ISSN 1883-9606

2023

Vol.147

ANNUAL REPORT OF
THE GRADUATE SCHOOL OF MEDICINEAND
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2022 ---- March 2023

ANNUAL REPORT OF THE GRADUATE SCHOOL OF
MEDICINE
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2022-March 2023

Introduction
This is volume 147(the edition of year 2023) 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.

Masaomi Nangaku, Dean
Graduate School of Medicine and Faculty of Medicine
The University of Tokyo
October, 2023

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

10

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

11

Department of Genome Informatics ···········································································

15

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

18

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

22

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

25

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

26

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

28

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

32

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

34

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

35

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

37

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

41

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

42

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

46

ii

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

49

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

50

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

54

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

59

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

60

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

65

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

66

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

69

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

70

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

75

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

77

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

80

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

84

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

85

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

89

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

95

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

96

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

98

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

99

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

103

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

111

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

120

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

121

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

125

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

130

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

131

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

135

iii

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

138

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

139

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

143

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

148

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

153

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

154

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

159

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

166

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

171

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

175

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

181

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

184

Department of Clinical Laboratory Medicine (See Department of Clinical Laboratory [P.502] )Department of Transfusion Medicine ·········································································

185

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

188

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

189

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

192

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

195

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

197

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

199

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

200

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

205

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

209

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

210

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

217

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

218

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

222

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

227

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

231

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

234

iv

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

241

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

246

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

249

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

252

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

253

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

256

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

259

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

264

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

273

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

277

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

284

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

287

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

288

Department of Emergency and Critical Care Medicine ······················································

292

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

295

Department of Health Sociology(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.373] )Department of Mental Health ··················································································

296

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

300

Department of Social Gerontology(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.373] )Department of Biomedical Ethics & Department of Health Promotion Sciences ·······················

303

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

307

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

308

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

311

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

314

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

316

Department of Gerontological Home Care and Long-term Care Nursing/Palliative Care Nursing ···317

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

321

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

325

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

330

v

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

336

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

337

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

340

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

343

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

344

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

345

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

348

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

352

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

355

Department of Biostatistics(See Department of Biostatistics / Epidemiology and Preventive Health Sciences [P.300] )Department of Social and Preventive Epidemiology ························································

356

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

359

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

369

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

372

Department of Mental Health (See Department of Mental Health [P.296] )Department of Health Sociology and Health Education(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.373] )Departments of Health and Social Behavior & Health Education and Health Sociology ···············

373

Department of Biomedical Ethics & Department of Health Promotion Sciences(See Department of Biomedical Ethics & Department of Health Promotion Sciences [P.303] )3. Health Services Sciences ·························································································

378

Department of Health Policy(See Department of Public Health / Department of Health Policy [P.125] )Department of Healthcare Informatics (See Department of Biomedical Informatics [P.135] )Department of Clinical Information Engineering ····························································

379

Department of Forensic Medicine and Medical Law(See Department of Forensic Medicine [P.131] )Department of Global Environmental Health ································································

381

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

383

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

384

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

387

vi

Science for joint reconstruction (See Department of Orthopaedic Surgery [P.264] )Department of Bone & Cartilage Regenerative Medicine(See Central Clinical Facilities Division of Tissue Engineering [P.563] )Department of Osteoimmunology ··············································································

391

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

395

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

398

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

400

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

402

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

406

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

409

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

414

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

416

Comprehensive Radiation Oncology ···········································································

418

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

421

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

424

Department of Eat-loss Medicine(See Central Clinical Facilities Division of Tissue Engineering [P.563] )Department of Medical Information Engineering ·····························································

425

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

427

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

430

Laboratory for cryo-electron microscopy ······································································

433

Department of Cellular and Tissue Communication ··························································

435

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

438

Department of Next-generation Endoscopic Computer Vision··············································

440

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

442

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

445

Department of Digital Mental Health ···········································································

447

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

450

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

453

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

456

Department of Precision Medicine Nurology··································································

460

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

464

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

470

Department of Functional Genomics and Immunological Diseases(See Department of Allergy and Rheumatology [P.171] )Department of Retinal Biology and Pathology ·······························································

473

Department of Real-world Evidence ···········································································

476

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

478

vii

Clinical stem cell biology(See Central Clinical Facilities Division of Tissue Engineering [P.563] )Department of Preventive Medicine for Locomotive Organ Disorders ··································

481

University Hospital
Clinical Services ······································································································
Internal Medicine
Cardiovascular Medicine (See Department of Cardiovascular Medicine [P.139] )Respiratory Medicine (See Department of Respiratory Medicine [P.143] )Gastroenterology (See Department of Gastroenterology [P.148] )Nephrology and Endocrinology (See Department of Nephrology and Endocrinology [P.154] )Diabetes and Metabolic Diseases (See Department of Diabetes and Metabolic Diseases [P.159] )Hematology and Oncology (See Department of Hematology and Oncology [P.166] )Allergy and Rheumatology (See Department of Allergy and Rheumatology [P. 171] )Infectious Diseases (See Department of Infectious Diseases (Internal Medicine) [P.175] )Neurology (See Department of Neurology [P.103] )Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research [P.210] )Psychosomatic Medicine(See Department of Stress Science and Psychosomatic Medicine [P.181] )Surgery
Stomach and Esophageal Surgery (See Department of Gastrointestinal Surgery [P.227] )Colon and Rectal Surgery (See Department of Surgical Oncology [P.241] )Hepatobiliary Pancreatic Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation
Division [P.231] )Vascular Surgery (See Department of Vascular Surgery [P.246] )Breast and Endocrine Surgery(See Department of Metabolic Care and Endocrine Surgery [P.249] )Artificial Organ and Transplantation Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation
Division [P.231] )Cardiovascular Surgery (See Department of Cardiac Surgery [P.222] )Thoracic Surgery (See Department of Thoracic Surgery [P.218] )Neurosurgery (See Department of Neurosurgery [P.111] )Anesthesiology and Pain Relief Center (See Department of Anesthesiology [P.288] )Urology and Andrology (See Department of Urology [P.234] )

484

viii

Gynecologic Surgery (See Obstetrics and Gynecology [P.188] )Sensory and Motor System Medicine
Dermatology (See Department of Dermatology [P.253] )Ophthalmology (See Department of Ophthalmology [P.273] )Orthopaedic Surgery and Spinal Surgery (See Department of Orthopaedic Surgery [P.264] )Otorhinolaryngology and Head and Neck Surgery(See Department of Otorhinolaryngology and Head & Neck Surgery [P.277] )Rehabilitation Medicine (See Department of Rehabilitation Medicine [P.284] )Plastic, Reconstructive and Aesthetic Surgery(See Department of Plastic and Reconstructive Surgery [P.256] )Oral-Maxillofacial Surgery and Orhtodontics(See Department of Oral-Maxillofacial Surgery [P.259] )Pediatrics, Perinatal and Women’s Medicine
Pediatrics(See Department of Pediatrics, Department of Developmental Pediatrics [P.200] )Pediatrics Surgery (See Department of Pediatric Surgery [P.205] )Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of Gynecologic Oncology /Department of Perinatal Medicine [P.189/P.192/P.195] )Neuropsychiatry
Neuropsychiatry (See Department of Neuropsychiatry [P.99] )Radiology
Radiology (See Department of Radiology [P.66] )Emergency and Critical Care Medicine
Emergency and Critical Care Medicine(See Department of Emergency and Critical Care Medicine [P.292] )Cross-Sectional Services
Advanced Medical Center for Heart Failure ·································································

485

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

488

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

490

Children, AYA and Family Centered Mental Care Center(See Department of Child Psychiatry [P.490] )Department of Pain and Palliative Medicine ·································································

493

Central Clinical Services ····························································································

497

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

498

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

502

Department of Blood Transfusion(See Department of Transfusion Medicine [P.185] )ix

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

507

Department of Infection Control and Prevention(See Department of Infection Control and Prevention [P.54] )Radiology Center ·································································································

511

Rehabilitation Center ····························································································

514

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

517

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

520

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

522

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

525

Department of Intensive Care Unit
(See Department of Emergency and Critical Care Medicine [P.292] )Immune-Mediated Diseases Therapy Center ·································································

528

Tissue Bank·········································································································

530

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

532

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

535

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

538

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

544

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

546

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

547

Palliative Care Consultation Team (See Department of Pain and Palliative Medicine [P.493] )Medical Community Network and Discharge Supporting Center ·········································

551

Cancer Resource Center ·························································································

553

Clinical Research Services
Clinical Research Promotion Center ··········································································

555

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

563

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

567

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

572

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

576

Hospital Management Services
Department of Clinical Research Governance ·······························································

578

Department of Healthcare Information Management ·······················································

580

University Hospital Medical Information Network Center ················································

582

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

585

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

587

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

588

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

590

x

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

592

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

594

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

599

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

604

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

607

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

610

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

613

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

614

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

616

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

618

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

621

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

623

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

625

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

628

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

630

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

632

Advisory Office for Conflict of Interest ············································································

634

The Tokyo Journal of Medical Sciences. Vol. 147, October 2023

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. 147, October 2023

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. 147, October 2023

2000

Apr.

xiii

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

2001

Apr.

The University Branch Hospital was united with the University Hospital.

2002

Mar.

Nursing School and Midwives School was Closed.

2002

Mar.

Experimental Building (First Stage) was constructed.

2003

Apr.

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

2004

Apr.

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

2005

Mar.

Experimental Building (Second Stage) was constructed.

2007

Apr.

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

2008

May

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

2010

Apr.

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

2011

Jan.

The Museum of Health and Medicine was established.

2012

Apr.

The Office for research Ethics Support was established.

2013

Apr.

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

2013

Oct.

The Life Sciences Core facility was established.

2015

Apr.

The Office for Clinical Practice and Medical Education was established.

2016

Apr.

The Advisory office for Conflicts of interest was established.

2017

Apr.

The Global Nursing Research Center was established.

2017

Apr.

The Institute for Life Science Research and Education was established.

2017

Apr.

The Research Institute for Biomedical Science and Engineering was established.

2019

May

The Bioethics Collaborative Research Organization was established.

2020

Apr.

The Collaborative Research Organization for Structural Life Sciences was established.

2021

Apr.

