of Helicobacter pylori infection
with serum lipid profiles: An evaluation based on
a combination of meta-analysis and a propensity
score-based observational approach. PLoS One.
2020 Jun 8;15(6):e0234433.
5. Yamamichi N, Yamaji Y, Shimamoto T, Takahashi
Y, Majima K, Wada R, Mitsushima T, Koike K.
Inverse time trends of peptic ulcer and reflux
esophagitis show significant association with

reduced prevalence of Helicobacter pylori
infection. Ann Med. 2020 Dec;52(8):506-514.
6. 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. Association of arterial stiffness withleft atrial structure and phasic function: acommunity-based cohort study. J Hypertens. 2020
Jun;38(6):1140-1148.
7. Nagao S, Tsuji Y, Sakaguchi Y, Takahashi Y,
Minatsuki C, Niimi K, Yamashita H, Yamamichi
N, Seto Y, Tada T, Koike K. Highly accurate
artificial intelligence systems to predict theinvasion depth of gastric cancer: efficacy of
conventional white-light imaging, nonmagnifying
narrow-band imaging, and indigo-carmine dye
contrast imaging. Gastrointest Endosc. 2020
Oct;92(4):866-873.e1.
8. Takahashi Y, Tsutsumi Y, Takeuchi C, Shiogama K,
Mizutani Y, Inada KI, Yamamichi N, Koike K.
Nuclear staining of claudin-18 is a new
immunohistochemical marker for diagnosing
intramucosal well-differentiated gastric adenocarcinoma. Pathol Int. 2020 Sep;70(9):644-652.
9. Yamada S, Hasumi E, Fujiu K, Yamauchi H,
Komuro I. Rapid Dilatation of False Lumen in a
Patient With Chronic Aortic Dissection Under
Suspicion of Anticoagulation Therapy-Induced
Recanalization. Circ Rep. 2020 Aug 27;2(9):542543.
10. Kurano M, Tsukamoto K, Hara M, Tsuneyama K,
Nishikawa T, Ikeda H, Yatomi Y. Modulation of
sphingosine 1-phosphate by hepatobiliary
cholesterol handling. FASEB J. 2020 Nov;34(11):14655-14670.
11. Hirokawa M, Daimon M, Kozuma K, Shinozaki T,
Kimura K, Nakao T, Nakanishi K, Sawada N,
Ishiwata J, Yoshida Y, Kato TS, Mizuno Y, Morita
H, Yatomi Y and Komuro I. Are there genderdifferences in the association between body massindex and left ventricular diastolic function? A
clinical observational study in the Japanesegeneral population. Echocardiography. 2020 Nov;
37(11):1749-1756.
12. Association Between Changes in Body Weightand Fat Weight in Middle Age General Population.
Itoh H, Kaneko H, Kiriyama H, Kamon T, Mizuno

505

Y, Morita H, Yamamichi N, Komuro I. Int Heart J.
2020;61(1):15-20.
13. Association Between Waist Circumference andCarotid Intima-Media Thickness in the General
Population. Kamon T, Kaneko H, Itoh H,
Kiriyama H, Mizuno Y, Morita H, Yamamichi N,
Komuro I. Int Heart J. 2020 Jan 31;61(1):103-108.
14. Effect of Metabolically Healthy Obesity on theDevelopment of Carotid Plaque in the General
Population: A Community-Based Cohort Study.
Itoh H, Kaneko H, Kiriyama H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yatomi Y, Yamamichi N, Komuro I. J Atheroscler
Thromb. 2020 Feb 1;27(2):155-163.
15. Effect of cigarette smoking on carotid arteryatherosclerosis: a community-based cohort study.
Kiriyama H, Kaneko H, Itoh H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yamamichi N, Komuro I. Heart Vessels. 2020
Jan;35(1):22-29.
International conferences
1. 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. Atrioventricular and VentricularFunctional Interdependence in the Community,
AHA Scientific Sessions 2020 (2020/11/13-17,
WEB congress)
2. Furukawa Y, Kodama K, Mizuno Y, Ohta M,
Takeda H, Kawai Y, Morishita T, Zeniya M,
Yamanaka H, Amano T. Data Evaluation
regarding lipid metabolism in Japan, The 4thWorld Congress on Ningen Dock (2020/11/2612/11, WEB congress)

506

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507

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.

508･ 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.

Kibi Y, Mikoshiba N, Igarashi A, Sumitani M,
Yamamoto-Mitani N. Development of a stylebook
for women with cancer-related lymphedema
troubled about clothing. Lymphoedema Res Prac
2020; 8: 27-39

2.

Ninagawa J, Sumitani M, Nishizawa D, Nagashima
M, Mietani K, Abe H, Inoue R, Hozumi J, TsuchidaR, Ikeda K, Yamada Y. Adiponectin receptor 1 geneis potentially associated with severity of
postoperative pain but not cancer pain. Medicine(Baltimore) 2020; 99: e18924
3. Tsuchida R, Sumitani M, Azuma K, Abe H, Hozumi
J, Inoue R, Oshima Y, Katano S, Yamada Y. A novel
technique using magnetic resonance imaging in thesupine and prone positions for diagnosing lumbar
adhesive arachnoiditis: a preliminary study. Pain
Prac 2020; 20: 34-43
4. Osumi M, Sano Y, Ichinose A, Wake N, Yozu A,
Kumagaya S, Kuniyoshi Y, Morioka S, Sumitani M.
Direct evidence of EEG coherence in alleviating
phantom limb pain by virtual referred sensation:
Case report. Neurocase 2020; 26: 55-9
5. Abe H, Sumitani M, Matsui H, Aso S, Inoue R,
Fushimi K, Uchida K, Yasunaga H, Yamada Y.
Comparing postoperative outcomes of lowerextremity amputation performed using peripheral
nerve block versus general anesthesia: a nation
exploratory retrospective cohort study in Japan.
Regional Anesthesia and Pain Medicine 2020; 45:399-404
6. Osumi M, Sumitani M, Otake Y, Imai R, Morioka S.
Fear of movement disturbs inter-limb coupling incomplex regional pain syndrome. Ann Phys Rehab
Med 2020; 63: 258-61
7. Tsuchida R, Sumitani M, Abe H, Ando M, Saita K,
Hattori K, Mietani K, Inoue R, Uchida K. Clopidorel,an ADP-P2Y12 receptor antagonist, can prevent
severe postoperative pain: a retrospective chart
review. Life 2020; 10: 92
8. Abe H, Inoue R, Tsuchida R, Azuma K, Ino K,
Konishi M, Hozumi J, Sumitani M. Use of
three-dimensional printing of a lumbar skeletal
model for intrathecal administration of nusinersen:
Brief Technical Report. Regional Anaesthesia andPain Medicine 2020; 45: 757-60
9. Azuma K, Abe H, Hozumi J, Inoue R, Konishi M,
Tsuchida R, Ando M, Saita K, Sumitani M.
Prefectural adequacy of opioid availability forcancer pain and its determinants in Japan: apreliminary study. JMA Journal 2020; 3: 340-6
10. Sumitani Mz, Osumi M, Abe H, Azuma K, TsuchidaR, Sumitani M. A robot has a mind of its own,

509

because we intuitively share it. Applied Sciences
2020; 10: 6531
(And, 17 Japanese articles)

510

Department of Disaster Medical
Management
Professor
Naoto Morimura, M.D.,Ph.D.

Lecturer
Chiaki Toida M.D.,Ph.D.

Research Associate
Kazutaka Fukushima M.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

511

Support Group, regularly for the purpose of developing leadership of health care professionals who canprovide ideal medical care in times of disaster. Also,
we are cooperating holding and teaching MCLS, Mass
Casualty Life Support, courses of Japan Association
for Disaster Medicine, and JATEC, Japan Advanced
Trauma Evaluation and Care, courses of Japanese
Association for Acute Medicine, and so on.

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.

2.

Toida C, Muguruma T, Gakumazawa M,
Shinohara M, Abe T, Takeuchi I, Morimura N.
Validation of age-specific survival prediction inpediatric patients with blunt trauma using trauma
and injury severity score methodology: a ten-year
Nationwide observational study. BMC Emerg
Med. 2020 Nov 18;20(1):91.
Toida C, Muguruma T, Gakumazawa M,
Shinohara M, Abe T, Takeuchi I, Morimura N.
Ten-Year in-Hospital Mortality Trends among
Paediatric Injured Patients in Japan: A
Nationwide Observational Study. J Clin Med.
2020 Oct 12;9(10):3273.

512International 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.

513

Department of Clinical Nutrition
Therapy
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- dietitian

514

system. 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
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.

515

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., mothers’classes, etc.
In 2020, due to the COVID-19 pandemic situation,
the instances of nutritional guidance of inpatients andoutpatients decreased, but recovered in the last half ofthe year and resulted in 2686 instances for inpatientsand 4865 instances for outpatients. Nutritional
guidance for malignant tumor patients was performedfor 424 instances. Perioperative guidance was 70
instances.
In July 2012, a physician, managerial dietitian, andnurse formed a dialysis prevention team, and started
calculating fees for diabetes and dialysis prevention
guidance and management in the outpatient clinic. The
managerial dietitian and nurse provide guidance on
Wednesday and Thursday afternoons, and there were
145 guidance sessions in 2020.
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. In
2020, due to the COVID-19 pandemic, only 84
instances were calculated, because the round was
performed by fewer team members for reduced numberof patients without calculating the NST charges forseveral months.
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.)
In 2017, the department was involved in the
curriculum of Clinical Clerkship, the medical education program of the Faculty of Medicine, the Universityof Tokyo. 116 medical students at M4 grade
participated in the two-day practice course in 2020.
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 were516

conducted online and the NST Conference wasadjourned. 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 topic: “Feasibility study assessing
improvement of postoperative complication rate byintroducing home enteral feeding for patients who
have undergone pancreaticoduodenectomy”
・Joint research with multiple institutes directed by
Chiba University
Research topic: “Interventional study to discover theappropriate target body weight for effective
treatment strategy and improvement of healthdisorder of obesity patients”
・Joint research with the Department of Stomach andEsophageal Surgery
Research topics: “A randomized control trial
evaluating exercise and nutritional intervention for
gastric cancer patients in the perioperative period forsarcopenia prevention”

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”
・Joint research with the Department of Hepatobiliaryand Pancreatic Surgery
Research topic: “Assessment of perioperative
improvement in nutrition status by an open trial ofbranched amino acids formula in patients ofhepatocellular carcinoma derived from livercirrhosis with abnormal ICGR15 and patients who
have undergone liver transplantation”

References<Publications (English)>
1. Oyama H, Tada M, Takagi K, Tateishi K, Hamada
T, Nakai Y, Hakuta R, Ijichi H, Ishigaki K, Kanai
S, Kogure H, Mizuno S, Saito K, Saito T, Sato T,
Suzuki T, Takahara N, Morishita Y, Arita J,
Hasegawa K, Tanaka M, Fukayama M, Koike K.
Long-term Risk of Malignancy in Branch-Duct
Intraductal Papillary Mucinous Neoplasms.
Gastroenterology. 158:226-237, 2020.
2. 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 fueledby high phosphatidylinositol turnover. Gut. Epub2020 Apr 6.
3. Toda G, Soeda K, Okazaki Y, Kobayashi N,
Masuda Y, Arakawa N, Suwanai H, Masamoto Y,
Izumida Y, Kamei N, Sasako T, Suzuki R, Kubota
T, Kubota N, Kurokawa M, Tobe K, Noda T,
Honda K, Accili D, Yamauchi T, Kadowaki T,
Ueki K. Insulin- and LipopolysaccharideMediated Signaling in Adipose Tissue
Macrophages Regulates Postprandial Glycemia
through Akt-mTOR Activation. Mol Cell. 79:4353, 2020.

517

4.

5.

6.

7.

8.

9.

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. Epub 2020 Aug
30.
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. Epub 2020 Sep 12.
Aida A, Svensson T, Svensson AK, Urushiyama H,
Okushin K, Oguri G, Kubota N, Koike K,
Nangaku M, Kadowaki T, Yamauchi T, Chung UI.
Using mHealth to Provide Mobile App Users With
Visualization of Health Checkup Data and
Educational
Videoson
Lifestyle-RelatedDiseases: Methodological Framework for Content
Development. JMIR Mhealth Uhealth. 8:e20982,
2020.
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. Epub 2020
Oct 21.
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. Epub 2020 Oct
23.
Hara H, Maemura S, Fujiwara T, Takeda N, Ishii
S, Yagi H, Suzuki T, Harada M, Toko H, Kanaya
T, Ijichi H, Moses HL, Takimoto E, Morita H,
Akazawa H, Komuro I. Inhibition of transforming

10.

11.

12.

13.

growth factor-β signaling in myeloid cells
ameliorates aortic aneurysmal formation in
Marfan syndrome. PLoS One. 15:e0239908, 2020.
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. Epub 2020 Nov 24.
Kato H, Tateishi K, Fujiwara H, Ijichi H,
Yamamoto K, Nakatsuka T, Kakiuchi M, Sano M,
Kudo Y, Hayakawa Y, Nakagawa H, Tanaka Y,
Otsuka M, Hirata Y, Tachibana M, Shinkai Y,
Koike K. Deletion of Histone Methyltransferase
G9a Suppresses Mutant Kras-driven Pancreatic
Carcinogenesis. Cancer Genomics Proteomics.
17:695-705, 2020.
Takahashi R, Ijichi H, Sano M, Miyabayashi K,
Mohri D, Kim J, Kimura G, Nakatsuka T, Fujiwara
H, Yamamoto K, Kudo Y, Tanaka Y, Tateishi K,
Nakai Y, Morishita Y, Soma K, Takeda N, Moses
HL, Isayama H, Koike K. Soluble VCAM-1
promotes gemcitabine resistance via macrophage
infiltration and predicts therapeutic response inpancreatic cancer. Sci Rep. 10:21194, 2020.
Kajiwara I, Sano M, Ichimaru Y, Oshima Y,
Kitajima O, Hao H, Masamune A, Kim J, Ishii Y,
Ijichi H, Suzuki T. Duloxetine improves cancerassociated pain in a mouse model of pancreaticcancer through stimulation of noradrenaline
pathway and its antitumor effects. Pain. 161:29092919, 2020.

518

Department of Clinical Genomics
Director & Professor
Katsutoshi Oda, 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.

(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.

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

2.

3.

4.

Shinozaki-Ushiku A, Kohsaka S, Kage H, Oda K,
Miyagawa K, Nakajima J, Aburatani H, Mano H,
Ushiku T. Genomic profiling of multiple primarycancers including synchronous lung adenocarcinoma and bilateral malignant mesotheliomas: Identification of a novel BAP1
germline variant. Pathol Int 70:775-780, 2020.
Shinozaki-Ushiku A, Ishikawa S, Komura D,
Seto Y, Aburatani H, Ushiku T. The first case ofgastric carcinoma with NTRK rearrangement:
identification of a novel ATP1B-NTRK1 fusion.
Gastric Cancer 23:944-947, 2020.
Ando M, Kobayashi H, Shinozaki-Ushiku A,
Chikuda H, Matsubayashi Y, Yoshida M, Saito Y,
Kohsaka S, Oda K, Miyagawa K, Aburatani H,
Mano H, Yamasoba T. Spinal solitary fibroustumor of the neck: Next-generation sequencingbased analysis of genomic aberrations. Auris
Nasus Larynx 47:1058-1063, 2020.
Kobayashi H, Shin M, Makise N, ShinozakiUshiku A, Ikegami M, Taniguchi Y, Shinoda Y,
Kohsaka S, Ushiku T, Oda K, Miyagawa K,

519

5.

6.

7.

Aburatani H, Mano H, Tanaka S. Genetic TestingDistinguishes Multiple Chondroid Chordomas
with Neuraxial Bone Metastases from Multicentric Tumors. Case Rep Genet 2020:8877722,
2020.
Watanabe K, Kage H, Nagoshi S, Toyama K,
Ohno Y, Shinozaki-Ushiku A, Nakazaki K,
Suzuki H, Kurokawa M, Nagase T. Dual EGFR
and ABL Tyrosine Kinase Inhibitor Treatment ina Patient with Concomitant EGFR-Mutated Lung
Adenocarcinoma and BCR-ABL1-Positive CML.
Case Rep Oncol Med 2020:4201727, 2020.
Kawata Y, Nagasaka K, Oda K, Makii C,
Takeuchi M, Oki S, Honjo H, Kojima M,
Miyagawa Y, Taguchi A, Tanikawa M, Sone K,
Hiraike H, Matsumoto Y, Wada-Hiraike O,
Ayabe T, Osuga Y, Fujii T. Effect of murine
double-minute 2 inhibitors in preclinical modelsof advanced clear cell carcinomas originatingfrom ovaries and kidneys. Cancer Sci 111:38243834, 2020.
Maru Y, Kawata A, Taguchi A, Ishii Y, Baba S,
Mori M, Nagamatsu T, Oda K, Kukimoto I,
Osuga Y, Fujii T, Hippo Y. Establishment andMolecular Phenotyping of Organoids from theSquamocolumnar Junction Region of the Uterine
Cervix. Cancers (Basel) 12(3):694, 2020.

520

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
Gaku Oguri, M.D., Ph.D., Takuya Kawahara, Ph.D., Mihoko Shibuya, M.D., Ph.D.

Project Assistant Professor
Mariko Inoue, M.D., Ph.D., Miki Ohta (from January)Homepage https://www.h.u-tokyo.ac.jp/english/centers-services/central-clinicalfacilities/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. It belongs to the central
clinical division of the hospital and provides supports
not only for clinical trials but also for investigatorinitiated (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521

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-sponsored 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-initiated medical treatment
and regenerative medicine; (2) Support for physiciansand others in formulating development strategies forclinical trials, advice on study design, and support forpharmaceutical affairs, funding, intellectual property,
and industry-academia collaborations; (3) Support forthe promotion of investigator-initiated clinical trials
conducted by physicians and others; (4) Monitoring,data management and data analysis required to ensure
the quality of investigator-initiated clinical 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 ofclinical trials.

522<Sponsor-Initiated Clinical Trials Promotion
Department>
The department is responsible for: (1) Supporting thesafe and smooth implementation of sponsor-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-sponsored 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

523

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.

524

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 Support Center has
established a system to conduct practical training forcourse participants.

scientific 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 (23 papers in English and 7 papers inJapanese).

Publications
1)

2)

3)

4)

5)

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 in

6)

Yoshida Y, Kashiwabara K, Hirakawa Y, Tanaka T,
Noso S, Ikegami H, Ohsugi M, Ueki K, Mita T,
Watada H, Koya D, Mise K, Wada J, Shimizu M,
Wada T, Ito Y, Narita I, Kashihara N, Nangaku M,
Matsuyama Y. Conditions, pathogenesis, andprogression of diabetic kidney disease and early
decliner in Japan. BMJ Open Diabetes Research &Care. 8(1): e000902, 2020
Tsurutani J, Hara F, Kitada M, Takahashi M,
Kikawa Y, Kato H, Sakata E, Naito Y, Hasegawa
Y, Saito T, Iwasa T, Taira N, Takashima T,
Kashiwabara K, Aihara T, Mukai H. Randomized
phase II study to determine the optimal dose of 3week cycle nab-paclitaxel in patients withmetastatic breast cancer. Breast. 55: 63–68, 2021
Takeuchi Y, Kashiwabara K, Hosoi H, Imai H,
Matsuyama Y. Longitudinal effects of anationwide lifestyle intervention program on
cardiometabolic outcomes in Japan: anobservational cohort study. Preventive Medicine.
141: article 106301, 2020
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 theprobability of restenosis at proximal edge after
2nd-generation drug-eluting-stent implantation:
development and internal validation using aquantitative coronary angiography from the postmarketing surveillance studies of everolimuseluting stent in Japan. Cardiovascular Intervention
and Therapeutics. 36(2): 190–197, 2020
Oguri G, Kojima T, Fujiu K, Komuro I. What is
the mechanism of irregular pacing spikes? Pacing
failure, sensing failure, or something else? A casereport. Eur Heart J Case Rep. 4; 4(3):1-4. doi:
10.1093/ehjcr/ytaa065, 2020
Oguri G, Nakajima T, Kikuchi H, Obi S,

525

Nakamura F, Komuro I. Allyl isothiocyanate(AITC) activates nonselective cation currents inhuman cardiac fibroblasts: possible involvementof TRPA1. Heliyon. 31; 7(1):e05816. doi:
10.1016/j.heliyon,2020
7) Kawahara T, Shinozaki T, Matsuyama Y. Doubly
robust estimator of risk in the presence of
censoring dependent on time-varying covariates:
application to a primary prevention trial forcoronary events with pravastatin. BMC Medical
Research Methodology. 20(1):204, 2020
8) Sawaki M, Taira N, Uemura Y, Saito T, Baba S,
Kobayashi K, Kawashima H, Tsuneizumi M,
Sagawa N, Bando H, Takahashi M, Yamaguchi M,
Takashima T, Nakayama T, Kashiwaba M, Mizuno
T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y,
Mukai H, for the RESPECT study group. A
randomized controlled trial of trastuzumab with orwithout chemotherapy for HER2-positive earlybreast cancer in older patients. Journal of ClinicalOncology. 38(32):3743-3752, 2020
9) Inui S, Kurokawa R, Nakai Y, Watanabe Y,
Kurokawa M, Sakurai K, Fujikawa A, Sugiura H,
Kawahara T, Yoon SH, Uwabe Y, Gonoi W, Abe O.
Comparison of Chest CT Grading Systems inCoronavirus
Disease2019(COVID-19)
Pneumonia. Radiology: Cardiothoracic Imaging.
2(6):e200492, 2020
10) Nakayama A, Nagayama M, Morita H, Kawahara
T, Komuro I, Isobe M. The use of geographicalanalysis in assessing the impact of patients’ homeaddresses on their participation in outpatient
cardiac rehabilitation: A prospective cohort study.
Environmental Health and Preventive Medicine.
25(1):76, 202011) Yanagiya M, Kawahara T, Ueda K, Yoshida D,
Yamaguchi H, Sato M. A meta-analysis ofpreoperative
bronchoscopic
markingforpulmonary nodules. European Journal of CardioThoracic Surgery. 58(1),40-50, 202012) Kizawa Y, Okada H, Kawahara T, Morita T.
Effects of brief nurse advance care planningintervention with visual materials on goal-of-care
preference of Japanese elderly patients withchronic disease. A pilot randomized controlled
trial. Journal of Palliative Medicine. 23(8):10761083, 202013) Tanaka M, Ishibashi Y, Hamasaki Y, Kamijo Y,
Idei M, Kawahara T, Nishi T, Takeda M, Nonaka
H, Nangaku M, Mise N. Hospitalization forpatients on combination therapy with peritoneal
dialysis and hemodialysis compared withhemodialysis. Kidney International Journal. 5(4):468-474, 2020
14) Fujimoto C, Kamogashira T, Takenouchi S,
Kinoshita M, Sugasawa K, Kawahara T,
Yamasoba T, Iwasaki S. Utriculo-ocular pathway
dysfunction is more frequent in vestibular
migraine than probable vestibular migraine.
Journal of Neurology. 267(8):2340-2346, 202015) Yanagiya M, Sato M, Ueda K, Nagayama K,
Kawahara T, Kawashima S, Yotsumoto T,
Yoshioka T, Fukumoto KJ, Nakajima J.
Preoperative lung surface localization for
pulmonary wedge resection: a single-center
experience. Journal of Thoracic Disease. 12(5):2129-2136, 202016) Hagiwara Y, Kawahara T, Shiroiwa T. What is a
Valid Mapping Algorithm in Cost-Utility
Analyses? An Answer from a Missing Data
Perspective. Value in Health. 23(9):1218-1224,
202017) Sun C, Anraku M, Kawahara T, Karasaki T, Kitano
K, Nagayama K, Sato M, Nakajima J. Prognostic
significance of low pectoralis muscle mass on
preoperative chest computed tomography inlocalized non-small cell lung cancer after
curative-intent surgery. Lung Cancer. 147:71-76,
202018) Fujimoto C, Kawahara T, Yagi M, Murofushi T.
Association between vestibular dysfunction andfindings of horizontal head-shaking and vibrationinduced nystagmus. Journal of Vestibular
Research. 30(5):319-327, 202019) Hagiwara Y, Shiroiwa T, Taira N, Kawahara T,
Konomura K, Noto S, Fukuda T, Shimozuma K.
Mapping EORTC QLQ-C30 and FACT-G onto
EQ-5D-5L Index for Patients with Cancer. Healthand Quality of Life Outcomes. 18(1):354, 202020) Morishita-Kawahara M, Kawahara T, Kamibeppu
K. Relation between family functioning andquality of life among family caregivers of patientswith terminal cancer hospitalized in general wards.
Open Journal of Nursing. 10:1233-1240, 2020

52621) Tsutsumi T, Sato H, Kikuchi T, Ikeuchi K, Lim LA,
Adachi E, Koga M, Okushin K, Kawahara T,
Koibuchi T, Yotsuyanagi H. Factors associatedwith clearance of hepatitis B virus surface antigen
in patients infected with human immunodeficiency virus. Medicine. 99(29):e21271, 202022) Inoue M, Fujio K. Evaluation of Response Criteria
in Rheumatoid Arthritis Treated With Biologic
Disease-Modifying
Antirheumatic
Drugs.
Arthritis Care Res (Hoboken). 72(7):942-949,
202023) Inoue M, Fujio K. Factors associated withdiscontinuation of glucocorticoids after starting
biological disease-modifying antirheumatic drugs
in rheumatoid arthritis patients. Mod Rheumatol.
30(1):58-63, 2020.

527

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.,

Fumiko Yano, D.D.S., Ph.D.

Kazumichi Yonenaga, D.D.S., M.D., Ph.D

Project Lecturer
Ysunori Omata, M.D. Ph.D.