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

xiv

The Tokyo Journal of Medical Sciences. Vol. 147, October 2023

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

Tumor Pathology
Molecular Oncology
Diagnoatic Radiology

Radiology

Radiotherapy
Nuclear Medicine

Radiology and Biomedical
Engineering

System Physiology
Biomedical Engineering

Chemical Biology and Molecular Imaging
Biosystem Construction and Control
Neuropathology

Basic Neuroscience

Neurochemistry
Neurobiology
Developmental Neuroscience

Neuroscience

Integrativ Medical
Neurosciences

Cognitive Neuroscience
Systems Medical Neuroscience
Child Neuropsychiatry
Neuropsychiatry

Clinical Neuroscience

Neurology
Neurosurgery

Collaborative Department

Biomedical Neural Dynamics

The Tokyo Journal of Medical Sciences. Vol. 147, October 2023

Preventive Medicine
Occupational, Environmental
andPublic 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

Hematology and Oncology
Medicine II

Allergy and Rheumatology
Infectious Diseases
Stress Sciences and Psychosomatic
Medicine

Clinical Laboratory Medicine
and Pathology
Collaborative Department

Clinical Laboratory Medicine
Transfusion 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

Collaborative Department

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

Surgery

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

Surgical Sciences

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

Orthopaedic Surgery
Ophthalmology

xv

xvi

The Tokyo Journal of Medical Sciences. Vol. 147, October 2023
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 Schoolof 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)

Developmental Medical Sciences
Human Ecology
Biomedical Chemistry
Biostatistics

Epidemiology and Health
Sciences

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

School of Public HealthBehavioral Health Sciences

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

Health Services Sciences

Clinical Information Engineering
Forensic Medicine and Medical Law
Global Environmental Health

Collaborative Department

Public Health Science

Laboratory of Molecular Biomedicine for Pathogenesis
Laboratory of Structural Physiology
Laboratory of Biomedical Equipment and Biomaterial
Center for Disease Biology andIntegrative medicine

Laboratory of Clinical Biotechnology
Laboratory of Environmental Health Sciences

The Tokyo Journal of Medical Sciences. Vol. 147, October 2023

xvii

Laboratory of Animal Resources

International Research Center for
Medical Education
Global Nursing Research Center

Laboratory of Molecular Radiology

Section of Animal Research

Division of Research Resources and Support

Section of Radiation Biology

Department of Medical Education Studies

Section of Bioinformatics

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

Institution

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

Endowed Department

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

Social Cooperation Program

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

General Affairs Office

Skincare Science

Personnel Office

Imaging Nursing Science

Finance Office

Department of Healthcare Quality
Assessment
Department of Innovative Dementia
Prevention
Department of Functional Genomics and
Immunological Diseases

Contract Office
External Fund Management Office
Accounting OfficexviiiThe Tokyo Journal of Medical Sciences. Vol. 147, October 2023

Department of Prevention of Diabetes andLife-style Related Disease

Faculty of
Medicine
Graduate Schoolof Medicine

Facilities Office
Research Support Office

Department of Next-Generation
Pathology Information Networking

Educational Affairs

Chronic kidney disease pathophysiology

Graduate Student Affairs
Acquisition Office Medical Library

Administrative office

Cataloging Office Medical Library

Administrative Division

Information Service Medical LibraryCenter for Disease Biology
and Integrative medicine

Administrative Office

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

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

School of Integrated
Health Sciences

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

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

The Tokyo Journal of Medical Sciences. Vol. 147, October 2023

xix

Infectious Diseases
Neurology
Geriatric Medicine
Clinical Services

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

University
Hospital

Vascular Surgery
Breast and Endocrine Surgery
Surgery

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

Sensory and Motor System
Medicine

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

Pediatrics, Perinatal and
Women's Medicine

Pediatric Surgery
Obstetrics and Gynecology

Neuropsychiatry

NeuropsychiatryRadiology

Radiology

Emergency and Critical Care
Medicine

Emergency and Critical Care Medicine
Advanced Medical Center for Heart Failure
Marfan Syndrome Center
Epilepsy Center
Dementia Center
Scleroderma Center
Lupus Center

Cross-Sectional Services

Osteoporosis Center
Center for Female Pelvic Medicine andReconstructive Surgery
Spine Center
Department of Clinical Genomics
Department of Child PsychiatryChildren, AYA and Family Centered Mental Care
Center
Department of Pain and Palliative Medicine

Department of Pharmacy
Nursing Department
Department of Clinical Laboratory
Department of Blood Transfusion

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The Tokyo Journal of Medical Sciences. Vol. 147, October 2023

Department of Pathology
Central Clinical Services

Department of Infection Control and Prevention
Radiology Center
Rehabilitation Center
Surgical Center
Central Supply Service
Department of Medical Engineering
Department of Endoscopy and Endoscopic Surgery
Department of Hemodialysis and Apheresis
Critical Care and Emergency Medical Center/ER
Department of Intensive Care Unit
Department of Pediatric and Neonatal Intensive Care Unit
Perinatal Center
Children's Medical Center
Department of Outpatient Chemotherapy Unit
Cancer Center
Immune-Mediated Diseases Therapy Center
Organ Transplantation Center
Tissue Bank
Department of Corneal Transplantation
Department of Cell Therapy and Transplantation Medicine
Admission and Discharge Center
Perioperative Assessment and Care Center
Clinical Nutrition Center
Swallowing Center
International Medical Center
Center for Epidemiology and Preventive Medicine
Center for International Preventive Medicine
Cancer Board
Vascular Board
Hip Fracture Board
Palliative Care Consulation Team
Nutrition Support Team
Medical Community Network and Discharge
Supporting Center
Office of Patient Support

Cancer Resource Center
Patient Relations and Clinical Ethics Center

Clinical Research Promotion Center
22nd Century Medical and Research Center
Department of Tissue Engineering
Clinical Research Services

Cooperative Unit of Medicine and Engineering Research
Translational Research Center
Genomic Research Support Center
Unit for Early and Exploratory Clinical Development
BioResource Center
Center for Brain Imaging in Health and Diseases

The Tokyo Journal of Medical Sciences. Vol. 147, October 2023

xxi

Medical Safety Management Center
Infection Control Center
Office of Performance
Monitoring and Risk

Office of Performance Monitoring

Office of Education andProfessional Development

Clinical Simulation Center

Department of Highly Advanced Novel Medical
Technologies Evaluation
Department of Unapproved New Drugs and Medical
Devices Evaluation
Professional Development Center

Hospitality Center
Office of Research Support

Department of Clinical Research Governance

Department of Healthcare Information Management
Department of Medical Record Management
Hospital Management Services

University Hospital Medical Information Network Center
Datebase Center of the National University Hospitals
Labor Safety and Health Management Office
Staff Wellness Consulting Office
Office of Medical Clerical Support for Physicians
Medical Devices Management Center
Department of Disaster Medical Management
Legal and Compliance Office
Center for Liaison and Public Relations
General Affairs Division
Human Resources and Labor Management Division
Accounting, Procurement and Facility Management
Division
Administration Department

Financial Strategy Management Division
Research Finance Operations Division
Hospital and Patient Services Management Division
Medical Accounting Division

Office of Personnel and Human Resources
Office of Performance Monitoring and Risk Magamenet
Hospital Management Support
Organization

Office of Education and Staff Development
Office of Hospital Planning and Management
Office of Research Support
Office of Inpatient Services

Clinical Management
Organization

Office of Outpatient Services
Office of Central Clinical Services
Office of Patient Support

xxii

The Tokyo Journal of Medical Sciences. Vol. 147, October 2023

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

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

Masahiro Umezaki

Director, Medical Library

Hideo Yasunaga

Director General, University Hospital

Yasuyuki Seto

Director, Center for Disease Biology and Integrative Medicine

Masanobu Kano

Director, International Research Center for Medical Education

Tatsuya Yamasoba

Director, Global Nursing Research Center

Noriko Yamamoto

Director,Center for Diversity in Medical Education and Research

Kiyoto Kasai

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

Yukinori Okada

Professor

Hiroki Kurihara

Professor

Radostin Stoyanov
Danev

Functional Biology
Department of Physiology

Department of Pharmacology

Professor

Kenichi Ohki

Professor

Masanori Matsuzaki

Professor

Masanobu Kano

Professor

Kenzo Hirose

Professor

Hiroki Ueda

Professor

Tetsuo Ushiku

Professor

Yasuhiro Yamada

Professor

Makoto Takeda

Professor

Takeya Tsutsumi

Professor

Hiroshi Takayanagi

Professor

Osamu Abe

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

The Tokyo Journal of Medical Sciences. Vol. 147, October 2023

Department of Biomedical Engineering

xxiii

Professor

Kiyoshi Miyagawa

Professor

Yasuteru Urano

Professor

Katsutoshi Oda

Professor

Takeshi Iwatsubo

Professor

Haruhiko Bito

Professor

Kiyoto Kasai

Professor

Tatsushi Toda

Professor

Nobuhito Saito

Department of Occupational, Environmental and Preventive

Professor

Shumpei Ishikawa

Medicine

Professor

Takahiro Higashi

Department of Forensic Medicine, and Medical Informatics

Professor

Hirotaro Iwase

and Economics

Professor

Kazuhiko Ohe

Professor

Issei Komuro

Professor

Takahide Nagase

Professor

Mitsuhiro Fujishiro

Professor

Masaomi Nangaku

Professor

Toshimasa Yamauchi

Professor

Mineo Kurokawa

Professor

Keishi Fujio

Professor

Takeya Tsutsumi

Professor

Yutaka Yatomi

Professor

Hitoshi Okazaki

Department of Obstetrics and Gynecology

Professor

Yutaka Osuga

Department of Pediatric Sciences

Professor

Motohiro Kato

Professor

Jun Fujishiro

Professor

Masahiro Akishita

Professor

Jun Nakajima

Professor

Minoru Ono

Professor

Yasuyuki Seto

Professor

Kiyoshi Hasegawa

Professor

Haruki Kume

Professor

Soichiro Ishihara

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

Social Medicine

Internal Medicine
Department of Medicine I

Department of Medicine II

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

Department of Aging Sciences
Surgical Sciences
Department of Surgery

xxiv

The Tokyo Journal of Medical Sciences. Vol. 147, October 2023

Department of Sensory and Motor System Medicine

Professor

Shinichi Sato

Professor

Mutsumi Okazaki

Professor

Kazuto Hoshi

Professor

Sakae Tanaka

Professor

Makoto Aihara

Professor

Tatsuya Yamasoba

Professor

Toru Ogata

Professor

Kanji Uchida

Professor

Kento Doi

Professor

Daisuke Nishi

Professor

Yutaka Matsuyama

Professor

Hideki Hashimoto

Professor

Akira Akabayashi

Department of Preventive and Administrative Nursing

Professor

Mari Ikeda

Department of Clinical Nursing

Professor

Noriko Yamamoto

Professor

Megumi Haruna

Professor

Daisuke Nishi

Professor

Gojiro Nakagami

Professor

Masahiro Hashizume

Professor

Masamine Jimba

Professor

Akihiro Fujimoto

Professor

Moi Meng Ling

Professor

Masahiro Umezaki

Professor

Tomoyoshi Nozaki

Professor

Yutaka Matsuyama

Professor

Satoshi Sasaki

Professor

Hideo Yasunaga

Professor

Takahiro Kiuchi

Professor

Daisuke Nishi

Professor

Hideki Hashimoto

Professor

Akira Akabayashi

Professor

Kazuhiko Ohe

Professor

Hiroshi Oyama

Professor

Hirotaro Iwase

Department of Vital Care Medicine
Health Sciences and Nursing
Department of Health Sciences