Research Associates
Yukiyo Asawa, D.V.M., Ph.D., Ryota Chijimatsu, 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 Cell & Tissue
Engineering (until 31 Oct, 2020), and Laboratory for
Pediatric Regenerative Medicine. One project associate
professor and one project research associates who areassigned to each department are conducting researchwith many graduate students. The researchers continue
their studies to make the center function as atranslational 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

528

Medicine for Hematopoiesis founded by a donationfrom 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.
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 the Department of Cell & Tissue Engineering, weaimed to produce regenerated cartilage and bone withhigh safety and usefulness, to realize production systemand establish practical quality control and to promote
the application of regenerated cartilage and bone. To
achieve these goals, we conducted research on adultstem cell biology in mesenchymal tissues, applicationof molecular biology on cartilage repair forregenerative medicine, development of novel scaffolds
in cartilage and bone regeneration, development of 3D reconstruction system for regenerated tissues,evaluation on biochemical and biophysical propertiesof regenerated tissues in vivo and clinical trials andapplication of regenerated 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).

529

In the department of Eat-loss medicine, in order tosupport "eating," which is the foundation of human life,
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.

References1.

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. Based on the findings and knowledge
gained through this clinical study, another investigatorinitiated clinical trial applying implant-type tissueengineered cartilage for the treatment of tracheal
stenosis has also been approved. In addition, a clinicalstudy of treatment for temporomandibular joint
disorder taking advantage of anti-inflammatory andtissue repairing abilities of adipose 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

2.

3.

4.

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.

5.

The small compound, TD-198946, protects
against intervertebral degeneration by enhancing
glycosaminoglycan synthesis in nucleus pulposus
cells. Kushioka J, Kaito T, Chijimatsu R, Okada R,
Ishiguro H, Bal Z, Kodama J, Yano F, Saito T,
Chung UI, Tanaka S, Yoshikawa H. Sci Rep. 2020
Aug 25;10(1):14190. doi: 10.1038/s41598-02071193-6. PMID: 32843678.
Type 2 innate lymphoid cells inhibit thedifferentiation of osteoclasts and protect fromovariectomy-induced bone loss. Omata Y, Frech
M, Lucas S, Primbs T, Knipfer L, Wirtz S, Kadono
Y, Saito T, Tanaka S, Sarter K, Schett G, Zaiss MM.
Bone. 2020 Jul; 136: 115335. doi: 10.1016/j.bone.2020.115335. Epub 2020 Mar 30. PMID:
32240850.
Associations of clinical outcomes and MRI
findings in intra-articular administration of
autologous adipose-derived stem cells for knee
osteoarthritis. Higuchi J, Yamagami R,
Matsumoto T, Terao T, Inoue K, Tsuji S,
Maenohara Y, Matsuzaki T, Chijimatsu R, Omata
Y, Yano F, Tanaka S, Saito T. Regen Ther. 2020
May 25; 14: 332-340. doi: 10.1016/j.reth.2020.
04.003. eCollection 2020 Jun. PMID: 32490058.
Targeting zonulin and intestinal epithelial barrier
function to prevent onset of arthritis. Tajik N,
Frech M, Schulz O, Schälter F, Lucas S, Azizov V,
Dürholz K, Steffen F, Omata Y, Rings A, Bertog
M, Rizzo A, Iljazovic A, Basic M, Kleyer A,
Culemann S, Krönke G, Luo Y, Überla K, Gaipl
US, Frey B, Strowig T, Sarter K, Bischoff SC,
Wirtz S, Cañete JD, Ciccia F, Schett G, Zaiss MM.
Nat Commun. 2020 Apr 24;11(1):1995. doi:
10.1038/s41467-020-15831-7.PMID: 32332732.
Ethanol consumption inhibits TFH cell responses
and the development of autoimmune arthritis.
Azizov V, Dietel K, Steffen F, Dürholz K,
Meidenbauer J, Lucas S, Frech M, Omata Y, Tajik
N, Knipfer L, Kolenbrander A, Seubert S,
Lapuente D, Sokolova MV, Hofmann J, Tenbusch
M, Ramming A, Steffen U, Nimmerjahn F, Linker
R, Wirtz S, Herrmann M, Temchura V, Sarter K,
Schett G, Zaiss MM. Nat Commun. 2020 Apr 24;

530

11(1):1998. doi: 10.1038/s41467-020-15855-z.
PMID: 32332730.
6. Hypoxia-inducible factor-1 alpha maintains
mouse articular cartilage through suppression of
NF-κB signaling. Okada K, Mori D, Makii Y,
Nakamoto H, Murahashi Y, Yano F, Chang SH,
Taniguchi Y, Kobayashi H, Semba H, Takeda N,
Piao W, Hanaoka K, Nagano T, Tanaka S, Saito T.
Sci Rep. 2020 Mar 25; 10(1): 5425. doi:
10.1038/s41598-020-62463-4.PMID: 32214220
7. Enhancement of chondrogenic differentiation
supplemented by a novel small compound forchondrocyte-based tissue engineering. Hamamoto
S, Chijimatsu R, Shimomura K, Kobayashi M,
Jacob G, Yano F, Saito T, Chung UI, Tanaka S,
Nakamura N. J Exp Orthop. 2020 Mar 7;7(1):10.
doi:
10.1186/s40634-020-00228-8.
PMID:
32146609.
8. Primary culture of mouse adipose and fibrous
synovial fibroblasts under normoxic and hypoxic
conditions. Sugimoto H, Murahashi Y, Chijimatsu
R, Miwa S, Yano F, Tanaka S, Saito T. Biomed Res.
2020;41(1):43-51. doi: 10.2220/biomedres.41.43.
PMID: 32092739.
9. Stepwise strategy for generating osteoblasts fromhuman pluripotent stem cells under fully defined
xeno-free conditions with small-molecule
inducers. Zujur D, Kanke K, Onodera S, Tani S,
Lai J, Azuma T, Xin X, Lichtler AC, Rowe DW,
Saito T, Tanaka S, Masaki H, Nakauchi H, Chung
UI, Hojo H, Ohba S. Regen Ther. 2020 Jan
14;14:19-31. doi: 10.1016/j.reth.2019.12.010.
eCollection 2020 Jun. PMID: 31988991.
10. Adipose-derived stem cells improve tendon repair
and prevent ectopic ossification in tendinopathy
by inhibiting inflammation and inducing
neovascularization in the early stage of tendon
healing. Kokubu S, Inaki R, Hoshi K, Hikita A.
Regen Ther. 2020 Jan 17;14:103-110.
11. Glial Fibrillary Acidic Protein as Biomarker
Indicates Purity and Property of Auricular
Chondrocytes. Nishizawa S, Kanazawa S,
Fujihara Y, Asawa Y, Nagata S, Harai M, Hikita A,
Takato T, Hoshi K. Biores Open Access. 2020 Mar
3;9(1):51-63.
12. Establishment of a new technique for the
fabrication of regenerative cartilage with a

13.

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microslicer device to prepare three dimensional
diced cartilage. Aoki E, Asawa Y, Hikita A, Hoshi
K. BiomedicalResearch. 2020;41(2):67-80.
InterpenetratingPolymer Network Hydrogels via a
One-Pot and in Situ Gelation System Based on
Peptide Self-Assembly and Orthogonal CrossLinking for Tissue Regeneration. Shohei Ishikawa,
Kazutoshi Iijima, Daisuke Matsukuma, Yukiyo
Asawa, Kazuto Hoshi, Shigehito Osawa*,
Hidenori Otsuka* Chem. Mater. 2020, 32, 6,2353-2364
Optimization of culture duration of bone marrowcells before transplantation with a β-tricalcium
phosphate/recombinant collagen peptide hybrid
scaffold. Umeyama R, Yamawaki T, Liu D,
Kanazawa S, Takato T, Hoshi K, Hikita A. Regen
Ther. 2020 May 19; 14: 284-295. doi:
10.1016/j.reth.2020.04.005. eCollection 2020 Jun.
Ear Cartilage Reconstruction Combining Induced
Pluripotent Stem Cell-Derived Cartilage andThree-Dimensional Shape-Memory Scaffold. Uto
S, Hikita A, Sakamoto T, Mori D, Yano F, Ohba S,
Saito T, Takato T, Hoshi K. Tissue Eng Part A.
2020 Nov 2. doi: 10.1089/ten.TEA.2020.0106.
Online ahead of print. PMID: 32883178
The usefulness of the decellularized matrix fromthree-dimensional regenerative cartilage as a
scaffold material. Watanabe T, Asawa Y, Watanabe
M, Okubo R, Nio M, Takato T, Hoshi K, Hikita A.
Regen Ther. 2020 Dec 10;15:312-322.
Tracheal cartilage growth promotion by intratracheal administration of basic FGF. Komura M,
Komura H, Ishimaru T, Konishi K, Komuro H,
Hoshi K, Takato T. Pediatr Surg Int. 2020 Jan;36(1):33-41.
Long-term observation of airway reconstruction
using decellularized tracheal allografts in microminiature pigs at growing stage. Ohno M,
Fuchimoto Y, Higuchi M, Yamaoka T, Komura M,
Umezawa A, Hsu HC, Enosawa S, Kuroda T.
Regen Ther. 2020 Jul 21;15:64-69.
A survey on total parenteral nutrition in
55,000hospitalized patients: Retrospective cohort
study using a medical claims database. Sasabuchi
Y, Ono S, Kamoshita S, Tsuda T, Murano H,
Kuroda A. Clinical Nutrition ESPEN. 39 198-205
2020

531

20. 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
21. Association between the Mallampati score andmaximal mouth opening in patients with
obstructive sleep apnea. onenaga K, Taga H, Eno
Y, Watanabe M, Matsuo A, Itai S, Ono S, Takato
T. Oral Science International 18(2) 116-119 2021
22. A survey on total parenteral nutrition in 55,000
hospitalized patients: Retrospective cohort study
using a medical claims database. Yusuke
Sasabuchi, Sachiko Ono, Satoru Kamoshita,
Tomoe Tsuda, Haruka Murano, Akiyoshi Kuroda
Clinical nutrition ESPEN 2020
23. Clinical Impact of Prescribed Doses of Nutrientsfor Patients Exclusively Receiving Total
Parenteral Nutrition in Japanese Hospitals: A
Retrospective Cohort Study. Yusuke Sasabuchi,
Sachiko Ono, Satoru Kamoshita, Tomoe Tsuda,
Akiyoshi Kuroda JPEN. Journal of parenteraland enteral nutrition 2020
24. 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
【Book】
1. Evidence of Green Tea 2020:Review Book ver.1
Itai S, Yonenaga K, Ono S, Watanabe R, Tonosaki
K, Hoshi K. DesignEgg 2020

532

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 of
Immunotherapeutics (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
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. Configuration

533

of 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

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
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

534

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 new therapy of life style-relateddeseases by Applied Metabolic Biotechnology
Department of Cardiovascular Medicine, Graduate
School of Medicine
Department of Diabetes and Metabolic Diseases,
Graduate School of Medicine
Department of Chemistry and Biotechnology, Schoolof Engineering
To establish the system and methods for engineering
the novel model mice of life style-related diseases
using RNAi technology and biotechnology. To
elucidate the mechanisms by which adipose tissue
derived factors, adipokines, contribute to thedevelopment of the metabolic syndrome. To explore
the molecular mechanisms of sarcopenia.
Development of bone and cartilage regeneration byscaffold and mechanical stress
Department of Orthopaedic Surgery, Faculty of
Medicine, The University of Tokyo
Division of Science for Joint Reconstruction,
Graduate School of Medicine, The University of Tokyo
Ishihara & Takai Lab, Department of Materials
Science, Graduate School of Engineering, The
University of Tokyo
Laboratory of Regenerative Medical Engineering,535

Center for Disease Biology and Integrative Medicine,
Faculty of Medicine, The University of Tokyo
Department of Oral and Maxillofacial Surgery,
Faculty of Medicine, The University of Tokyo
Inhibition of aseptic loosening of artificial joints bynano-grafting of a novel biocompatible polymer MPC.
Creation of biocompatible biomaterials optimized forbone, cartilage and vascular regeneration. Regeneration of bone and cartilage tissue in vitro promoted byphysical stimulation
Development of a non-viral gene delivery system bysupramolecular nanotechnology.
Department of Materials Science, Graduate School ofEngineering, The University of Tokyo
Department of Bone & Cartilage Regenerative
Medicine, Graduate School of Medicine, The
University of Tokyo
Department of Orthopaedic Surgery, Faculty of
Medicine, The University of Tokyo
Department of Oral and Maxillofacial Surgery,
Faculty of Medicine, The University of Tokyo
Division of Clinical Biotechnology, Center for Disease
Biology and Integrative
Medicine, Graduate School of Medicine, The
University of Tokyo
Division of Tissue Engineering, The University ofTokyo Hospital
Development of a non-viral siRNA delivery system bysupramolecular nanotechnology. Production ofregenerated cartilage and bone with high safety andusefulness. Establishment of practical production
and quality control systems. Promotion of the clinicalapplication of regenerated cartilage and bone.
Development of easy, precise, non-invasive systems todetect osteoblastic and chondrogenic differentiation.
Determination of a finite set of signaling factors
sufficient for induction of osteoblasts andchondrocytes. Development of a method to induce
osteogenesis and angiogenesis simultaneously.
Development of a cell-sheet culture system for bone
and cartilage. Screening for compounds that inducebone and cartilage regeneration

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"
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.
Development and application of biomolecule
visualization probes
Department of Cardiovascular Medicine
Laboratory of Chemistry and Biology, Graduate
School of Pharmaceutical Sciences
We have developed biomolecule visualization probes
and investigated model animals for application. As abiomolecule visualization probe, we are improving
and more applying fluorescent probes for cancer
lesion detection. Moreover, we are going to develop
labeled probes which can elucidate disease treatment
mechanism of microRNA and adipose stem cells. Now
as fundamental study, we are researching diseasemodels for applying these treatments. In particular, we
are investigating diabetic nephropathy, liver fibrosis
and atherosclerosis models as non-coding RNA andadipose stem cells treatment targets.