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

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

The Tokyo Journal of Medical Sciences. Vol. 147, October 2023

xxv

Laboratory of Structural Physiology
Laboratory of Biomedical Equipment and Biomaterials

Professor

Taichi Ito

Laboratory of Clinical Biotechnology

Professor

Ungil Chung

Laboratory of Microenvironmental and Metabolic Health Sciences Professor

Makoto MurakamiLaboratory of Animal Resources

Professor

Atsu Aiba

Laboratory of Molecular Radiology

Professor

Kiyoshi Miyagawa

Professor

Masato Eto

Center for Diversity in Medical Education and Research

Associate Professor

Yoshihiro Satomura

Medical LibraryProfessor

Hideo Yasunaga

International Academic Affairs

Professor

Shinichi Sato

Medical Scientist Training Program

Professor

Kenzo Hirose

Museum of Health and Medicine

Professor

Kazuhiko Ohe

Office for Human Research Studies

Professor

Masaomi Nangaku

Life Sciences Core Facility

Associate Professor

Yoshihiro Kita

Office for Clinical Practice and Medical Education

Professor

Masato Eto

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

Promotion of CPC Education and General Integrative Medicine Lecturer

Masako Ikemura

Endowed Departments
Artificial Intelligence in Healthcare

Project Associate professor

Yoshimasa Kawazoe

Department of Bone & Cartilage Regenerative Medicine

Project Associate professor

Yasunori Omata

Department of Immunotherapeutics

Project Professor

Kazuhiro Kakimi

Department of Advanced Clinical Science andProject Associate professor

Mutsuo Harada

Project Professor

Naoto Hayashi

Science for Joint Reconstruction

Project professor

Toru Moro

Therapeutic Strategy for Heart Failure

Project Associate professor

Eisuke Amiya

Department of Advanced Translational Research andProject Associate professor

Yuichi Ikeda

Project Associate professor

Hiroyuki Oka

Department of Osteoimmunology

Project Associate professor

Kazuo Okamoto

Department of Biostatistics and Bioinformatics

Project Professor

Daisuke Koide

Laboratory for Advanced Research on Pathophysiology

Project Associate Professor

Miki Iwabu

Department of Home Care Medicine

Project Associate Professor

Takashi Yamanaka

Department of Advanced Cardiology

Project Associate Professor

Katsuhito Fujiu

Research on Cell Therapy of Regenerative Medicine

Project Associate Professor

Dehua Chang

Therapeutics
Computational Diagnostic Radiology and Preventive
Medicine

Medicine in Management of Pulmonary Hypertension
Medical research and Management for Musculoskeletal
painof Metabolic Diseases

xxvi

The Tokyo Journal of Medical Sciences. Vol. 147, October 2023

Comprehensive radiation oncology

Project Professor

Keiichi Nakagawa

Department of Lipidomics

Project Professor

Yoshiya Oda

Department of Health Services Research

Project Associate professor

Taisuke Jo

Healthcare Quality Assessment

Project Professor

Hiroaki Miyata

Department of Innovative Dementia Prevention

Project Associate professor

Tomoko Wakabayashi

Department of Next-Generation Pathology Information

Project Professor

Takeshi Sasaki

Project Associate professor

Satoko Yamaguchi

Chronic Kidney Disease Pathophysiology

Project Professor

Reiko Inagi

Department of Functional Genomics andProject Associate professor

Tomohisa Okamura

Tissue stem cell / life dentistry

Project Professor

Makoto Komura

Department of Next Generation Locomotive Imaging

Project Associate professor

Toru Doi

Department of Eat-loss Medicine

Project Associate professor

Kazumichi Yonenaga

Department of Preventive Medicine for Locomotive

Project Professor

Noriko Yoshimura

Project Associate professor

Hidenori Kage

Department of Pain & Palliative Medical Sciences

Project Associate professor

Maiko Hasegawa

Department of Retinal Biology and Pathology

Project Professor

Sumiko Watanabe

Medical information engineering

Project Associate professor

Taichi Kin

Laboratory for cryo-electron microscopy

Project Associate professor

Chieko Saito

Department of Digital Mental Health

Project Professor

Norito Kawakami

Department of Cellular and Tissue Communication

Project Professor

Jun Yamashita

Clinical stem cell biology

Project Professor

Atsuhiko Hikita

Department of Precision Medicine Nurology

Project Associate professor

Jun Mitsui

Department of Real-world Evidence

Project Associate professor

Yusuke Sasabuchi

Next-generation Endoscopic Computer Vision

Project Associate professor

Yosuke Tsuji

Department of Healthcare economics and Health policy

Project Professor

Tomoyuki Takura

Social Cooperation Program

Networking
Department of Prevention of Diabetes andLifestyle-Related Diseases

Immunological Diseases

SystemOrgan Disorders
Next-Generation Precision Medicine Development
Laboratory

The Tokyo Journal of Medical Sciences. Vol. 147, October 2023

xxvii

University Hospital
Clinical Services･Department of Internal Medicine
General Internal Medicine

Head

Masahiro Akishita

Cardiovascular Medicine

Head

Issei Komuro

Respiratory Medicine

Head

Takahide Nagase

Gastroenterology

Head

Mitsuhiro Fujishiro

Nephrology and Endocrinology

Head

Masaomi Nangaku

Diabetes and Metabolic Medicine

Head

Toshimasa Yamauchi

Hematology and Oncology

Head

Mineo Kurokawa

Allergy and Rheumatology

Head

Keishi Fujio

Infectious Diseases

Head

Takeya Tsutsumi

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

Hepato-Biliary-Pancreatic Surgery

HeadKiyoshi Hasegawa

Vascular Surgery

HeadSoichiro Ishihara

Breast and Endocrine Surgery

Head

Masahiko Tanabe

Artificial Organ and Transplantation Surgery

HeadKiyoshi Hasegawa

Cardiovascular Surgery

HeadMinoru Ono

Thoracic Surgery

Head

Jun Nakajima

Neurosurgery

Head

Nobuhito Saito

Anesthesiology and Pain Relief Center

Head

Kanji Uchida

Urology and Andrology

Head

Haruki Kume

Gynecologic Surgery

Head

Yutaka Ohsuga

Dermatology

HeadShinichi Sato

Ophthalmology

Head

Makoto Aihara

Orthopaedic Surgery and Spinal Surgery

Head

Sakae Tanaka

Otorhinolaryngology and Head and Neck Surgery

Head

Tatsuya Yamasoba

Rehabilitation Medicine

Head

Toru Ogata

Plastic, Reconstructive and Aesthetic Surgery

Head

Mutsumi Okazaki

Oral-Maxillofacial Surgery and Orthodontics

Head

Kazuto Hoshi･Department of Surgery･Department of Sensory and Motor System Medicine

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The Tokyo Journal of Medical Sciences. Vol. 147, October 2023

･Department of Pediatrics, Perinatal and Women's Medicine
Pediatrics

Head

Motohiro Kato

Pediatric Surgery

Head

Jun Fujishiro

Obstetrics and Gynecology

Head

Yutaka Ohsuga

Head

Kiyoto Kasai

Head

Osamu Abe

Head

Kento Doi

Advanced Medical Center for Heart Failure

Head

Masaru Hatano

Marfan Syndrome Center

Head

Norifumi Takeda

Epilepsy Center

Head

Naoto Kunii

Dementia Center

Head

Tatsushi Toda

Scleroderma Center

Head

Hayakazu Sumida

Lupus Center

Head

Keishi Fujio

Osteoporosis Center

Head

Taku Saito

Center for Female Pelvic Medicine and Reconstructive Surgery

Head

Yutaka Osuga

Spine Center

Head

Yasushi Oshima

Department of Clinical Genomics

Head

Katsutoshi Oda

Department of Child Psychiatry

Head

Yukiko Kano

Children, AYA and Family Centered Mental Care Center

Head

Yukiko Kano

Department of Pain and Palliative Medicine

Head

Masahiko Sumitani

Pharmaceutical Department

Head

Tappei Takada

Department of Clinical Laboratory

Head

Yutaka Yatomi

Department of Blood Transfusion

Head

Hitoshi Okazaki

Department of Pathology

Head

Tetsuo Ushiku

Department of Infection Control and Prevention

Head

Takeya Tsutsumi

Radiology Center

Head

Osamu Abe

Rehabilitation Center

Head

Toru Ogata

Surgical Center

Head

Kazuhiko Fukatsu

Central Supply Service

Head

Kazuhiko Fukatsu

Department of Medical Engineering

Head

Kento Doi

Department of Endoscopy and Endoscopic Surgery

Head

Yosuke Nakai

Department of Hemodialysis and Apheresis

Head

Masaomi Nangaku

Critical Care and Emergency Medical Center/ER

Head

Kento Doi･Department of Neuropsychiatry
Neuropsychiatry･Department of Radiology
Radiology･Department of Emergency and Critical Care Medicine
Emergency and Critical Care Medicine･Department of Cross-Sectional Services

Central Clinical Services

The Tokyo Journal of Medical Sciences. Vol. 147, October 2023

xxix

Department of Intensive Care Unit

Head

Kento Doi

Department of Pediatric and Neonatal Intensive Care Unit

Head

Naoto Takahashi

Perinatal Center

Head

Yutaka Osuga

Children's Medical Center

Head

Motohiro Kato

Department of Outpatient Chemotherapy Unit

Head

Kiyoshi Miyagawa

Immune-Mediated Diseases Therapy Center

Head

Hiroko Kanda

Organ Transplantation Center

Head

Jun Nakajima

Tissue Bank

Head

Sumihito Tamura

Department of Corneal Transplantation

Head

Takashi Miyai

Department of Cell Therapy and Transplantation Medicine

Head

Mineo Kurokawa

Admission and Discharge Center

Head

Keita Okada

Perioperative Assessment and Care Center

Head

Kanji Uchida

Clinical Nutrition Center

Head

Kazuhiko Fukatsu

Swallowing Center

Head

Rumi Ueha

International Medical Center

Head

Sumihito Tamura

Center for Epidemiology and Preventive Medicine

Head

Nobutake Yamamichi

Center for International Preventive Medicine

Head

Yoko Iizuka

Cancer Board

Head

Kiyoshi Miyagawa

Vascular Board

Head

Katsuyuki Hoshina

Hip Fracture Board

Head

Taro Kojima

Palliative Care Consulation TeamHead

Masahiko Sumitani

Nutrition Support Team

Head

Kazuhiko Fukatsu

Medical Community Network and Discharge SupportingCenter

Head

Masahiko Sumitani

Cancer Resource Center

Head

Sachiyo Nomura

Patient Relations and Clinical Ethics Center

Head

Yoshiyuki Takimoto

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

BioResource Center

Head

Tetsuo Ushiku

Center for Brain Imaging in Health and Diseases

Head

Kiyoto Kasai

HeadTomotaka Yamamoto

Clinical Research Services

Hospital Management Services
Medical Safety Management Center

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The Tokyo Journal of Medical Sciences. Vol. 147, October 2023

Infection Control Center

Head

Takeya Tsutsumi

Office of Performance Monitoring

Head

Tomotaka Yamamoto

Department of Highly Advanced Novel MedicalTechnologies

Head

Jun Nakajima

Head

Kanji Uchida

General Education Center

Head

Masato Eto

Clinical Simulation Center

Head

Masato Eto

Department of Clinical Research GovernanceHead

Yutaka Osuga

Department of Healthcare Information Management

Head

Kazuhiko Ohe

Department of Medical Record Management

Head

Kazuhiko Ohe

University Hospital Medical Information Network Center

Head

Takahiro Kiuchi

Labor Safety and Health Management Office

HeadTomotaka Yamamoto

Staff Wellness Consulting OfficeHeadKiyoto Kasai

Office of Medical Clerical Support for Physicians

Head

Sakae Tanaka

Department of Disaster Medical Management

Head

Kento Doi

Legal and Compliance Office

Head

Sakae Tanaka

Center for Liaison and Public Relations

Head

Yutaka Osuga

Office of Personnel and Human Resources

Head

Yutaka Yatomi

Office of Performance Monitoring and Risk Magamenet

Head

Sakae Tanaka

Office of Education and Staff Development

Head

Tatsuya Yamasoba

Office of Hospital Planning and Management

Head

Jun Nakajima

Office of Research Support

Head

Yutaka Osuga

Office of Inpatient Services

Head

Haruki Kume

Office of Outpatient Services

Head

Kiyoshi Miyagawa

Office of Central Clinical Services

Head

Masahiko Sumitani

Office of Patient Support

Head

Yutaka Osuga

Evaluation
Department of Unapproved New Drugs and MedicalDevices
Evaluation

Hospital Management Support Organization

Clinical Management Organization

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
Akira Takai, 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), Akira Takai(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.

Hirano M, Ando R, Shimozono S, Sugiyama M,
Takeda N, Kurokawa H, Deguchi R, Endo K,
Haga K, Takai-Todaka R, Inaura S, Matsumura Y,
Hama H, Okada Y, Fujiwara T, Morimoto T,

3

2.

3.

Katayama K, Miyawaki A. A highly photostableand bright green fluorescent protein. Nat
Biotechnol 40: 1132-1142, 2022.
Saji T, Nishita M, Ikeda K, Endo M, Okada Y,
Minami Y. c-Src-mediated phosphorylation andactivation of kinesin KIF1C promotes elongationof invadopodia in cancer cells. J Biol Chem.
298:102090, 2022.
Haraguchi T, Koujin T, Shindo T, Bilir Ş,
Osakada H, Nishimura K, Hirano Y, Asakawa H,
Mori C, Kobayashi S, Okada Y, Chikashige Y,
Fukagawa T, Shibata S, Hiraoka Y. Transfected
plasmid DNA is incorporated into the nucleus via
nuclear envelope reformation at telophase.
Commun Biol. 5:78, 2022.

4

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

LecturerHaruaki Yanagisawa, Ph.D.

Project Lecturer
Yoshiyuki Fukuda, Ph.D.

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

Homepage

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

Introduction and Organization
Our laboratory is one of the laboratories in
Department of Cell Biology and Anatomy. Since thereorganization of School of Medicine in 1997, the lab
was named as “Structural Biology”. The current lab
was established in 2009 when Masahide Kikkawa was
appointed as a professor.
Currently the lab members include: Masahide
Kikkawa (professor), Haruaki Yanagisawa (Lecturer),
Tsukasa Makino, Hiroshi Yamaguchi (research
associates), Akihisa Tsutsumi (project research
associate), (project researcher), Ryohei Sasaki,
Jiancheng An, Yuma Tani, Yuqing Liu, and Jingfei
Yang (graduate students), Takeru Mutoh (MSTP
students), Akiko Oosakaya, Sakamaki Yoichi, Toshie
Furuya, Miku Takagishi, Tony Wang, Yoriko Akuzawa(technical assistant), and Mikako Yanagiuchi and Ai
Naruse (assistant clerk).

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

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

Research activities
Our lab focuses on the structure and function ofepithelicalstructures,
especiallyeukaryotic
flagella/cilia. Flagella/cilia are both “propeller” and“antenna” of cells, whose diameter is about 250 nm.
From recent studies, it is becoming clear thatflagella/cilia are involved in various important cellfunctions.
To study the functions of flagella/cilia, we employ
various imaging techniques, including cryo-electron
microscopy and 3D-tracking microscope incombination with genetic manipulations.
Cryo-electron microscopy and cryo-electron
tomography
One of our strengths is in high-resolution
cryo-electron microscopy (cryo-EM). This techniqueenables preserving biological samples by quickly

5

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.

References[1] K. J. Malawska, S. Takano, K. Oisaki, H.
Yanagisawa, M. Kikkawa, T. Tsukuda, and M.
Kanai. Bioconjugation of Au(25) Nanocluster to
Monoclonal Antibody at Tryptophan. Bioconjug
Chem, 2023.
[2] Z. Chen, S. Watanabe, H. Hashida, M. Inoue, Y.
Daigaku, M. Kikkawa, and K. Inaba. Cryo-EM
structures of human SPCA1a reveal themechanism of Ca(2+)/Mn(2+) transport into theGolgi apparatus. Sci Adv, 9(9):eadd9742, 2023.
[3] C. Ito, T. Makino, T. Mutoh, M. Kikkawa, andK. Toshimori. The association of ODF4 with
AK1 and AK2 in mice is essential for fertility
through its contribution to flagellar shape. Sci
Rep, 13(1):2969, 2023.
[4] H. Takeda, J. V. Busto, C. Lindau, A. Tsutsumi,
K. Tomii, K. Imai, Y. Yamamori, T. Hirokawa, C.
Motono, I. Ganesan, L. S. Wenz, T. Becker, M.
Kikkawa, N. Pfanner, N. Wiedemann, and T.
Endo. A multipoint guidance mechanism forbeta-barrel folding on the SAM complex. Nat
Struct Mol Biol, 30(2):176–187, 2023.
[5] F. Eisenstein, H. Yanagisawa, H. Kashihara, M.
Kikkawa, S. Tsukita, and R. Danev. Parallel
cryo electron tomography on in situ lamellae. Nat
Methods, 20(1):131–138, 2023.
[6] Y. Zhang, C. Kobayashi, X. Cai, S. Watanabe, A.
Tsutsumi, M. Kikkawa, Y. Sugita, and K. Inaba.
Multiple sub-state structures of SERCA2b reveal
conformational overlap at transition steps during
the catalytic cycle. Cell Rep, 41(10):111760,
2022.

6

Department of Cytoarchitectonics
Lecturer
Yosuke Tanaka, M.D., Ph.D.

Homepage

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

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

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

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

References
1.

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

7

2. Wang S, Tanaka Y, Xu Y, Takeda S, Hirokawa N.
KIF3B promotes a PI3K signaling gradientcausing changes in a Shh protein gradient andsuppressing polydactyly in mice. Dev Cell.;57(19):2273-2289, Oct 10, 2022.

8

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

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

Homepage

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

Introduction and Organization
The Department of Cellular Neurobiology was
initially established as the Neuroanatomy departmentof former Brain Institute of Medical School ofImperial University of Tokyo in 1936. Since thestructural reconstruction of the School of Medicine in1997, this department became one of the departmentsof Cell Biology and Anatomy of the Graduate Schoolof Medicine. Professor Shigeo Okabe had currently
organized this department since September 2007. The
department is constituted of 21 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.

M, Noda K, Kamiyama H, Tanikawa R, Nagane
M, Shibahara J, Tanaka T, Rikitake Y, Mataga N,
Takahashi S, Kosaki K, Okano H, Furihata T,
Nakaki R, Akimitsu N, Wada Y, Ohtsuka T,
Kurihara H, Kamiguchi H, Okabe S, Nakafuku
M, Kato T, Nakagawa H, Saito N, Nakatomi H.

Publications

Increased PDGFRB and NF-κB signaling caused

1. Terashima H, Minatohara K, Maruoka H, Okabebyhighlyprevalentsomatic

mutationsin

S. Imaging neural circuit pathology of autism

intracranial aneurysms. Sci Transl Med. 2023

spectrum disorders: autism-associated genes,

15(700):eabq7721. doi: 10.1126/scitranslmed.abq

animal models and the application of in vivo

7721.

two-photon imaging. Microscopy (Oxf). 2022
71(Supplement_1):i81-i99. doi: 10.1093/jmicro/
dfab039.
2. Kamei R, Urata S, Maruoka H, Okabe S. In vivo
Chronic Two-Photon Imaging of Microglia in the
Mouse Hippocampus. J Vis Exp. 2022 6;(185).
doi: 10.3791/64104.
3. Maruoka H, Kamei R, Mizutani S, Liu Q, Okabe
S. Simultaneous Imaging of Microglial Dynamics
and Neuronal Activity in Awake Mice. J Vis Exp.
2022 Aug 23;(186). doi: 10.3791/64111.
4. Nozawa O, Miyata M, Shiotani H, Kameyama T,
Komaki R, Shimizu T, Kuriu T, Kashiwagi Y,
Sato Y, Koebisu M, Aiba A, Okabe S, Mizutani
K,

Takai

Y.