536

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lengths of inorganic polyphosphate. Biomacromoleculesd 2020, 21(7), 2694-2704. DOI:10.
1021/acs.biomac.0c00390
Kiriyama H, Kaneko H, Itoh H, Kamon T,
Mizuno Y, Fujiu K, Morita H, Yamamichi N,
Komuro I. Association between Changes in Body
Weight and Lipid Profile in the General
Population: A Community-Based Cohort Study.
Eur Heart J Qual Care Clin Outcomes. 2021 Jan
25;7(1):109-110.
Hirokawa M, Daimon M, Kozuma K, Shinozaki
T, Kimura K, Nakao T, Nakanishi K, Sawada N,
Ishiwata J, Yoshida Y, Kato TS, Mizuno Y,
Morita H, Yatomi Y and Komuro I. Are there
gender differences in the association between
body mass index and left ventricular diastolic
function? A clinical observational study in theJapanese general population. Echocardiography.
2020 Nov;37(11):1749-1756.
Nakanishi K, Daimon M, Yoshida Y, Ishiwata J,
Sawada N, Hirokawa M, Kaneko H, Nakao T,
Mizuno Y, Morita H, Di Tullio, Homma S,
Komuro I. Serum Uric Acid Level and
Subclinical Left Ventricular Dysfunction: A
Community-Based Cohort Study. ESC Heart Fail.
2020 Jun;7(3):1031-1038.
Itoh H, Kaneko H, Kiriyama H, Kamon T,
Mizuno Y, Morita H, Yamamichi N, Komuro I.
Association Between Changes in Body Weightand Fat Weight in Middle Age General
Population. Int Heart J. 2020;61(1):15-20.
Yoshida Y, Nakanishi K, Daimon M, Ishiwata J,
Sawada N, Hirokawa M, Kaneko H, Nakao T,
Mizuno Y, Morita H, Di Tullio, Homma S,
Komuro I. Association of arterial stiffness with

20.

21.

22.

23.

24.

25.

left atrial structure and phasic function: acommunity-based cohort study. J Hypertens.
2020 Jun;38(6):1140-1148.
Kamon T, Kaneko H, Itoh H, Kiriyama H,
Mizuno Y, Morita H, Yamamichi N, Komuro I.
Association Between Waist Circumference andCarotid Intima-Media Thickness in the General
Population. Int Heart J. 2020 Jan 31;61(1):103108.
Kamon T, Kaneko H, Itoh H, Kiriyama H,
Mizuno Y, Morita H, Yamamichi N, Komuro I.
Gender-specific association between the bloodpressure category according to the updated
ACC/AHA guidelines for hypertension andcardio-ankle vascular index: a community-based
cohort study. J Cardiol. 2020 May;75(5):578-582.
Itoh H, Kaneko H, Kiriyama H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yatomi Y, Yamamichi N, Komuro I. Effect ofMetabolically
Healthy
ObesityontheDevelopment of Carotid Plaque in General
Population: A community-based cohort study. J
Atheroscler Thromb. 2020 Feb 1;27(2):155-163.
Kiriyama H, Kaneko H, Itoh H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yamamichi N, Komuro I. Effect of Cigarette
Smoking on Carotid Artery Atherosclerosis: acommunity-based cohort study. Heart and Vessels.
2020 Jan;35(1):22-29.
今江 禄一, 鍛冶 静雄, 木田 智士, 松田 佳
奈子, 竹中 重治, 青木 淳, 仲本 宗泰, 尾崎翔, 名和 要武, 山下 英臣, 中川 恵一, 阿部
修, “サイクル敵対的生成ネットワークを用いた治療中 CBCT 画像の画質改善”, 日本放射線技術学会雑誌 76 巻 11 号, 1173-1184 (2020).
水野由子：高齢者の循環器疾患における健診・人間ドックの役割. 臨床雑誌内科 2020;
126:857-861

538

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 Project Associate Professor Nobuhiro
Shojima, participate in the activities as follows; (1)large scale analysis of genomes utilizing next
generation sequencers and establishment of pipelinesof genome informatic analysis, (2) elucidation ofhereditary factors and pathogenesis of various
diseases, (3) integrated research and education of
genomic and clinical information, (4) analysis ofpolymorphism and mutation of genes involved insusceptibility and response to treatment in various
diseases such as life-style disease, and (5)establishment of database and integrated data miningof associated clinical information.

2. Activities
In collaboration with RIKEN, we have identified
genetic variations conferring susceptibility to type 2
diabetes, myocardial infarction, renal dysfunction,
and atherosclerosis obliterance (ASO) in the Japanese
population. We are now performing a genome-wide
association study to identify variations conferring
susceptibility to type 2 diabetes in the Japanese
population. About 500,000 variants directly
genotyped were imputed using the 1000 Genomes
Project Phase 3 reference panel in 36,000 cases andmore than 155,000 controls. We identified novel type2 diabetes associated loci, which had distinct minor
allele frequency spectra between Japanese andEuropeans, such as the missense variants in genes
related to insulin secretion. Trans-ethnic comparisonsof the molecular pathways from the genome-wide
association study (GWAS) results highlighted bothethnically shared and distinct impacts of a series ofpathways on type 2 diabetes. These findings
illustrated the etiology of type 2 diabetes in Japaneseand Europeans. We identified 88 type 2 diabetes –associated loci, of which 28 loci were novel. Twentyeight missense variants were in linkage disequilibriumwith the lead variants, including missense variants ingenes related to insulin secretion (GLP1R) （Suzuki
K, et al. Nat Genetics 51, 379-386, 2019）. Mahajan
et al. reported type 2 diabetes genome-wide
association
study
meta-analysis
dataonapproximately 900,000 individuals of European
ancestry, increasing the association signals in over
240 loci associated with type 2 diabetes (Mahajan A,
et al. Nature Genetics 50, 1505-1513, 2018). Type 2
diabetes GWAS meta-analysis performed in a
Japanese population identified no less than 20 novel
type 2 diabetes loci that were not associated with type2 diabetes in Europeans. This article is referenced in
the position statement from science council of Japan.
To examine type 2 diabetes risk in East Asian
individuals, our team carried out a meta-analysis of
GWAS data from 77,418 individuals with type 2
diabetes and 356,122 healthy control individuals. We
identified 61 loci that are newly implicated in
predisposition to type 2 diabetes. (Spracklen CN, et al.
Identification of type 2 diabetes loci in 433,540 East

539

Asian individuals, Nature 582, 240-245, 2020).
We conducted whole genome sequence andanalyzed the sequence data of 1,987 subjects with type2 diabetes in collaboration with the Osaka University,
RIKEN and BioBank Japan. We conducted
metabolome analysis and analyzed the data of 300
subjects with diabetic complications. 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 are interviewed and contributed to the report by
the project of Japan Agency for Medical Research andDevelopment (AMED) concerning ethical, legal andsocial issue of secondary findings in genomic research(Aizawa Y, et al. A proposal on the first Japanesepractical guidance for the return of individual
genomic results in research settings. J Hum Genet. 65,
251-261, 2020).
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. Suzuki K, Akiyama M, Ishigaki K, Kanai M,
Hosoe J, Shojima N, et al. Identification of 28

new susceptibility loci for type 2 diabetes in theJapanese population. Nat Genet. 2019 Mar; 51(3):379-386. doi:10.1038/s41588-018-0332-4. Epub
2019 Feb 4.
2. Inoue S, Hirota Y, Ueno T, Fukui Y, Yoshida E,
Hayashi T, Kojima S, Takeyama R, Hashimoto T,
Kiyono T, Ikemura M, Taguchi A, Tanaka T,
Tanaka Y, Sakata S, Takeuchi K, Muraoka A,
Osuka S, Saito T, Oda K, Osuga Y, Terao Y,
Kawazu M, Mano H. Uterine adenomyosis is anoligoclonal disorder associated with KRAS
mutations. Nat Commun. 2019 Dec 19; 10(1):5785. doi: 10.1038/s41467-019-13708-y.
3. Yamada T, Lee CL, Liu WJ, Shojima N. Slow
Weight Loss During Comprehensive Treatment
and Worse Metabolic Control with Higher Weight
Regain: A Trajectory Analysis. Obesity (Silver
Spring). 2019 Dec; 27(12): 1925-1926. doi:10.
1002/oby.22655. Epub 2019 Nov 3.

540

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
Since the introduction of TNF inhibitors forrheumatoid arthritis in Japan in 2003, biologic agentstargeting cytokines and selective small-molecule
inhibitors of intracellular signal transduction events
have been developed and have shown significant
results in the treatment of various immune-mediateddiseases. These drugs are called “molecular targeted
therapies” and are targeted at diseases such as
rheumatoid arthritis, juvenile rheumatoid arthritis,
systemic lupus erythematosus, Behcet's disease,autoinflammatory diseases, spondyloarthritis, psoriasis
and psoriatic arthritis, inflammatory bowel disease,multiple sclerosis, nocturnal paroxysmal hemoglobinuria, and recently expanded to atopic dermatitis.
Currently available molecular targeted agents are 8
TNF inhibitors, 3 IL-6 inhibitors, 1 CTLA4-Ig, 3 IL-17
inhibitors, 1 IL-12/23 inhibitor, 2 IL-23 inhibitors, 2 α4integrin inhibitors, 2 IL-5 inhibitors, 1 IL-4/13 inhibitor,
1 anti-IgE antibody, 1 IL-1 inhibitor, and 5 JAK
inhibitors. Molecular targeted agents are not only
highly effective, but are also expected to reduce thelong-term side effects of steroids by reducing thedosage of corticosteroids, which are often used for
immunological diseases.
In 2017, with the expansion of molecular targeted

agents, the “Immune-mediated Diseases Therapy
Center Outpatient Department” was established in theoutpatient consultation division. In order to further
increase the number of molecular targeted agents andexpand the range of indications, it was approved as adepartment of the University of Tokyo Graduate Schoolof Medicine in April of last year (2020). At the sametime, the " Immune-mediated Diseases Therapy
Center" was established on the 12th floor of Inpatient
Unit B as an outpatient center to provide intravenous
molecular targeted therapy for all patients withimmune-mediated diseases in the university of Tokyo
hospital. There are eight departments: Allergy andRheumatology, Dermatology, Ophthalmology, Orthopaedics surgery and Spinal 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 moleculartargeted therapy. We also hold a bimonthly meeting of
the Immune Disease Treatment Center as a place toshare information and improve problems.
The current number of prescriptions for molecularly
targeted agents has more than doubled from 550 in2017 to 1,300 in 2020, with 65% subcutaneous, 30%
intravenous, and 5% oral. As a cross-sectional center,541

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.

2.

3.

Inoue M, Kanda H, Tateishi S, Fujio K. Factors
associated with discontinuation of glucocorticoids
after starting biological disease-modifying antirheumatic drugs in rheumatoid arthritis patients.
Mod Rheumatol 2020; 30: 58-63
Inoue M, Kanda H, Tateishi S, Fujio K. Evaluationof response criteria in rheumatoid arthritis treatedwith biological disease-modifying antirheumatic
drugs. Arthritis Care Res (Hoboken). 2020; 72:
942-9
Yamada S, Nagafuchi Y, Kono M, Hatano H,
Tateishi S, Harada H, Sumitomo S, Kubo K, Shoda
H, Kanda H, Fujio K: High incidence ofmalignancy in SAPHO syndrome. Clin Exp
Rheumatol. 2020; 38: 805-6

542

Medical Community Network andDischarge Planning Center
Associate Professor
Masahiko Sumitani, M.D., Ph.D. (concurrently)

Assistant Profeesor
Jun Hozumi, M.D, Ph.D.

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%.

543

Teaching activities
We educate undergraduate students of the Medical
Social Working and Welfare of other university.

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.

544

Department of Cancer Resource
CenterChief
Sachiyo Nomura, M.D.,Ph.D.

Associate chief
Takako Wakeda, M.D.,Ph.D.

Counseling staff
Megumi Yasuda, 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 findout about cancer, for instance the treatment and545

screening 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.

References and Presentation
1. Makeup as care for changes in appearance due tocancer treatment. FRAGRANCE JOURNAL 22
Research and Development for Cosmetics,
Toiletries & Allied industries Special issue p126
2. Inadequacy of Appearance Care for cancer
patients in Japan. MASCC/ISOO Annual Meetingon Supportive Care in Cancer 2019, HYATTREGENCY SAN FRANCISCO

Center for Disease Biology andIntegrative Medicine

547

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
decomposes fatty droplets resulting in controlling the548

progression of obesity. However, when this process
undergoes effectively and excessively under the obese
condition, oppositely to control the progression ofobesity, chronic inflammation of adipose tissue andinsulin resistance are triggered and Type II diabetes
and atherosclerosis 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, on Japan Agency for Medical Researchand 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.

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. Takahata A, Arai S, Hiramoto E, Kitada K, Makita
Y, Suzuki H, Nakata J, Araki K, Miyazaki T &Suzuki Y. Crucial role of AIM/CD5L in thedevelopment of glomerular inflammation in IgANephropathy. J. Am. Soc. Nephrol. 31, 2013-2024,
2020

549

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
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 inthe University of Tokyo in November, 2005. The
Kasai laboratory has moved to the first building ofFaculty of Medicine in January, 2006. It belongs to theSection of Functional Biology in the Graduate Schoolof 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), theInstitute of Advanced Studies of the University ofTokyo since it has established in 2017.10, and thelaboratory is cooperating the activity of IRCN.
The 20 members of our laboratories in the March of2019 are Haruo Kasai, Sho Yagishita (Lecturer),
Kazuhiko Ishii (Research Associate), Kenji
Yamagushi (Project Researcher), Hasan Ucar (Project
Researcher), Yusuke Iino (Resaerch Associate), Mio
Tajiri (D4), Takeshi Sawada (D4), Yuichi Morimoto(D4), Toshiaki Kume (D3), Hongyu Amy Chang(Master course student, M2), Hitoshi Okazaki(Medical Intern), Monami Nishio (Medical school
student, M2), and as technical staffs, Haruka Ohno,

Arisa Kurabayashi, Yuki Sakata, Masayoshi Asaumi,
Rie Yonemoto and Yumiko Saikachi.

Teaching activities
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.
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
are preserved. We have been exploring two-photon
excitation microscopy with a new type of laser, an
infrared femtosecond-pulse laser, as a means toachieve this goal. The two-photon microscope has theability to penetrate deep into tissues and is the only
imaging instrument that allows investigations of intact
tissues at the cellular and molecular levels. Twophoton microscopy can also be readily combined withmolecular biological and other physiological methods,

550

and it promises to provide important insight into
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 area major cellular basis for learning and memory (Kasai,
et al. 2010. Spine generation and elimination arerobust processes, even in the adult brain, and spine
enlargement and shrinkage play key roles in theplasticity of dendritic spines. We previously used
two-photon glutamate uncaging to stimulate
individual spines and demonstrated that dendritic
spine enlargement underlay long-term potentiation(LTP) at the level of single spines (Matsuzaki,, Kasai,Nature 2004). We also reported that spine shrinkage
and elimination can be induced when glutamate
uncaging was paired with action potentials in thepresence of GABAergic inhibition (Hayama,,Kasai,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(dp-cofilin) 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
of cofilin are inhibited by its phosphorylation at theserine-3 residue, as phosphorylated cofilin (p-cofilin)
dissociates from F-actin. Thus, the entire lifecycle of
F-actin is regulated by cofilin. Dendritic spine
enlargement and shrinkage are likely also regulated by
the phosphorylation and dephosphorylation of cofilin1(Noguchi,, Kasai 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 relationshipbetween 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., thepsychotic state of hallucinations, delusions anddisordered thought represent an existential threat to anafflicted human mind. Now, a team of researchers
from the International Research Center for
Neurointelligence (IRCN) and the Graduate School of
Medicine at the University of Tokyo, and the Graduate
School of Informatics at Kyoto University, proposesthat psychosis involves defective neural signaling in a
deep brain area called the ventral striatum during abehavior called discrimination learning (Ref. 1).
We studied the way mice predict future rewards intheir environment, a behavior known as reward
learning, which is shared by us humans and othermammals, too. Reward learning involves the releaseof 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 team searched 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
in neurons 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 asecond.
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

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technologies to artificially increase or decrease thedips for the first time and measured their effects on
how the mice estimated rewards. Optogenetics is a
way to activate artificial light-sensitive proteins withfinely controlled laser light to turn neuronal activity
on or off.
(2) The D2 system and new computational models.
To corroborate the experimental studiesl we firstexamined the intracellular molecular machinery that
shuttles dopamine signals from cell receptors tochanges in specialized cell compartments called
postsynaptic spines, the small protrusions on cell
dendrites that enable intercellular communication (Ref.
6). In a deep brain area called the ventral striatum
reside two types of cells with dopamine receptors,
called D1 and D2 that handle, respectively, reward andrisk (or punishment) learning. The researchers built adetailed molecular model of the protein cascade that
resides in D1 and D2 cells. D1 and D2 cells learn thelanguage, so to speak, of dopamine pulses and dips,
respectively, to enlarge their spines in the form of
memory. Interestingly, the model reveals the role of aprotein enzyme called adenylyl cyclase type 1 in“contingency detection” where two signals arrive on asingle cell in the same time window, allowing the cellto learn what the researchers call “temporalcontiguity” or the pattern of dopamine in reward
learning.
In the second study (Ref. 5), we zoomed out to theanimal behavioral level by developing a model ofreinforcement learning that has D1-like and D2-likecells in a multilayered neural network designed after aform of network configuration called an extreme
learning machine (ELM). The model, called
OVaRLAP, contains computational elements similar to
the D1 and D2 neurons that are known to processrespective positive or negative dopamine reward
prediction error signals. These distinct signals arethought to drive two different patterns of reinforcement learning, generalization and discrimination, thatwere recently validated by the group in Iino et al.
(2020) Nature. The team tested the performance ofOVaRLAP against a computer game called the painfulgrid world navigation task where the agent controlled
by the model has to avoid the “painful” walls of amaze to move to safety.
OVaRLAP showed high performance due to a fast
generalization resulting from the D1- and D2-likeelements in the network’s final layer (Ref. 5).
However, in a similar game played with impairment in
discrimination learning by D2-like elements andbackground noise applied to the ELM, the model
surprisingly failed to generate proper behavior. We
suggest this aberrant behavior might mimic mental
conditions such as schizophrenia related to theintrinsic design of the dopamine reward system and its
powerful generalization and discrimination capacity,where high performance is associated with a higher
risk of system breakdown. Intriguingly, the results
imply that future neuro-inspired AI might inherit both
high cognitive capacity and mental disorders fromtheir biological antecedents, a cautionary note.
Together, the two studies show that multiscalemodeling, from molecules to behavior, can reveal
insights not only on dopamine reward learning but on
the human brain itself.

References
1.

2.

3.

4.

5.

Iino, Y., Sawada, T., Yamaguchi, Tajiri, M., K.,
Ishii, S., Kasai, H.* & Yagishita, S.* (2020)
Dopamine D2 receptors in discrimination
learning and spine enlargement. Nature 579:
555-560.
Seaton, G., Hodges, G., de Haan, A., Grewal, A.,
Pandey, A., Kasai, K. & Fox, K. (2020)
Dual-component 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,
79-91.
Fujita, Y., Yagishita, S., Kasai, H., Ishii, S. (2020)
Computational Characteristics of the Striatal

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6.

7.

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.

553

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.

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

554

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 has
been analyzed to quantify surgical skills. For example,
an image processing method to track the needle posein the microscopic view has been developed toquantify the manipulation skills of expert surgeons.
VR surgical simulators have also been developed forautonomous surgical process modeling (SPM).
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
Robots to assist scientific experiments, such as
dissection of mouse, has been designed. Collaborationis planned with mathematicians, AI researchers, robot
researchers, and scientists.

References(1) 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(2) T. Hozumi, A. M. Sreedevi, S. Ohta, T. Ito"Nonlinear Pressure Drop Oscillations during
Gelation in a Kenics Static Mixer" Industrial &Engineering Chemistry Research, 2020, 59, 10,4533-4541(3) S. Ohta, E. Kikuchi, A. Ishijima, T. Azuma, I.
Sakuma, T. Ito "Investigating the optimum size of
nanoparticles for their delivery into the brain
assisted by focused ultrasound-induced blood–brain

barrier opening", Scientific Reports 2020, 10,18220(4) K. Mitsuhashi, P. Qi, A. Takahashi, S. Ohta, and T.
Ito, “Prevention of postoperative peritoneal
adhesions in rats with sidewall defect-bowel
abrasions using metal ion-crosslinked N-succinyl
chitosan hydrogels”, Reactive and Functional
Polymers 2019 (145) 104374(5) P. Qi, Y. G. Zheng, S. Ohta, N. Kokudo, K.
Hasegawa, T. Ito, “In situ fabrication of
double-layered hydrogels via spray processes toprevent postoperative peritoneal adhesion”, ACS
Biomaterials Science and Engineering, 2019,(5), 4790-4798.
(6) Y. Amano, S. Ohta, K. L. Sakura, T. Ito,
"Pemetrexed-conjugated hyaluronan for thetreatment of malignant pleural mesothelioma",
European Journal of Pharmaceutical Sciences,
2019, 138, 105008(7) AK. Lefor, K. Harada, A. Dosis, M. Mitsuishi,”
Motion analysis of the JHU-ISI Gesture and Skill
Assessment Working Set using Robotics Videoand Motion Assessment Software”, Int J Comput
Assist Radiol Surg, 2020, 15(12):2017-2025.
(8) 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.
(9) AK. Lefor, K. Harada, H. Kawahira, M. Mitsuishi,“The effect of simulator fidelity on procedure skill
training: a literature review”, Int J Med Educ, 2020,
11:97-106.
(10) 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.
(11) 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.

555

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.

Education
The development of advanced medical systems, such

556

as 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;

557

Regen Ther 6, 100-107, 2017; Int J Mol Sci. 20(24).
pii: E6324, 2019; Bone. 137:115458, 2020). A fuller
understanding of cell fate specification processes
during skeletal formation, we believe, will enable thedevelopment of novel therapeutic strategies, in whichbone and cartilage repair and regeneration are inducedby 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
detection of osteoblast and chondrocyte differentiation

558(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). The high-performancehydrogel unit would integrate signaling factors withshape-controlled scaffold materials, leading to thedevelopment of implant devices that work as scaffolds
for tissue repair and also as carriers of bioactive
factors. Through a series of these studies, we areaiming to create a "four-dimensional scaffold system"that achieves efficient tissue regeneration bycontrolling cell proliferation and differentiation in
temporal and spatial manners. The system will not
only be applicable 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.

2.

Tani S, Chung UI, Ohba S, Hojo H.
Understanding paraxial mesoderm development
and sclerotome specification for skeletal repair.
Exp Mol Med.52(8):1166-1177, 2020
Onodera S, Saito A, Hojo H, Nakamura T, Zujur
D, Watanabe K, Morita N, Hasegawa D, Masaki
H, Nakauchi H, Nomura T, Shibahara T,
Yamaguchi A, Chung UI, Azuma T, Ohba S.
Hedgehog
Activation
Regulates
Human

559

3.

4.

5.

Osteoblastogenesis. Stem Cell Reports. 15(1):125-139, 2020.
Hojo H, Ohba S. Gene regulatory landscape inosteoblast differentiation. Bone. 137:115458,
2020.
Zujur D, Kanke K, Onodera S, Tani S, Lai J,
Azuma T, Xin X, Lichtler AC, Rowe DW, Saito T,
Tanaka S, Masaki H, Nakauchi H, Chung UI,
Hojo H, Ohba S. Stepwise strategy for generating
osteoblasts from human pluripotent stem cells
under fully defined xeno-free conditions withsmall-molecule inducers. Regen Ther. 14:19-31,
2020.
Yasuda T, Sakumichi N, Chung UI, Sakai T.
Universal Equation of State Describes Osmotic
Pressure throughout Gelation Process. Phys Rev
Lett. 125(26):267801, 2020

560

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 (two for the doctoral course and one
for the master course), four external researchers, andone research assistant conducted the researches
together during the year of 2020.
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

561

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 sPLA2-IIE is highly induced in brown andbeige adipocytes in response to cold and that its 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).