A

novel

Necl-2/3-mediatedmechanism for tripartite synapse formation.
Development. 2023 Feb 15;150(4):dev200931.
doi: 10.1242/dev.200931.
5. Urata S, Okabe S Three-dimensional mousecochlea imaging based on the modified Sca/eS
using confocal microscopy. Anatomical Science
International 2023 Feb 11. doi: 10.1007/s12565023-00703-z. Online ahead of print.
6. Kamei R, Okabe S In vivo imaging of thephagocytic

dynamics

underlying

efficientclearance of adult-born hippocampal granulecells by ramified microglia. Glia. 2023 Aug;71(8):2005-2023. doi: 10.1002/glia.24379.
7. Shima Y, Sasagawa S, Ota N, Oyama R, Tanaka
M,

Kubota-Sakashita

M,

Kawakami

H,

Kobayashi M, Takubo N, Ozeki AN, Sun X, Kim
YJ, Kamatani Y, Matsuda K, Maejima K, Fujita

Molecular Cell Biology
2. Biochemistry and Molecular Biology

11

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

Associate Professor
Ikuko Koyama-Honda, Ph.D.

Associate
Saori Yoshii, M.D., Ph.D., Tomoya Eguchi, M.D., Ph.D.

Project Associate Professor
Chieko Saito, Ph.D.

Project Lecturer
Taki Nishimura, Ph.D.

Project Research Associate
Junichi Sakamaki, Ph.D.

Homepagehttps://molbiolut.jp/en/

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

School and Faculty of Medicine at Tokyo Medical and
Dental University in 2006, and succeeded Professor
Okayama in 2012.

Research Activities
Our current study focuses on the understanding of themolecular mechanism and physiological roles of
autophagy and other intracellular degradation systems.
In 2022, we reported the following novel findings.
1. Molecular mechanism of autophagy
Autophagy is one of the major degradation
pathways in the cell. In autophagy, intracellularcomponents are sequestered by autophagosomes
and then degraded upon fusion with lysosomes.
Yeast genetic studies have identified more than 40
autophagy-related (ATG) genes. Many of thesegenes are conserved in higher eukaryotes, whichallows us to perform genetic analysis of
autophagy in mammals. We are currently
addressing some of the central questions
remaining in the autophagy field and trying toelucidate the mechanisms of (1) regulation of
autophagy, (2) initiation of autophagosome
formation, (3) elongation of the autophagic
membrane, (4) closure, fusion, and degradation of
the autophagosome (5) recognition of selective
substrates. In addition, we are also working on
intracellular degradation systems other than
autophagy.
Ferritin, an iron storage protein, forms aspherical, cage-like complex that stores iron ionsinside. When cells become iron-deficient, ferritin
is transported to lysosomes via autophagy (macroautophagy) or the endosomal multivesicularicularbody pathway (microautophagy) to release theinternal iron ions. It has been suggested that
NCOA4 mediates autophagic degradation of
ferritin as a receptor for ferritin, but the details of
this mechanism remained unclear. We found thatferritin and NCOA4 form droplets by liquid-liquid
phase separation (LLPS), and that these ferritin
droplets(ferritin-NCOA4
droplets)areincorporated into autophagosomes and endosomes.
Thus, NCOA4 is not only a receptor but also adriver molecule essential for droplet formation.

13This study clarifies the role of liquid-liquid phaseseparation in ferritinolysis, a central process in theintracellular iron metabolism pathway, andprovides new evidence for a link between liquidliquid phase separation and microautophagy(Ohshima et al. J Cell Biol 2022).
It has been reported that organelles such as
endoplasmic reticulum and mitochondria are
involved in the formation of autophagosomes. We
quantitatively analyzed the contacts between
autophagy-related structures and surrounding cellorganelles by three-dimensional light-electron
correlation microscopy. As in previous reports, allforming autophagosomes were in contact with theendoplasmic reticulum, and the contact area
decreased as they matured into autolysosomes.
However, the majority of autophagosomes andautolysosomes were still in contact with theendoplasmic
reticulum,
indicatingthat
autophagosomes do not need to completely detachfrom the ER for fusion with lysosomes. Analysis
ofthesubstrates
incorporated
into
autophagosomes revealed that the ER is mostfrequently
engulfed
byautophagosomes(Takahashi et al. Cell Struct Funct 2022).
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.
Autophagy is also known to have bothnon-selective and selective effects. In 2019, we
identified a novel endoplasmic reticulum
autophagy (ER-phagy) receptor, TEX264, which
is an ER membrane protein with an LC3 bindingsite (LIR) that binds to LC3/GABARAP family
proteins of the autophagosome membrane andthrough which induces the endoplasmic reticulumon autophagosomes. In the present study, we
found that serine residues in the LIR of TEX264
are phosphorylated by casein kinase and that

phosphorylation is required for binding to the
LC3/GABARAP family and for ER-phagy
function. The phosphorylated serines formhydrogen bonds with GABARAPL1, thereby
enabling stronger binding. While other ER-phagy
receptors have an α-helix at the C-terminus of LIR
that enables strong binding to LC3, TEX264,
which does not have a C-terminal α-helix, wasfound to be able to bind as strongly as otherER-phagy receptors by phosphoserine of LIR.
This study provides new insights into the binding
mode of selective autophagy receptors to
LC3/GABARAP (Chino et al. EMBO Rep 2022).
3. Methods for monitoring autophagic activity
Measuring autophagic activity is critical todissecting molecular mechanisms and functions ofautophagy but remains challenging due to the lackof a definitive method. We have discovered thatthe covalent binding of a ligand to HaloTag makes
it resistant to degradation in lysosomes, and wehave used this finding to develop a new methodfor quantifying autophagy activity. This method
not only allows quantification of cargo-specificautophagic flux but also of random degradation ofcytosolic proteins. Thus, this new method allows
for the evaluation of non-selective autophagy,
unlike conventional methods that rely on LC3 andother factors (Yim et al. eLife 2022).
4. Autophagy-independent pathway
Ubiquitin, a protein ubiquitously present ineukaryotes, covalently binds to other proteins andacts as a signal for degradation or change in theirproperties. Although ubiquitin has been thought tobind mainly to proteins, we have discovered thatubiquitin
can
also
be
conjugatedtophosphatidylethanolamine (PE), a phospholipidthat constitutes the membrane of cell organelles.
This is similar to the covalent binding of theubiquitin-like protein ATG8 (LC3 and GABARAP
in mammals) to PE, which is required for
autophagy. Ubiquitination of PE is found inorganelles such as endosomes and lysosomes andin some viruses. This modification is catalyzed bya series of reactions similar to protein
ubiquitination, which involves the ubiquitin-

14

activating enzyme Uba1, the ubiquitinconjugating enzyme Ubc4/5, and the ubiquitin
ligase Tul1. Ubiquitin bound to PE is either
removed by the ubiquitin deubiquitinating enzyme
Doa4 or transported to the vacuole for degradation.
Ubiquitination of PE recruits ESCRT protein
complexes involved in membrane deformationand fission and may be involved in the process ofvesicle formation in the endosomal lumen(intraluminal vesicle formation). Furthermore, theubiquitin-like proteins NEDD8 and ISG15 werealso found to covalently bind to phospholipids.
These results suggest that covalent binding tophospholipids is not specific to ATG8, but is a
general feature of ubiquitin and ubiquitin-likeproteins.

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

Publication
1.

2.

3.

4.

Takahashi S, Saito C, *Koyama-Honda I,*Mizushima, N. Quantitative 3D correlative lightand electron microscopy of organelle association
during autophagy. Cell Struct Funct. 47:89-99(2022) doi: 10.1247/csf.22071
Yim, W.W., *Yamamoto, H., *Mizushima, N. A
pulse-chasable reporter processing assay for
mammalian autophagic flux with HaloTag. eLife
11:e78923 (2022) doi: 10.7554/eLife.78923
Ohshima, T., Yamamoto, H., Sakamaki, Y., Saito,
C., *Mizushima, N. NCOA4 drives ferritin phaseseparation to facilitate macroferritinophagy andendosomal microferritinophagy. J Cell Biol. 221:e202203102 (2022) doi: 10.1083/jcb.202203102
Sakamaki, J.I., Ode, K.L., Kurikawa,Y., Ueda,
H.R., Yamamoto,H., *Mizushima, N.
Ubiquitination of phosphatidylethanolamine inorganellar membranes. Mol. Cell 82:3677-3692(2022) doi: 10.1016/j.molcel.2022.08.008

5.

6.

7.

8.

9.

10.

11.
12.

13.

14.

15.

Chino, H., Yamasaki, A., Ode, K.L., Ueda, H.R.,*Noda, N.N., *Mizushima, N. Phosphorylation
by casein kinase 2 ensures ER-phagy receptor
TEX264 binding to ATG8 proteins. EMBO Rep.
23:e54801 (2022).
Zhang, S., Yazaki, E., Sakamoto, H., Yamamoto,H., *Mizushima, N. Evolutionary diversificationoftheautophagy-related
ubiquitin-likeconjugation systems. Autophagy 18:2969-2984(2022).
Yim, W.W., Yamamoto, H., *Mizushima, N.
Annexins A1 and A2 are recruited to larger
lysosomal injuries independently of ESCRTs topromote repair. FEBS Lett. 596:991-1003 (2022)
Yim, W.W., Kurikawa, Y., *Mizushima, N. An
exploratory text analysis of the autophagy
research field. Autophagy 18:1648-1661 (2022)*Sakamaki, J.-i., *Mizushima, N. Protocols to
detectubiquitinatedphospholipids
byimmunoblotting. STAR Protoc. 4:101935 (2022)
doi: 10.1016/j.xpro.2022.101935
Holthuis, J.C.M., Jahn, H., Menon, A.K.,
Mizushima, N. An alliance between lipid transfer
proteins and scramblases for membrane
expansion. Fac. Rev. 11:22 (2022)*Mizushima, N. SnapShot: Organelle degradation.
Mol. Cell 82:1604-1604.e1 (2022)
Chino, H., *Mizushima, N. ER-phagy: quality
and quantity control of the endoplasmic
reticulum by autophagy. Cold Spring Harb.
Perspect. Biol. 8:a041256 (2022)
Hama, Y., Morishita, H., *Mizushima, N.
Regulation of ER-derived membrane dynamics
by the DedA domain-containing proteins VMP1
and TMEM41B. EMBO Rep. 23:e53894 (2022)*Morishita, H. Role of autophagy in the eye:from physiology to disease. Current Opinion in
Physiology 100592 (2022) https://doi.org/10.
1016/j.cophys.2022.100592
Koyama-Honda, I., *Mizushima, N. Transient
visit of STX17 (syntaxin 17) to autophagosomes.
Autophagy 18:1213-1215 (2022) doi: 10.1080/
15548627.2022.2079337

15

Department of Genome
Informatics
Professor
Yukinori Okada, M.D.,Ph.D.

Assistant Professor
Kyuto Sonehara, M.D.

Homepage

http://www.sg.med.osaka-u.ac.jp/index.html

Introduction and Organization
The Department of Genome Informatics was initiallyestablished as the second department of Biochemistryin 1975. Since the structural reconstruction of the
School of Medicine in 1997, this Department became
one of the Departments of Biochemistry andMolecular Biology of the Graduate School of
Medicine. This Department has previously beenheaded by the four professors (Prof. Kazutomo
Imahori, Yoshitaka Nagai, Takao Shimizu, andHiroyuki Mano). Prof. Yukinori Okada had currently
organized this Department since 2022. The
Department is constituted of one professor, one
assistant professor, one JSPS fellow, and one
administrative assistant.

Teaching activities
As one of the Departments of Biochemistry andMolecular Biology, our Department is responsible forthe basic lecture series of biochemistry for medical
students (M0).
To teach basic theory of statistical genetics andbioinformatics skills, our Department had an open
seminar named “Statistical Genetics Summer School”(August 26th-28th, online).

Research activities
The Department is developing research activities on
elucidation of disease biology, genomic drug
discovery, and personalized medicine through analysis

of human omics analysis. The main research activities
this year are as follows:
1) Identification of intracranial germ cell tumor
susceptibility genes
Intracranial germ cell tumors account for
approximately 10% of pediatric brain tumors in Japanand have a higher incidence in East Asians than inEuropean. We performed genome-wide association
analysis (GWAS) of intracranial germ cell tumors. We
identified that susceptibility gene mutations in the
BAK1 gene region alter enhancer activity and confer
risk of developing the disease.
2) Shared genetic background between autoimmune
and allergic diseases
Through the analysis of the human genome
information of 840,000 individuals in Japanese andEuropean populations, we identified the shared
genetic backgrounds between autoimmune andallergic diseases. It was practically possible to classify
autoimmune and allergic diseases based solely on
genetics. There are novel genetic variants that areshared in both diseases. Genetic risk was enriched in
the HLA gene region in autoimmune diseases, while
enriched toward the cytokine gene regions in allergic
diseases.
3) Elucidation of the severe COVID-19 biology
In the COVID-19 pandemic, the Japan COVID-19
Task Force was established (Representative: Keio
University), which collected genomic DNA, RNA,

16

plasma, and clinical information from >6,000
COVID-19-infected Japanese patients. GWAS wasconducted in the young severe patients. We identified
DOCK2, an immunoregulatory gene, as a responsible
gene for COVID-19 severity, based on blood
single-cell analysis and a Syrian hamster infection
model.
4) Gene expression analysis of COVID-19
We conducted an eQTL analysis to examine theassociation between blood cell gene expression andindividual differences in human genome sequence in
465 COVID-19-infected patients collected by theCorona Control Task Force. We quantified changes ingene expression regulation patterns according to theseverity of COVID-19 infection and reported the
involvement of neutrophil activation behind thechanges by interaction eQTL analysis of gene
expression regulation by COVID-19 severity andgenomic mutations. The involvement of neutrophil
activation was suggested.
5) Best practices for genomic drug discovery
Through international biobank collaboration, we
proposed a best practice of genomic drug discovery to
search for candidate compounds based on the GWAS
results. The combination of three genomic drug
discovery methods enables comprehensive search for
drug candidates. The method was applied to 13
diseases including asthma, gout, COPD, and venous
thromboembolism, and an drug candidate list
containing more than 250 compunds was generated.
This was an achievement of the methodology tosearch for therapeutic drug candidates based on
disease genetics.
6) Germline and somatic mutation interactions incancer development
Based on the large-scale GWAS results for various
types of cancer, we constructed a polygenic risk score(PRS) that strongly reflects inborn genetic risk ofcancer development. Individuals with high PRS
develop cancer at a younger age and have fewer
somatic abnormalities. Such characteristics associatedwith genetic cancer risk constitution were commonly
found in several types of cancer.

7) Identification of rheumatoid arthritis risk genes
Through international collaboration, we conducted alarge-scale GWAS of ~280,000 individuals
comprising five ethnic groups, including Japanese,and the risk variants associated with rheumatoid
arthritis were newly identified. A risk score forpredicting the development of rheumatoid arthritis
was constructed, and the prediction accuracy in the
East Asian population was confirmed to becomparable to that in the Europeans.
8) Database of the gut microbiome bacteria and virusof Japanese
We reconstructed bacterial and viral genome
sequences from the gut microbiome sequencing of 787
Japanese individuals as a database. The constructed
database included bacterial and genetic information
related to Japanese food (e.g., nori and natto). Using
the gut virus genome database, we conducted ananalysis focusing on crAss-like phage. We reported
that β crAss-like phage was less common in Asians,
Europeans, and Americans, while more common in
Africana and Oceanians. CrAss-like phage in multiple
subfamilies is decreased in autoimmune diseases.

References
1.

2.

Namba S, Saito Y, Kogure Y, Masuda T, Bondy
ML, Gharahkhani P, Gockel I, Heider D, Hillmer
A, Jankowski J, MacGregor S, Maj C, Melin B,
Ostrom QT, Palles C, Schumacher J, Tomlinson I,
Whiteman DC, Okada Y, Kataoka K. (2023)
Common germline risk variants impact somatic
alterations and clinical features across cancers.
Cancer Res 83:20-27.
Tomofuji Y, Kishikawa T, Maeda Y, Ogawa K,
Otake-Kasamoto Y, Kawabata S, Nii T, Okuno T,
Oguro-Igashira E, Kinoshita M, Takagaki M,
Oyama N, Todo K, Yamamoto K, Sonehara K,
Yagita M, Hosokawa A, Motooka D, Matsumoto
Y, Matsuoka H, Yoshimura M, Ohshima S,
Shinzaki S, Nakamura S, Iijima H, Inohara H,
Kishima H, Takehara T, Mochizuki H, Takeda K,
Kumanogoh A, Okada Y. (2022) Prokaryotic andviral genomes recovered from 787 Japanese gut
metagenomes revealed microbial features linked
to diets, populations, and diseases. Cell Genom

17

3.

4.

5.

6.

7.

8.

9.

2:100219.
Ishigaki K, Sakaue S, Terao C, Luo Y, Sonehara
K, Yamaguchi K, Amariuta T, Too CL, Laufer VA,
Scott IC, Viatte S, Takahashi M, Ohmura K,
Murasawa A, Hashimoto M, Ito H, Hammoudeh
M, Emadi SA, Masri BK, Halabi H, Badsha H,
Uthman IW, Wu X, Lin L, Li T, Plant D, BartonA, Orozco G, Verstappen SMM, Bowes J,
MacGregor AJ, Honda S, Koido M, Tomizuka K,
Kamatani Y, Tanaka H, Tanaka E, Suzuki A,
Maeda Y, Yamamoto K, Miyawaki S, Xie G,
Zhang J, Amos CI, Keystone E, Wolbink G, vander Horst-Bruinsma I, Cui J, Liao KP, Carroll RJ,
Lee HS, Bang SY, Siminovitch KA, de Vries N,
Alfredsson L, Rantapää-Dahlqvist S, Karlson EW,
Bae SC, Kimberly RP, Edberg JC, Mariette X,
Huizinga T, Dieudé P, Schneider M, Kerick M,
Denny JC, BioBank Japan Project, Matsuda K,
Matsuo K, Mimori T, Matsuda F, Fujio K, Tanaka
Y, Kumanogoh A, Traylor M, Lewis CM, Eyre S,
Xu H, Saxena R, Arayssi T, Kochi Y, Ikari K,
Harigai M, Gregersen PK, Yamamoto K, Louis
Bridges S Jr, Padyukov L, Martin J, Klareskog L,
Okada Y, Raychaudhuri S. (2022) Multi-ancestry
genome-wide association analyses identify novel
genetic mechanisms in rheumatoid arthritis. Nat
Genet 54:1640-1651.
Namba S, Konuma T, Wu KH, Zhou W, Global
Biobank Meta-analysis Initiative, Okada Y.
(2022) A practical guideline of genomics-driven
drug discovery in the era of global biobank
meta-analysis. Cell Genom 2:100190.
The GIANT consortium. (2022) A saturated mapof common genetic variants associated withhuman height. Nature 610:704-712.
Japan COVID-19 Task Force. (2022) The whole
blood transcriptional regulation landscape in 465
COVID-19 infected samples from Japan
COVID-19 Task Force. Nat Commun 13:4830.
Japan COVID-19 Task Force. (2022) DOCK2 isinvolved in the host genetics and biology ofsevere COVID-19. Nature 609:754-760.
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second update on mapping the human geneticarchitecture of COVID-19. Nature 621:E7-E26.
Sonehara K, Kimura Y, Nakano Y, Ozawa T,
Takahashi M, Suzuki K, Fujii T, Matsushita Y,

Tomiyama A, Kishikawa T, Yamamoto K, Naito T,
Suzuki T, Yamaguchi S, Miwa T, Sasaki H,
Kitagawa M, Ohe N, Fukai J, Ogiwara H,
Kawamura A, Miyawaki S, Matsuda F, Kiyokawa
N, Ichimura K, Nishikawa R, Okada Y,
Terashima K. (2022) A common deletion at
BAK1 reduces enhancer activity and confers riskof intracranial germ cell tumors. Nat Commun
13:4478.

18

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

Associate Professor
Yukiko Kurihara, M.D., Ph.D.

Research Associate
Yasunobu Uchijima, Ph.D.

Project Assistant Professor
Akiyasu Iwase, Ph.D.

Project Researcher
Hiroki Higashiyama, Ph.D.

Homepage 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, 4 graduate students (doctor course) and 1
secretary. Professor Tomoichiro Asano (Hiroshima
University) is invited as a part-time lecturer to instruct
graduate students and give lectures to 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-Exposure-to-Medicine”
courses every year. Several students are staying in ourlab 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
cranio¬facial 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 an endotheliumderived vasoconstrictor peptide, and its receptor ETAR
signaling acts as a molecular switch that determines thelower jaw identity by using mouse genetics.
From this research, several new insights in the field19

of evolutionary developmental biology have beenobtained. In mouse embryos, the absence of theEndothelin signal results in the failure to form theeardrum and the external ear canal. In contrast, inchicken embryos, there is instead an occurrence of
duplication formation. This reveals that the eardrum isa product of convergent evolution that independently
evolved in mammals and reptiles/birds. Furthermore,
the facial structure of mammals deviates significantly
from the common facial development pattern found in
jawed vertebrates. It undergoes dynamic evolution,
altering the tip of the upper jaw in reptiles andamphibians to create a protruding nose while
simultaneously developing new bones to reshape themouth tip. This has been elucidated throughexperimental embryology and comparative studies,including the analysis of fossils.
Recently, two different recurrent mutations in the
Endothelin-A receptor (ETAR) gene EDNRA have been
identified as causative for mandibulofacial dysostosis
with alopecia (MFDA), a rare congenital disorder inhumans. The mechanism of its pathogenesis has been
elucidated through the use of mouse genetics,
pharmacological experiments, and molecular dynamics(MD) simulations. This has revealed that the singleamino acid EDNRA mutations distant from the ligand
binding site allosterically affect ligand binding,inhibiting ligand dissociation and increasing binding
affinity.
(2) Cardiac development
We have advanced our analysis regarding three cell
types that migrate through the cardiac outflow tract andcontribute to heart formation:①

We clarified that mesodermal cells from theextraembryonic somatopleure, which serves as theamniotic primordium, migrate into the embryoand differentiate into cardiomyocytes andvascular endothelial cells. We also revealed that
BMP and FGF signals are involved in inducing
these differentiations.