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). Furthermore, by phenotypic screening (withperturbation of skin barrier function as a readout)using a series of PLA2 knockout strains, as well as bygene expression profiling of PLA2-related genes inmouse and human skins, we have identified several
PLA2s that appear to be linked to the regulation ofskin homeostasis and diseases.
Among these PLA2s, PLA2G4E (cPLA2, whichis expressed in epidermal keratinocytes, exhibits aunique N-acyltransferase activity that transfers a fatty
acid from the sn-1 position of PC to the amino groupof phosphatidylethanolamine (PE) to give rise to Nacyl 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.
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, Pla2g3-/- mice display more severe atopic
dermatitis-like symptoms with increased expressionof type 2 cytokines and chemokines (IL-4, IL-13, IL33, TSLP, and CCL17), serum IgE levels, eosinophil
infiltration, and scratching behavior. Global or skinspecific deletion of EP4 (PGE2 receptor) or FP (PGF2
receptor) largely if not solely recapitulate these
phenotypes, suggesting that the PLA2G3-driven
PGE2-EP4/PGF2-FP signaling in keratinocytes plays
an important role in skin barrier formation and thereby

562

skin homeostasis, perturbation of which leads toexacerbation of atopic dermatitis.
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) and that PAF-AH2,
a unique PLA2 that hydrolyzes oxidized phospholipids,
ensures optimal MC activation and thereby allergic
responses through producing unique EPA/DHA
metabolites (ω3 epoxides) (Shimanaka et al, Nat Med2017). We have recently confirmed the role of PLA2G3in MCs by demonstrating that mice lacking PLA2G3
specifically in MCs, like those lacking the enzyme inall tissues, have immature MCs and display reduced
local and systemic anaphylactic responses. In addition,
MC-specific Pla2g3-null mice display an aggravatedcontact hypersensitivity (CHS), which is phenocopied
by MC-specific deletion of hematopoietic PGD2synthase. Thus, MC-secreted PLA2G3 promotes MCmaturation via PGD2, thereby facilitating acuteanaphylactic reaction and limiting delayed CHS
response (Taketomi et al, Cells 2021). 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), an orphan sPLA2, is
induced in Th17 cells and participates in Th17
differentiation. Global and CD4+ T cell-specificPla2g12a-deficient mice have lower psoriaticinflammation with decreased Th17 and T cells in theskin and draining lymph nodes. We are now analyzinga particular lipid mediator that acts downstream of
PLA2G12A in inducing Th17 immunity.
4) Cancer
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.
These results highlight a new aspect of PLA2G2A as amodulator of gut microbiota, perturbation of which
affects distal skin responses (Miki et al, JCI Insight, inpress).
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 macrophages of Epstein-Barrvirus (EBV) lymphoma, increases the production of
fatty acids, lysophospholipids and their metabolites.
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. Overall, the sPLA2-driven EV modification
promotes tumor development (submitted).
5) Infectious diseases
PLA2G2D expressed in dendritic cells and M2
macrophages attenuates anti-viral Th1 immunity bysupplying 3 PUFAs and PGD2. In collaboration witha foreign group, we have reported that Pla2g2d
deficiency protects mice from pneumonia caused bycoronavirus infection (Vijay et al, J Exp Med 2015;
Zheng et al, J Clin Invest 2021; Roy Wong et al, bioRxiv
2021). Therefore, PLA2G2D may be an attractive drug
target for treatment of COVID-19.
6) Neuronal 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. However, it is unclear how PNPLA6
mutations lead to these disorders. We have confirmedthat PNPLA6 acts a phospholipase B (PLA1/A2 +lysophospholipase), hydrolyzing PC to give rise to two
fatty acids and GPC, in cells. Intriguingly, neuronspecific deletion of PNPLA6 and its closest homolog
PNPLA7 leads to neurodegenerative disorders similar

563

to hereditary spastic paraplegia and that tamoxifeninducible eye-specific deletion of PNPLA6 results inretinal degeneration. Clarifying the regulatory roles oflipid metabolism driven by PNPLA6/PNPLA7 willshed light on the molecular mechanism underlying the
PNPLA6-related neuronal and retinal disorders.
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).

Publications
1.

2.

3.

4.

Inazumi T, Yamada K, Shirata N, Sato H,
Taketomi Y, Morita K, Hohjoh H, Tsuchiya S,
Oniki K, Watanabe T, Sasaki Y, Oike Y, Ogata Y,
Saruwatari J, Murakami M, Sugimoto Y.
Prostaglandin E2-EP4 axis promotes lipolysis
and fibrosis in adipose tissue leading to ectopic
fat deposition and insulin resistance. Cell Rep. 33,
108265, 2020.
Morishita H, Kanda Y, Kaizuka T, Chino H,
Nakao K, Miki Y, Taketomi Y, Guan. JL,
Murakami M, Aiba A, Mizushima N. Autophagy
is required for maturation of surfactantcontaining lamellar bodies in the lung and swim
bladder. Cell Rep. 33, 108477, 2020.
Murakami M, Sato H, Taketomi Y. Updating
phospholipase A2 biology. Biomolecules 10,
E1457, 2020. (Review)
Kitaura J, Murakami M. Positive and negativeroles of lipids in mast cells and allergic responses.
Curr. Opin. Immunol. 72, 186-195., 2021.
(Review)

564

5.

Zheng J, Meyerholz D, Wong LR, Gelb M,
Murakami M, Perlman S. Coronavirus-specificantibody production in middle-aged micerequires phospholipase A2G2D. J Clin Invest.
131, e147201, 2021.
6. 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. bioRxiv. 2021.04.
20.440676.
7. Taketomi Y, Endo Y, Higashi T, Murase R, Ono T,
Taya C, Kobayashi T, Murakami M. Mast cellspecific deletion of group III secreted
phospholipase A2 impairs mast cell maturation andfunctions. Cells. 10, 1691, 2021.
8. 村上誠. 脂質とアレルギー疾患. アレルギー.
69 (4), 250-255, 2020.
9. 村上誠. 脂質メディエーターによるマスト細胞とアレルギー炎症の制御. アレルギーの臨
床. 41 (2), 13-16, 2021.
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 A, 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.

565

Laboratory of Animal Resources
Professor
Atsu Aiba, Ph.D.

Associate Professor
Hidetoshi Kassai, Ph.D.

Assistant Professor
Harumi Nakao, Ph.D., Hiromitsu Kono, Ph.D., Ryo Saito, Ph.D., Shoko Noda-Narita 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, a project academic support
specialist, 2 assistant laboratory animal technicians,
and 4 assistant clerks. In addition, about 15 contracted
employees are involved in animal breeding andmaintenance 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 1023 at the end of academic year 2020.
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(mTOR). We also try to generate murine andmarmoset models for human genetic diseases.

566

1. Establishment of model marmosets for fragile
X syndrome
Common marmoset (Callithrix jacchus) is a nonhuman primate and recently used for human model,
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
region of FMR1 gene. We found that expression of
FMRP was reduced in these mutant marmosets. Thereis an “mGluR5 hypothesis” that symptoms of fragile
X syndrome are caused by activation of mGluR5
pathway. To examine the mGluR5 hypothesis in
non-human primates, we generated FMR1/GRM5
double mutant marmosets. We will analyze FMR1
mutants and FMR1/GRM5 double mutants to examine
the mGluR5 hypothesis.
2. Analysis of Group I mGluRs
Metabotropic glutamate receptor subtype 1 (mGluR1)
and subtype 5 (mGluR5) are coupled to trimeric G
protein Gq, shared ligand specificity and homologous
amino acid sequences, and constitute group I mGluRs.
They exhibit nearly complementary distributions,spatially and temporally, throughout central nervous
system. Significance of complementary expression of
the receptors and their functional redundancy are still
unknown.
Therefore,
we
have
generated“mGluR5-rescue” mice, in which mGluR5 is
specifically expressed in cerebellar Purkinje cells in
mGluR1-KO background. We found that themGluR5-rescue mice showed apparently normal
motor coordination, although mGluR1-KO mice show
severe ataxia. Furthermore, we found that abnormal
synapse elimination at climbing fiber synapse in
mGluR1-KO mice is rescued by ectopic expression ofmGluR5 in Purkinje cells. These results indicate afunctional redundancy between mGluR1 and mGluR5
in cerebellar Purkinje cells.

References
1.

2.

3.

4.

5.

6.

Ueyama T, Sakuma M, Nakatsuji M, Uebi T,
Hamada T, Aiba A, and Saito N.
Rac-Dependent Signaling from Keratinocytes
Promotes Differentiation of Intradermal White
Adipocytes.
J Invest Dermatol, 140(1), 75-84, 2020.
Kurano M, Tsukamoto K, Shimizu T, Kassai H,
Nakao K, Aiba A, Hara M, and Yatomi Y.
Protection Against Insulin Resistance by
Apolipoprotein M/Sphingosine-1-Phosphate.
Diabetes, 69(5), 867-881, 2020.
Saito R, Koebis M, Nagai T, Shimizu K, Liao JZ,
Wulaer B, Sugaya Y, Nagahama K, Uesaka N,
Kushima I, Mori F, Maruyama K, Nakao K,
Kurihara H, Yamada K, Kano M, Fukada Y,
Ozaki N, and Aiba A.
Comprehensive analysis of a novel mouse modelof the 22q11.2 deletion syndrome: a model withthe most common 3.0-Mb deletion at the human
22q11.2 locus.
Transl Psychiatry, 10(1), 35, 2020.
Toyoda Y, Takada T, Miyata H, Matsuo H, Kassai
H, Nakao K, Nakatochi M, Kawamura Y,
Shimizu S, Shinomiya N, Ichida K, Hosoyamada
M, Aiba A, and Suzuki H.
Identification of GLUT12/SLC2A12 as a uratetransporter that regulates the blood urate level inhyperuricemia model mice.
Proc Natl Acad Sci U S A, 117(31), 18175-18177,
2020.
Nagahama K, Sakoori K, Watanabe T, Kishi Y,
Kawaji K, Koebis M, Nakao K, Gotoh Y, Aiba A,
Uesaka N, and Kano M.
Setd1a Insufficiency in Mice Attenuates
Excitatory Synaptic Function and Recapitulates
Schizophrenia-Related Behavioral Abnormalities.
Cell Rep, 32(11), 108126, 2020.
Morishita H, Kanda Y, Kaizuka T, Chino H,
Nakao K, Miki Y, Taketomi Y, Guan JL,
Murakami M, Aiba A, and Mizushima N.
Autophagy Is Required for Maturation ofSurfactant-Containing Lamellar Bodies in theLung and Swim Bladder.
Cell Rep, 33(10), 108477, 2020.

567

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
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568

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

569

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.

Ito T, Hanafusa N, Iwase S, Noiri E, Nangaku M,
Nakagawa K, Miyagawa K. Ascitic IL-10
concentration predicts prognosis of patients
undergoing cell-free and concentrated ascites
reinfusion therapy. Ther Apher Dial 24:90-95,
2020.
Shinozaki-Ushiku A, Kohsaka S, Kage H, Oda K,
Miyagawa K, Nakajima J, Aburatani H, Mano H,
Ushiku T. Genomic profiling of multiple primarycancers including synchronous lung adenocarcinoma and bilateral malignant mesotheliomas: Identification of a novel BAP1
germline variant. Pathol Int 70:775-780, 2020.
Kobayashi H, Shin M, Makise N, ShinozakiUshiku A, Ikegami M, Taniguchi Y, Shinoda Y,
Kohsaka S, Ushiku T, Oda K, Miyagawa K,
Aburatani H, Mano H, Tanaka S. Genetic testing
distinguishes multiple chondroid chordomas withneuraxial bone metastases from multicentric
tumors. Case Rep Genet 2020:8877722, 2020.
Ikegami M, Kohsaka S, Ueno T, Momozawa Y,
Inoue S, Tamura K, Shimomura A, Hosoya N,
Kobayashi H, Tanaka S, Mano H. Highthroughput functional evaluation of BRCA2
variants of unknown significance. Nat Commun
11:2573, 2020.

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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571

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572

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)574

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 andresearch under the control of Graduate School of
Medicine since April 2013. IRCME previously
consisted of two departments of International
Cooperative Study in Medical Education, andPlanning & Cooperation for International Cooperative
Projects and Information on Medical Education.
Names of two new departments are Department ofMedical Education Studies and Department ofInternational 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 ofTokyo 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 ofFaculty of Medicine in such as academic affair
committee, medical education reform working group,and clinical clerkship. Moreover, the department
offers educational activities such as PBL (problembased learning) and clinical skill practical training.
The department operates OSCE (objective structured
clinical examination). The department also runs andmanages “Tsutsuji no kai” under the consortium with
Tokyo Medical Dental University to develop
simulated patients indispensable for education of
medical interview.

575

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 umbrella of Graduate School of
Medicine since April 2013. IRCME currently consistsof Department of Medical Education Studies andDepartment of International Cooperation for Medical
Education (ICME).
Department of ICME is a handling comprehensive
practices and research, both in the field ofinternational cooperation in health-professionseducation-related area and in the field linking policies
and actual practices such as international health,community medicine, and general practice.
Specifically, it is as follows.

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576

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) 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.

References1.

2.

Ie, K., Murata, A., Tahara, M., Komiyama, M.,
Ichikawa, S., Takemura, Y. C., & Onishi, H. (2020).
Relationship between medical students’ careerpriority and specialty choice: A nationwide
multicenter survey. Journal of General and Family
Medicine, 21(6), 219-225.
Ernawati, D., Aryana, I. G. P. S., & Onishi, H.
(2020). An impact of simulated interprofessional
workshop on healthcare professionals’ andpatients’ values recognition. IAKMI Public Health
Journal Indonesia, 1(1), 1-4.

577

Global Nursing Research Center
Director, Professor
Hiromi Sanada, R.N., P.H.N., W.O.C.N., Ph.D.

Vice Director, Professor
Kiyoko Kamibeppu, R.N., P.H.N., Ph.D.
Noriko Yamamoto-Mitani, R.N, Ph.D.

Project Assistant Professor
Hiromi Tobe, R.N., P.H.N., Ph.D.

Project Researcher
Mayumi Morisaki, R.N., P.H.N., Ph.D., Sofoklis Koudounas, Ph.D., Sameh Eltaybani, 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 withcommercial 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 new578

research 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 2020, two international joint research projects andan industry-government-academia research projects
were undertaken. In addition, 79 original English
articles were published.

Executing Innovative Research
1. International Invited Faculty
In 2020, we appointed one Project Professor: Prof.
Ardith Doorenbos: Professor in , Biobehavioral
Nursing Science, University of Illinois, Chicago, andinvited two researchers: Prof. Seonae Yeo: Professorof School of Nursing, University of North Carolina at
Chapel Hill and Prof. Carolina D. Weller: Professor,
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 2020, two PD researchers participated in thisprogram, and completed the program.
3. Other Universities’ Young Researchers
In 2020, our PD seminars and lectures were opened toyoung researchers from other universities, and by theend of the year, a total of 1953 participants attended.
Furthermore, we conducted research consultations or
technical assistance and training for two young
researchers.