②

Through transcriptome analysis of neural crest
cells migrating into the heart and spatialtranscriptome analysis, we unveiled a diverse cell
population, including undifferentiated cell groups
resembling stem cells and precursors, as well assmooth muscle-like cells. We also conducted atime-evolving lineage prediction for these cell
populations.
③

In coronary artery formation, we found the
involvement of lymphatic endothelial cells thatare believed to originate from the periaortic
capillary plexus around the aortic root during
embryonic development. We demonstrated therole of Semaphorin signals in this process.
Furthermore, through comparative anatomical anddevelopmental analysis of coronary arteries, we
elucidated that in amphibians, teleost fish, andcartilaginous fish, the primary vessels formed during
embryonic development directly supply the heart,
whereas, in amniotes (mammals, birds, reptiles), theseprimary vessels undergo remodeling during
development, forming a new entrance to establish thecoronary arteries. This provides a new foundation forunderstanding the causes of congenital coronary arteryabnormalities.
(3) Angiogenesis
Angiogenesis is a morphogenetic process that produces
branching vascular structures during embryogenesis
and various (patho-)physiological conditions. We haveidentified characteristic cellular behaviors inangiogenic processes, including dynamic changes inforward-backward movement, tip cell overtaking andresultant cell mixing. Although the cellular behaviors
appear complex and arbitrary, different types ofmathematical modeling (stochastic vs. deterministic)
and experimental verification indicated that somedeterministic cell-cell interactions are critical for
vascular elongation and possibly branching. Recently,
we found differences in branch-forming capacity
among cell types and some regularities in directional
cell movement using in vitro angiogenesis experiments
using mouse vascular explants and an endothelial cellline by refined cell-tracking system. Together withsingle-cell analyses of cell movement and gene
expression, novel mathematical modeling andexperimental
verification
using
constitutional
approaches are under way in collaboration withProfessor Tetsuji Tokihiro (Graduate School ofMathematical Sciences, The University of Tokyo,
Musashino University) and his colleagues, to elucidate
the possible cellular mechanisms underlying branchformation in angiogenesis.

20

To elucidate the collective motility characteristics
of endothelial cells that enable sprout elongation, we
analyzed the dynamics of mouse pancreatic islet
microvascular-derived endothelial cell line MS-1 cells.
We discovered that their directional movement is
influenced by cell contacts, with a combination of
linear motion with directionality and rotational
movement as its basis. Through various inhibitors andgenetic modifications using genome editing, it has
become evident that these endothelial cell-specificmotility characteristics are specifically regulated byadhesion molecules such as VE-cadherin. Currently,
we are advancing the elucidation of the coordination
mechanism between cell motility and transcriptional
control by contrasting gene expression profiles and cell
behavioral phenotypes.

References
1.

2.

3.

4.

5.

6.

Aouci R, Soudany ME, Maakoul Z, Fontaine A,
Kurihara H, Levi G, Narboux-Nême N. Dlx5/6
expression levels in mouse GABAergic neurons
regulate adult parvalbumin neuronal density andanxiety/compulsive behaviours. Cells 11(11):1739, 2022.
Maruyama K, Miyagawa-Tomita S, Haneda Y,
Kida M, Matsuzaki F, Imanaka-Yoshida K,
Kurihara H. The cardiopharyngeal mesoderm
contributes to lymphatic vessel development.
eLife e81515, 2022.
Hayashi T, Yura F, Mada J, Kurihara H, Tokihiro
T. Pattern formation of elliptic particles by twobody interactions: A model for dynamics ofendothelial cells in angiogenesis. J. Theor. Biol.
555:111300, 2022.
Higashiyama H, Koyabu D, Kurihara H. Evolutionof the therian face through complete loss of thepremaxilla. Evol. Dev. 25(1):103-118, 2023.
Kurihara Y, Ekimoto T, Gordon CT, Uchijima Y,
Sugiyama R, Kitazawa T, Iwase A, Kotani R, Asai
R, Pingault V, Ikeguchi M, Amiel J, Kurihara H.
Mandibulofacial dysostosis with alopecia resultsfrom ETAR gain-of-function mutations via
allosteric effects on ligand binding. J. Clin. Invest.
133(4):e151536, 2023.
Shima Y, Sasagawa S, Ota N, Oyama R, Tanaka M,
Kubota-Sakashita M, Kawakami H, Kobayashi M,

Takubo N, Ozeki AN, Sun X, Kim YJ, Kamatani
Y, Matsuda K, Maejima K, Fujita M, Noda K,
Kamiyama H, Tanikawa R, Nagane M, Shibahara
J, Tanaka T, Rikitake Y, Mataga N, Takahashi S,
Kosaki K, Okano H, Furihata T, Nakaki R,
Akimitsu N, Wada Y, Ohtsuka T, Kurihara H,
Kamiguchi H, Okabe S, Nakafuku M, Kato T,
Nakagawa H, Saito N, Nakatomi H. Increased
PDGFRB and NF-κB signaling caused by highly
prevalent somatic mutations in intracranial
aneurysms. Sci Transl Med. 15(700):eabq7721,
2023.
7. Tonami K, Hayashi T, Uchijima Y, Kanai M, Yura
F, Mada J, Sugahara K, Kurihara Y, Kominami Y,
Ushijima T, Takubo N, Liu X, Tozawa H, Kanai Y,
Tokihiro T, Kurihara H. Coordinated linear androtational movements of endothelial cells
compartmentalized by VE-cadherin drive
angiogenic sprouting. iScience. 26(7):107051,
2023.
8. Oda H, Tonami K, Nakata Y, Takubo N, Kurihara
H. Persistent homological cell tracking technology.
Sci Rep. 13(1):10882, 2023.
9. Mizukami K, Higashiyama H, Arima Y, Ando K,
Okada N, Kose K, Yamada S, Takeuchi JK,
Koshiba-Takeuchi K, Fukuhara S, MiyagawaTomita S, Kurihara H. Coronary artery establishedthrough amniote evolution. eLife 12:e83005, 2023.
10. Watanabe Y, Wang Y, Tanaka Y, Iwase A,
Kawamura T, Saga Y, Yashiro K, Kurihara H,
Nakagawa O. Myocardial progenitor cells definedby Hey2 enhancer activity at the early stage of
cardiaccrescent
formation
specificallydifferentiate into cardiomyocytes of the left
ventricle. Proc. Natl. Acad. Sci. U.S.A. 120(37):e2307658120, 2023
11. Liu N, Kawahira N, Nakashima Y, Nakano H,
Iwase A, Uchijima Y, Wu SM, Minamisawa S,
Kurihara H, Nakano A. Notch and retinoid acidsignals regulate macrophage formation fromendocardium downstream of Nkx2-5. Nat
Commun. 14(1):5398, 2023.
12. Agostini V, Tessier A, Djaziri N, Khonsari RH,
Galliani E, Kurihara Y, Honda M, Kurihara H,
Hidaka K, Tuncbilek G, Picard A, Konas E, AmielJ, Gordon CT. Biallelic truncating variants in
VGLL2 cause syngnathia in humans. J Med Genet.

21

jmg-2022-109059, 2023.
13. Sakai K, Hayashi T, Sakai Y, Mada J, Tonami K,
Uchijima Y, Kurihara H, Tokihiro T. A threedimensional model with two-body interactions forendothelial cells in angiogenesis. Sci Rep. 13(1):20549, 2023.
14. Haneda Y, Miyagawa-Tomita S, Uchijima Y Iwase
A, Asai R, Kohro T, Wada Y, Kurihara H. Diverse
contribution of amniogenic somatopleural cells to
cardiovascular development: with specialreference to thyroid vasculature. Dev. Dyn. 253:
59-77, 2024.

22

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

JSPS fellows
Fabian Eisenstein, Ph.D.
Irwin Selvam, Ph.D.

Homepage

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

Introduction and Organization
Our laboratory was established in 2018. We aresupported by grants from 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), Fabian Eisenstein (JSPS fellow),and Irwin Selvam (JSPS fellow).

Teaching activities
We conduct training and provide support for the usersof the 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 inJapan and abroad. We also give introductory lectures
about structural biology as part of the following
programs:
1) MD scientist training program (MDSTP)
2) Master student class3) Ph.D. student guidance4) School of Medicine Introductory Lecture

Research activities
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 five years, we have been investigating animportant class of membrane proteins called G
protein-coupled receptors (GPCRs). GPCRs constitutethe largest family of membrane proteins in the humangenome. They are responsible for the detection andtransduction of many extracellular signals that
regulate various physiological processes across theplasma membrane. Because of their broad regulatory
functions, GPCRs are implicated in numerous chronic
diseases, such as diabetes, obesity, nervous systemdisorders, migraine, asthma, allergies, cardiovasculardisorders, cancer, and others. Consequently, they also
represent the biggest group of drug targets and are thesubject of more than 30% of approved drugs.
To understand the mechanisms of GPCR activationand signal transduction on the atomic level, we use themodern and very prolific method of cryo-EM single
particle analysis. In an ongoing international
collaboration with a group at Monash University inAustralia, which specializes in GPCR pharmacology
and has substantial experience in expression andpurification of target complexes, we are studying
receptor activation by both native and synthetic
ligands. In the past four years, our results comprise
more than 40 sub-3 Å unmodified full-length GPCR