Building Future Research
1. Global Nursing Research Center FundThe Global Nursing Research Center Fund wascontinued for the purpose of fostering young
researchers.

Accomplishments
1.

2.

3.

4.

Noguchi H, Oe M, Takehara K, Mori T, Sanada H.
Onsite visualization of shoe fitting for educationof the people with diabetes using 3D scanner: A
pilot study. J Nurs Sci Eng. 2020;7:162-9.
Koyano Y, Noguchi H, Sanada H. Can the use ofa human-shaped communication robot enhance
motivation for inpatient rehabilitation? J Nurs Sci
Eng. 2020;7:170-6.
Koyano Y, Nakagami G, Tamai N, Sugama J,
Sanada H. Morphological characteristics of skintears to estimate the etiology-related external
forces that cause skin tears in an elderly
population. J Nurs Sci Eng. 2020;7:68-78.
Nakagami G, Morita K, Matsui H, Yasunaga H,
Fushimi K, Sanada H. Association between
pressure injury status and hospital discharge tohome: A retrospective observational cohort study
using a national inpatient database. Ann Clin
Epidemiol. 2020;2(2):38-50.

579

5.

6.

7.

8.

9.

10.

11.

12.

13.

Oe M, Koike N, Tobe H, Ohashi Y, Kuramochi E,
Ikeda M, et al. Difficulties of self-monitoring
blood glucose in the aged with diabetes: An
analysis based on observations of self-monitoring
blood glucose. J Nurs Sci Eng. 2020;7:141-48.
Nakagami G, Schultz G, Kitamura A, Minematsu
T, Akamata K, Suga H, et al. Rapid detection of
biofilm by wound blotting following sharp
debridement of chronic pressure ulcers predicts
wound healing: a preliminary study. Int Wound J.
2020;17(1):191-6.
Kimura N, Nakagami G, Minematsu T, Sanada H.
Noninvasive detection of local tissue responses topredict pressure ulcer development in micemodel. J Tissue Viability. 2020;29(1):51-7.
Koyano Y, Nakagami G, Tamai N, Sugama J,
Sanada H. Morphological characteristics of skintears to estimate the etiology-related external
forces that cause skin tears in an elderly
population. J Nurs Sci Eng. 2020;7:68-78.
Mugita Y, Nakagami G, Minematsu T, Kitamura
A, Sanada H. Combination of urease inhibitor
and antiseptic inhibits urea decompositioninduced ammonia production by Proteus
mirabilis. Int Wound J. 2020;17(6):1558-65.
Astrada A, Nakagami G, Suriadi, Sanada H. A
successful wound treatment of a deep diabetic
foot ulcer exposing bone with Trigona honey: acase study. J Wound Care. 2020;28(12).
Kunimitsu M, Nakagami G, Kitamura A,
Minematsu T, Koudounas S, Ogai K, et al.
Temporal changes in the diversity andcomposition of the bed microbiota of patientswith pressure ulcers. J Jpn Wound Ostomy
Continence Manag. 2020;24(4):366-78.
Dai M, Minematsu T, Nakagami G, Sugama J,
Sanada H. Awareness and attitudes of lymphoedema patients toward compression stockings in
the summer: a cross-sectional questionnaire
survey. J Lymphoedema. 2020;15(1):49-53.
Matsumoto M, Yabunaka K, Yoshida M,
Nakagami G, Miura Y, Okawa Y, et al.
Improvement of constipation symptoms in anolder adult patient by defecation care based onusing a hand-held ultrasound device in home caresettings: a case report. J Wound Ostomy
Continence Nurs. 2020;47(1):75-8.

14. Matsumoto M, Yoshida M, Yabunaka K,
Nakagami G, Miura Y, Fujimaki S, et al. Safety
and efficacy of a defecation care algorithm basedon ultrasonographic bowel observation in
Japanese home-care settings: a single-case,multiple-baseline study. Geriatr Gerontol Int.
2020;20(3):187-94.
15. Tamai N, Minematsu T, Maeda T, Yabunaka K,
Sanada H. The relationship between skinultrasound images and muscle damage using skinblotting in wheelchair basketball athletes. Spinal
Cord. 2020;58(9):1022-9.
16. Yoshida M, Kagaya H, Kamakura Y, Miura Y,
Saitoh E, Okawa Y, et al. Safety and theeffectiveness of a new education program fornurses to assess swallowing function using
fiberoptic endoscopic evaluation of swallowing(FEES). Jpn J Nurs Sci. 2020;17(2):e12313.
17. Matsumoto M, Tsutaoka T, Nakagami G, Tanaka
S, Yoshida M, Miura Y, et al. Deeplearning-based classification of rectal fecal
retention and property using ultrasound images inolder adult patients. Jpn J Nurs Sci. 2020;17(4):e12340.
18. Matsumoto M, Yoshida M, Miura Y, Sato N,
Okawa Y, Yamada M, et al. Feasibility of theconstipation point-of-care ultrasound educational
program in observing fecal retention in thecolorectum: a descriptive study. Jpn J Nurs Sci.
2020;18(1):e12385.
19. Miura Y, Yabunaka K, Karube M, Tsutaoka T,
Yoshida M, Matsumoto M, et al. Establishing amethodology for ultrasound evaluation ofpharyngeal residue in the pyriform sinus andepiglottic vallecula. Respir Care. 2020;65(3):304-13.
20. Miura Y, Nakagami G, Tohara H, Ogawa N,
Sanada H. The association between jaw-opening
strength, geniohyoid muscle thickness and echo
intensity measured by ultrasound. Med Ultrason.
2020;22(3):299-304.
21. Tamai N, Kuwata M, Urai T, Ushiro T, Yamashita
Y, Minematsu T, et al. Effect of an education
program on the prevention of skin tears fornurses in a Japanese long-term care hospital: apre-post study. J Jpn Wound Ostomy ContinenceManag. 2020;24(4):379-87.

580

22. 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. 2020;8:143-50.
23. 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. Jpn J Nurs Sci. 2020;17(3):e12329.
24. Takahashi T, Murayama R, Abe-Doi M,
Miyahara-Kaneko M, Kanno C, Nakamura M, etal. Preventing peripheral intravenous catheter
failure by reducing mechanical irritation. Sci Rep.
2020;10(1):1550.
25. Kanno C, Murayama R, Abe-Doi M, Takahashi T,
Shintani Y, Nogami J, et al. Development of analgorithm using ultrasonography-assisted peripheral intravenous catheter placement for reducing
catheter failure. Drug Discov Ther. 2020;14(1):27-34.
26. Abe-Doi M, Murayama R, Tanabe H, Kamiyama
E, Komiyama C, Matsui Y, et al. Usability andfeasibility test of a new thermosensitive liquid
crystal film for the early detection of
extravasation in clinical practice: a pilot study. J
Nurs Sci Eng. 2020(7):89-98.
27. Abe-Doi M, Murayama R, Tanabe H, Komiyama
C, Sanada H. Evaluation of a thermosensitive
liquid crystal film for catheterization site
assessment immediately following chemotherapy
administration: an observational study. Eur J
Oncol Nurs. 2020;48:101802.
28. Oe M, Sasaki S, Shimura T, Takaki Y, Sanada H.
Effects of multi-layer silicone foam dressings forthe prevention of pressure ulcers in high-riskpatients: A randomized clinical trial. Adv Wound
Care. 2020;9(12):649-56.
29. Oe M, Yotsu RR, Defa A, Suriadi, Sakai Y, Imran,et al. Validity of DMIST for monitoring healingof diabetic foot ulcers. Wound Repair Regen.
2020;28(4):539-46.
30. Tsuruoka K, Oe M, Minematsu T, Tomida S,
Ohashi Y, Mori Y, et al. Skin characteristics
associated with foot callus in people withdiabetes: A cross-sectional study focused on

31.

32.

33.

34.

35.

36.

37.

38.

Desmocollin1 in corneocytes. J. Tissue Viability.
2020;29(4):291-6.
Oe M, Koike N, Tobe H, Ohashi Y, Kuramochi E,
Ikeda M, et al. Difficulties of self-monitoring
blood glucose in the aged with diabetes: An
analysis based on observations of self-monitoring
blood glucose. Jpn J Nurs Sci. 2020;7:141-8.
Ikeda M, Tamai N, Kanai H, Osaka M, Kondo K,
Yamazaki T, et al. Effects of the appearance careprogram for breast cancer patients receiving
chemotherapy: A Mixed method study. Cancer
Rep. 2020;3(3):e1242.
Nakajima S, Sato I, Soejima T, Koh K, Kato M,
Okamoto Y, et al. Comparison of child andfamily reports of health-related quality of life inpediatric acute lymphoblastic leukemia patients
after induction therapy. BMC Pediatr. 2020;20:
390.
Suetsugu Y, Haruna M, Kamibeppu K. A
longitudinal study of bonding failure related to
aspects of traumatic birth experience among
Japanese mothers. BMC PREGNANCY CHILDB.
2020;20:434.
Suzuki S*, Kita S*, Nakamura M, Kikuchi R,
Sato I, Iwasaki M, et al. Nurses’ perceptions
regarding transitional care for adolescents andyoung adults with childhood-onset chronic
diseases. Jpn J Nurs Sci. 2020;17(3):e12323. *Equally contributed
Tobe H*, Kita S*, Hayashi M, Umeshita K,
Kamibeppu K. Mediating effect of resilienceduring pregnancy on the association between
maternal trait anger and postnatal depression.
Compr Psychiatry. 2020;102:152190. * Equallycontributed
Soejima T, Sato I, Takita J, Koh K, Kaneko T,
Inada H, et al. Impacts of physical late effects onpresenteeism in childhood cancer survivors.
Pediatr Int. 2020;62(11):1241-9.
Kita S, Hayashi M, Umeshita K, Tobe H, Uehara
N, Matsunaga M, et al. Intimate partner violence
and maternal child abuse: the mediating effects ofmothers’ postnatal depression, mother-to-infantbonding failure, and hostile attributions tochildren’s behaviors. Psychol Violence. 2020;10(3):279-89.

581

39. 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. Appl Res Qual Life. 2020;
1-21.
40. Kita S, Tobe H, Umeshita K, Hayashi M,
Kamibeppu K. Impact of Intimate Partner
Violence and Childhood Maltreatment onMaternal-Infant Maltreatment: A Longitudinal
Study. Jpn J Nurs Sci. 2020;e12373.
41. Sato I, Sakka M, Soejima T, Kita S, Kamibeppu
K. Randomized comparative study of child andcaregiver responses to three software functions
added to the Japanese version of the electronic
Pediatric Quality of Life Inventory (ePedsQL)
questionnaire. J Patient Rep Outcomes. 2020;4:49.
42. Sato I, Soejima T, Ishida Y, Maeda M, Koh K,
Kamibeppu K. Simple change in logistic
procedure improves response rate to QOL
assessment: a report from the Japan Children’s
Cancer Group. J Patient Rep Outcomes. 2020;4:48.
43. Morishita-Kawahara M, Kamibeppu K. Whatcontributes to satisfaction with care for family
caregivers of terminal cancer patients admitted togeneral wards? A qualitative study. Open J Nurs.
2020;10(11):1081.
44. Morishita-Kawahara M, Kawahara T, Kamibeppu
K. Relation between Family Functioning and
Quality of Life among Family Caregivers ofPatients with Terminal Cancer Hospitalized in
General Wards. Open J Nurs. 2020;10:1233-40.
45. Nakahachi T, Ishii R, Canuet L, Sato I,
Kamibeppu K, Ueda M, et al. Frontal activation
patterns during Tetris game play and estimateddifferences between high and low performers: apreliminary functional near-infrared spectroscopy
study. J cogn rehabil. 2020;1(1):43-55.
46. Usui Y, Haruna M, Shimpuku Y. Validity andreliability of the Karitane Parenting Confidence
Scale among Japanese mothers. Nurs Health Sci.
2020;22(2):205-11.
47. Kita S, Haruna M, Matsuzaki M, Kamibeppu K.
Does Antenatal Social Support Affect theRelationships Between Intimate Partner Violence

48.

49.

50.

51.

52.

53.

54.

55.

56.

During Pregnancy And Perinatal Mental Health?
Violence Against Women. 2020;26(6-7):573-89.
Yonezawa K, Haruna M. Validity of infant faceskin assessment by parents at home. Asian Pac Isl
Nurs J. 2020;4(4):128-34.
Hikita N, Haruna M, Matsuzaki M, Sasagawa E,
Murata M, Ariunaa Y, et al. Factors Associatedwith Hypertension Among Men in Darkhan-Uul
Province, Mongolia: A Cross-Sectional Study.
Asian Pac Isl Nurs J. 2020;4(4):151-8.
Haruna M, Nishi D. Perinatal mental health and
COVID-19 in Japan. Psychiatry Clin Neurosci.
2020;74(9):502-3.
Takano A, Miyamoto Y, Shinozaki T, Matsumoto
T, Kawakami N. Effect of a web-based relapse
prevention program on abstinence among
Japanese drug users: A pilot randomized
controlled trial. J Subst Abuse Treat. 2020;111:
37-46.
Kotake R, Kanehara A, Miyamoto Y, Kumakura
Y, Sawada U, Takano A, et al. Reliability andvalidity of the Japanese version of the INSPIRE
measure of staff support for personal recovery incommunity mental health service users in Japan.
BMC Psychiatry. 2020;20(1):51.
Futami A, Noguchi-Watanabe M, Mikoshiba N,
Yamamoto-Mitani
N.
Criticalthinking
disposition among hospital nurses in Japan:
Impact of organizational versus personal factors.
Jpn J Nurs Sci. 2020;17(2):e12298.
Igarashi A, Matsumoto H, Takaoka M, Kugai H,
Suzuki M, Yamamoto-Mitani N. Educational
Program for Promoting Collaboration Between
Community Care Professionals and Convenience
Stores. J Appl Gerontol. 2020;39(7):760-9.
Eltaybani S, Igarashi A, Yamamoto-Mitani N.
Palliative and end-of-life care in Egypt: overview
and recommendations for improvement. Int J
Palliat Nurs. 2020;26(6):284-91.
Kitamura S, Igarashi A, Yamauchi Y, Senjyu H,
Horie T, Yamamoto-Mitani N. Self-management
activities of older people with chronic obstructive
pulmonary disease by types of healthcare
services utilised: A cross-sectional questionnaire
study. Int J Older People Nurs. 2020;15(3):e12316.

582

57. Sari DW, Igarashi A, Takaoka M, Yamahana R,
Noguchi-Watanabe M, Teramoto C, et al. Virtual
reality program to develop dementia-friendly
communities in Japan. Australas J Ageing. 2020;
39(3):e352-9.
58. Eltaybani S, Igarashi A, Yamamoto-Mitani N.
Assessing the Palliative and End-of-Life Care
Education-Practice-Competence
TriadinIntensive Care Units: Content Validity, Feasibility,
and Reliability of a New Tool. J Palliat Care.
2020:825859720948972.
59. Eltaybani S, Abdelwareth M, Abou-Zeid NA,
Ahmed N. Recommendations to prevent nursing
errors: Content analysis of semi-structured
interviews with intensive care unit nurses in adeveloping country. J Nurs Manag. 2020;28(3):690-8.
60. Yamamoto-Mitani N, Saito Y, Futami A, Takaoka
M, Igarashi A. Staff nurses' evaluation of care
process quality and patient outcomes inlong-term care hospitals: A cross-sectionalquestionnaire survey. Int J Older People Nurs.
2020;15(4):e12334.
61. Matsumoto H, Igarashi A, Suzuki M,
Yamamoto-Mitani N. Dementia education is thefirst step for cooperation: An observational studyof the cooperation between convenience storesand community general support centers. Geriat
Gerontol Int. 2020;20(10):956-60.
62. Numata H, Noguchi-Watanabe M, Mukasa A,
Tanaka S, Takayanagi S, Saito N, et al. Medical
Care-Related
Decisionsamong
Patients
Diagnosed with Early Stage Malignant Brain
Tumor: A Qualitative Study. Glob Qual Nurs Res.
2020;7:2333393620960059.
63. Anezaki S, Sakka M, Noguchi-Watanabe M,
Igarashi A, Inagaki A, Sumikawa Tsuno Y, et al.
Association between participation in hospital-led
community activities and sense of security incontinued community living among older adults
in a rural district of Japan: A cross-sectional study.
Health Soc Care Community. 2020. Forthcoming.
doi: 10.1111/hsc.13191
64. Igarashi A, Eltaybani S, Takaoka M, NoguchiWatanabe M, Yamamoto-Mitani N. Quality
Assurance in Long-Term Care and Development

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66.

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of Quality Indicators in Japan. Gerontol Geriatr
Med. 2020;6:2333721420975320.
Inagaki A, Noguchi-Watanabe M, Sakka M,
Yamamoto-Mitani
N.
Home-carenurses'community involvement activities and preference
regarding the place for end-of-life period among
single older adults: A cross-sectional study inJapan. Health Soc Care Community. 2020.
Forthcoming. doi: 10.1111/hsc.13224
Kibi Y, Mikoshiba N, Igarashi A, Sumitani M,
Yamamoto-Mitani N. Development of astylebook for women with cancer-related
lymphedema troubled about clothing. Lymphoedema Research and Practice. 2020; 8(1):27-39.
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. 2020; 29(4):721-30.
Takemura Y, Kunie K, Ichikawa N. The effect ofwork environment on burnout among nurse
directors: a cross sectional study. J. Nurs. Manag.
2020;28(1):157–66.
Ikeda M, Kanai H, Osaka M, Tamai N, Takemura
Y, Sanada H. Implementing appearance-care
program research for breast cancer patients into
routine clinical practice. Open J Nursing, 2020;10(3):308-319.
Saiki M, Kunie K, Takemura Y, Takehara K,
Ichikawa N. The relationship between nurses’
perceptions of nursing assistant roles andinformation-sharing behaviors: a cross-sectional
study. Nurs Health Sci. 2020;22(3):706-13.
Isobe T, Kunie K, Takemura Y, Takehara K,
Ichikawa N, Ikeda M. Frontline nurse managers’
visions for their units: A qualitative study. J Nurs
Manag. 2020;28(5):1053-61.
Komagata M, Takemura Y, Ichikawa N, Takehara
K, Kunie K. Quality of work among part-timenurses and its relationship to job satisfaction andwork values: A cross-sectional study. Nurs HealthSci. 2020;22(4):1010-21.
Ichikawa N, Yamamoto-Mitani N, Takai Y,
Tanaka M, Takemura Y. Understanding andmeasuring nurses’ professionalism: development
and validation of the Nurses’ Professionalism
Inventory. J Nurs Manag. 2020;28(7):1607-18.

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74. Honda C, Naruse T, Tsuchiyia-ito R, Yamamoto
N, Nagata S. Home safety practices to preventchild injury and its association with family andchildren’ s daily routines in Japan: a crosssectional study. Jpn J Nurs Sci.2020;17(1):e12274.
75. Kawasaki H, Yamasaki S, Rahman MM, Murata
Y, Iwasa M, Teramoto C. Teachers-parents
cooperation in disaster preparation when schools
become as evacuation centers.Int. J. Disaster Risk
Reduct. 2020; 44:101445.
76. Ishizaki T, Mitsutake S, Hamada S, Teramoto C,
Shimizu S, Akishita M, et al. Drug prescription
patterns and factors associated with polypharmacy in over one million older adults inTokyo. Geriatr Gerontol Int. 2020;20(4):304-11.
77. Naruse T, Kitano Y, Matsumoto H, Nagata S. A
logic model for evaluation and planning in an
adult day care for disabled Japanese old people.
Int J Environ Res Public Health. 2020;17(6):2061.
78. Naruse T, Anthony GT, Matsumoto H,
Yamamoto-Mitani N. Measurement development
for Japanese clients’ experiences during adult day
care service use (the J-AdaCa Tool). Healthcare.
2020;8(4):363.
79. Honda C, Yamana H, Matsui H, Nagata S,
Yasunaga H, Naruse T. Age in months and birthorder in infant nonfatal injuries: a retrospective
cohort study. Public Health Pract. 2020;1.

584

Office ofInternational Academic Affairs
HeadShinichi Sato

Assistant Professors
Keiko Nanishi
David Kipler
Florence Ene
Yosuke MatsumiyaHomepage: 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 2020-21 academic year (1 April 2020 through 31
March 2021).
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 event was cancelled becauseof 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 the cancellation of elective
clerkships scheduled in 2020-21.
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, University of Chicago, National
Taiwan University, National University of Singapore,
Karolinska Instutite and Ludwig Maximilian
University of Munich. The OIAA nominates qualified

585

students for each university and assists in their
preparation for study abroad.
Although students were nominated for electives
scheduled for April through July 2021, the pandemic
caused the host institutions to cancel these electives.
Arrangements to send three students to Harvard
University from April to July 2021 for one to twomonths of research were also cancelled.
1.3 Support for overseas training of graduates
The OIAA assists
graduatesin
preparing
documents for applications to graduate schools andother institutions abroad and in obtaining medical
licensure in other countries. During 2020-21, the
OIAA assisted in preparing Medical Student
Performance Evaluations for two applicants.

2.

3.

4.
2. International Academic and Research
Agreements
During the 2020-21 academic year, a newinterdepartmental agreement for the exchange of
medical students was signed with Karolinska
Institute, and the interdepartmental agreement with
the University of Munich was renewed.
3. Education and Research Activities
Dr. Yosuke Matsumiya and Dr. Florence Enesupervised 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 taught "Basic tools forPopulation/Public Health Research" and served as alecturer in the School of International Health, where
she supervised graduate students and conducted
research on international health.

Publications
1.

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

5.

health in Ghana: The RE-AIM framework-based
evaluation. J Glob Health. 2021 Mar 27;11:04017.
Binns C, Lee MK, Yun Low W, Baker P, Bulgiba
A, Dahlui M, Thuy Duong DT, Guldan G, Hairi
N, Hokama T, Kagawa M, Karunathilake I, Abdul
Majid H, Maycock B, Nanishi K, Qiu L, Raheem
RA, Scott J, Tang L. Guidelines forComplementary Feeding of Infants in the Asia
Pacific Region: APACPH Public Health
Nutrition Group. Asia Pac J Public Health. 2020
May;32(4):179-187.
Hongo H, Green J, Shibanuma A, Nanishi K,
Jimba M. The Influence of Breastfeeding Peer
Support on Breastfeeding Satisfaction AmongJapanese Mothers: A Randomized Controlled
Trial. J Hum Lact. 2020 May;36(2):337-347.
Nanishi K, Seo T, Hongo H, Tokoro K, Nakamura
K, Kato I, Wada Y, Tanaka N, Oku K. Calling for
Evidence-Based Intimate Support of Mother-toChild Dyad by the Japanese Association of
Lactation Consultants in Response to the
National Infant and Young Child Feeding
Guideline for Health Professionals Revised in
March 2019. Journal of Ambulatory and General
Pediatrics. 2020; 23(1):2-12.
Kipler D, Kageyama I. Cleft Lip. In: Kageyama
I, Hamura A, eds. Comprehensive Medical
English for Dentistry. Gakken Shoin; 2020:27-40.

586

MD Scientist Training Program
Professor and Director
Haruhiko Bito, M.D., Ph.D.
Lecturer
Yuki Sugaya, M.D., Ph.D.

Assistant Professor
Kei Takahashi, 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) and Prof. Masahide
Kikkawa (2011-2014), the Program currently consistsof its director Prof. Haruhiko Bito and 2 staff
members, Yuki Sugaya (lecturer) and Kei Takahashi(assistant professor), and over 100 students who areseeking extracurricular basic medical research training
through the 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, and has received governmental
funding support to dramatically boost its activities.
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,
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.

587

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.
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 2020, thepandemic of COVID-19 prevented students fromdoing research abroad. Instead, 7 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.
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.

2) Organizing an MD scientist training program
retreat
A MDSTP online retreat was held on February, 13,2021 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-affiliatedprofessors attended it. Lively discussions among peers
were exciting throughout the meeting and thefeedback from all participants was outstanding andunequivocal in emphasizing the critical importance fora research progress retreat to promote their future
research projects. One important aspect of the retreat
was to provide students, interns and professors to
discuss opportunities in various career paths available
in the basic medical research field.
3) Cooperating with other medical universities acrossJapan
With the availability of governmental support from2011 on, 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 inimproving the basic medical research training at the 4
medical schools, joint retreats were held to promote
communication and networking among the medical
students with research minds. The previous retreat washeld in Nagoya in 2019, at the occasion of the Japan
Medical Congress. More than 90 people including
medical school students and teachers from all overJapan participated in this retreat and enthusiastically
discussed about their research and future career as
researchers. Four celebrated MD scientists presented
their research achievements and carrier path in a joint
forum of this meeting.
The MSDTP also currently cooperates with 10 otheruniversities in eastern Japan to organize annual
research students’ retreats. However, in 2020, annual
summer retreats was canceled due to the pandemic of
COVID-19.

Activities (2020)
The number of registered students: 116 (3rd and 4th
grade: 64, 5th and 6th: 35)

588

Lectures for students in Years 1 and 2
Introduction to Medical Biology: 13 lectures
Group reading of Molecular Biology of the Cell: 12
lectures
Seminar for students (in Year 3 or above)
Journal Club for basic medical research: 6 lectures
Medical Research Communications: 69 lectures
Presentation of research progress: 1 times at the online
retreat of MD scientist training program in the
University of Tokyo
The number of students receiving travel supports forresearch : 7 (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: 7 (the Dean’s Prize and theSatoshi Arima memorial fellowship were awarded to 2
and 1 student, respectively)589

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.

590

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.

591

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,・ Preperation 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 2020
・Research Ethics Committee (except for clinical
trial, GCP):
399 new applications, 1047 minor alterations ofapproved studies
・Clinical Research Review Board:111
・New clinical documentary examinations: 102

592

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 2020 with 3359 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.

593

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.

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Research activities
Presently the “Research of the coherence between thestudents’ daily life and the outcome at the graduation”
is being conducted. The results-in-progress werereleased in the domestic and international conferencesof medical education in 2018 and 2019, being followedin 2020. This research is also developing into multiple
institutional investigation.