23

structures, approximately half of which are at
resolutions better than 2.5 Å. This is an unprecedented
achievement in structural biology, both in terms of thenumber of structures and their resolution. Our successis not coincidental. To reach such a level of
performance, we conducted a careful systematicquantification and optimization of the cryo-EM
experimental parameters for sample preparation anddata collection. We adopted a highly efficientsynergistic experimental approach that combined datacollection from real samples with testing of individual
experimental factors. The method had the advantage
of not requiring extra observation time on the costly
and heavily booked electron cryo-microscopes. The
results from this work led us toward a better
experimental design and allowed us to routinely
produce sub-2.5 Å resolution results in our recent
studies. Most prominently, in the summer of 2020 wewere able to produce the first sub-2 Å resolution
reconstructions of GPCR complexes that to this dateremain unsurpassed.
In 2022 we expanded our structural research towards
other pharmacologically important proteins. We began
expression and purification trials and functional
characterization of potential drug targets from
Mycobacterium tuberculosis. Following computational
interrogation, we generated several constructs thatwere taken forward to expression and purification.
Where workable samples were obtained, negative
stain EM and cryo-EM were utilized to derive
preliminary structural information. This information
was then fed back to the molecular biology stage in an
iterative process. Cryo-EM investigation of the mostpromising preparations resulted in 2D classes thatshowed partially ordered oligomers, but unfortunately
the data did not yield a 3D reconstruction. Although
the high-resolution structures of the targets were notobtained, this work established a substantial basis for
future research towards better understanding of thedisease mechanisms of tuberculosis and thedevelopment of effective treatments.
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, we are working on the development of new
experimental methods for cryo-EM. One of ourcurrent projects aims to develop and implement ahigh-speed real-time synchronous modulation of theelectron beam that will expand the capabilities of the
microscope. With the so-called FADE method (fastand accurate defocus modulation), we hope totransform the instrument from a static and rigid
system into a dynamic and adaptable optical platform.
This will give researchers more freedom to tune theirexperiments for optimal performance. We finished thedevelopment and construction of the first FADE
hardware prototype, and it is already installed on oneof the microscopes at the facility (JEOL JEM-F200).
Hardware-wise, the system performs as expected andproduces data of good quality. The main challenge thatremains is the analysis of the data. All existing
software packages for cryo-EM data processing aredesigned for conventional constant defocus data. To
process FADE data, we must modify or write our own
data processing routines and we are currently working
in this direction. In the near future, the FADE
hardware will be added to the new JEOL CryoARM
200 electron microscope that was installed in thespring of 2022 at the Kashiwa II campus of the
University of Tokyo. This microscope has superior
optical and cryogenic performance and will
demonstrate the benefits of the new method at a muchhigher level than the current test system.
Other areas of our research include cryo-electron
tomography (cryo-ET) of cellular samples combinedwith advanced sample preparation through cryogenic
focused ion beam milling (cryo-FIB). The ability toobserve proteins and complexes in their nativeenvironment within a cell, “in situ”, offers tremendous
opportunities for fundamental biological, pharmacological, and medical contributions. Nevertheless, thecryo-ET field is still quite young and there are
multiple challenges related to sample preparation anddata acquisition. This makes the research even moreinteresting and rewarding. In 2022 we started thedevelopment of a new method for high-throughput andhigh-resolution cryo-ET data acquisition. The new
approach, called PACE-tomo (parallel cryo electron
tomography), uses accurate computer-controlled
optical shifts of the electron beam and the image on
the detector to acquire multiple tomographic tilt series
in parallel. It circumvents the need for mechanicalspecimen stage movements that cause significant
delays and sample drift. In this way, PACE-tomo24achieves a fivefold improvement in the overallthroughput of cryo-ET data acquisition. In the coming
years, we will continue making further contributions
to the methodology and performance of cryo-ET and
thereby hope to one day reach the ultimate (utopian)goal of “visual proteomics”; where researchers will beable to identify each individual protein and its
interactions with neighboring proteins within anelectron cryo-tomogram of a cellular volume.
We are also expanding our investigations towards
state-of-the-art deep learning experiment automation
for both cryo-EM single particle analysis andcryo-electron tomography. Deep learning (DL)methods have become ubiquitous in many areas ofresearch, and some groups are already developing
DL-based experimental frameworks for cryo-EM andcryo-ET. However, at present, many experimental
steps still require human intervention. Most of theseactions involve image evaluation and feature
recognition and are therefore perfect candidates for
DL algorithms, which have already been proven to
match or surpass human performance in suchactivities. With further automation, the experiments
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 leveland number of scientific results will continue to grow.

References
1. Cary BP, Deganutti G, Zhao P, Truong TT, Piper
SJ, Liu X, Belousoff MJ, Danev R, Sexton PM,
Wootten D, Gellman SH. Structural and functional
diversity among agonist-bound states of the
GLP-1 receptor. Nat Chem Biol. 2022;18(3):256263.
2. Deganutti G, Liang YL, Zhang X, Khoshouei M,
Clydesdale L, Belousoff MJ, Venugopal H,
Truong TT, Glukhova A, Keller AN, Gregory KJ,
Leach K, Christopoulos A, Danev R, Reynolds
CA, Zhao P, Sexton PM, Wootten D. Dynamics of
GLP-1R peptide agonist engagement are
correlated with kinetics of G protein activation.
Nat Commun. 2022;13(1):92.
3. Cao J, Belousoff MJ, Liang YL, Johnson RM,
Josephs TM, Fletcher MM, Christopoulos A, Hay

DL, Danev R, Wootten D, Sexton PM. A
structural basis for amylin receptor phenotype.
Science. 2022;375(6587).
4. Piper SJ, Deganutti G, Lu J, Zhao P, Liang YL, Lu
Y, Fletcher MM, Hossain MA, Christopoulos A,
Reynolds CA, Danev R, Sexton PM, Wootten D.
Understanding VPAC receptor family peptide
binding and selectivity. Nat Commun. 2022;13(1):7013.

Functional Biology
1. Physiology

26

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

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

Introduction and Organization
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.

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

Research
Most of our research is focused on the higher brain
function of the mammalian central nervous system.
(1) Hierarchical and parallel visual networks in the
cerebral cortex are conserved across mammalian
species and are considered the basic structure of visual
information processing in the brain. During
development, the brain forms the complex visual
network based on both gene expression and neuralactivity including spontaneous activity. The
development of neural networks is an important topic
in the neuroscience. However, previous investigations

27

have been limited to lower order pathways from theperiphery to the primary sensory cortex via thethalamic nuclei. Thus, the development of the entire
neural network, including higher order cortical areasand higher-order thalamic nuclei, remains largely
unexplored.
To elucidate the development of neural networks, itis necessary to investigate the formation of inter-areal
connections throughout the visual network, including
cortical and thalamic visual areas. However, it has
been technically difficult to precisely identify thelocations of the visual areas in the immature,developing brain. We found that the locations of the
primary (V1) and higher visual areas can be identified
by analyzing spontaneous activity observed in thedeveloping mouse cortex. Using this method, weinvestigated how interregional connections wereformed throughout the mouse visual network. In
addition, we examined the functional role of
spontaneous activity in the formation of intercorticalconnections.
We found that early in development, the projections
from the thalamic nuclei to the visual cortex (primary
thalamic nuclei to V1 and higher thalamic nuclei tohigher visual cortex) were established before theformation of the intercortical connections. In addition,
the primary and higher thalamic nuclei each received
input from the retina through independent pathways,
forming parallel pathways from the retina to V1 orhigher visual cortex.
Functional calcium imaging of neuronal activity
revealed that, spontaneous activity propagated fromthe retina to the cortex through the parallel pathways,
and that the activity showed retinotopic patterns inboth the thalamic nuclei and visual cortical areas
including V1 and higher visual areas. These results
indicate that these parallel pathways have retinotopic
connections even at an early stage of development andsuggest that the parallel pathways may support theformation of intercortical connections based on theirretinotopic structures.
To investigate the role of spontaneous retinal activity
in the formation of inter-cortical connections, weremoved the retinal activity immediately after birth.
Removal of the retinal activity disrupted the
projection from V1 to higher visual areas, indicatingthat spontaneous retinal activity is important for theformation of intercortical connections.
This study not only demonstrates the developmental
process of the cortical neural network, but also
provides a basic knowledge for elucidating themechanisms underlying the neural network formation
depending on neural activity and gene expression.
(2) In adult mice, a higher order thalamic nucleus
sends its axons not only to higher visual areas, butalso to the primary visual cortex (V1). However, thefunction of the latter pathway has not been fully
understood. Using functional axon imaging, we
revealed that the higher order thalamic nucleus sends
different visual information to V1 compared to theprimary thalamic nucleus, indicating the different
roles of the primary and higher thalamic nuclei inmodulation of V1 activity.
(3) Neural activity is important for the development ofprojections of interhemispheric callosal connections.
However, when the neural activity is important during
the development of the callosal projections has notbeen investigated. We genetically controlled theactivity of the callosal projections and showed that theneural activity during a limited developmental period
is important for the proper formation of the callosal
projections, suggesting a critical period for neuralactivity dependence in the development of the callosal
connections.

Publications(1) Tomonari Murakami, Teppei Matsui, Masato
Uemura, Kenichi Ohki. Modular strategy fordevelopment of the hierarchical visual network inmice Nature, 608, 578-585, 2022
(2) Satoru Kondo, Yuko Kiyohara, Kenichi Ohki.
Response Selectivity of the Lateral Posterior
Nucleus Axons Projecting to the Mouse Primary
Visual Cortex Frontiers in neural circuits 16:825735, 1-13, 2022;(3) Yuto Tezuka, Kenta M Hagihara, Kenichi Ohki,
Tomoo Hirano, Yoshiaki Tagawa. Developmental
stage-specific spontaneous activity contributes tocallosal axon projections Elife 11, e72435, 2022

28

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

Lecturer
Teppei Ebina, Ph.D.

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

Homepage

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

Introduction and Organization

Research activities

The Department of Cellular and Molecular Physiology
succeeded the former ‘Second Department of Physiology’, and belongs to the Department of Physiology.
We participate in the teaching of physiology atundergraduate school and graduate school.
The present members include the above staff, 2secretary staff, 4 technical staff, 1 project research
associate, 6 graduate students.

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

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

(1) Transition of distinct context-dependent
ensembles from secondary to primary motor cortex
in skilled motor performance

29

In practicing short-distance running, one may startrunning on their own timing or start running in
response to the sound of a pistol. The various actions
we perform daily can be divided into 'internallygenerated' movements, which start spontaneously, and'externally trigged' movements, which start in
response to sensory stimuli such as visual andauditory stimuli.
In patients with Parkinson's disease, it is
known that while it is difficult to start movements
spontaneously, they can relatively robustly initiate
movements in response to exogenous stimuli. It is
assumed that the neural processing pathways in thebrain for these two types of movements are largely
different. Previous studies reported that while thehigher motor cortex shows neural activity dependent
on each start signal, the primary motor cortex exhibits
the same activity regardless of the signal. However, it
was still unclear what information is transmitted
between these areas, how these different activities
converge into the same activity, and whether these are
dependent on the individual's learning status.
In this study, we first constructed internallygenerated and externally triggered movement tasks inmice. In these tasks, mice could obtain rewards bypulling a lever either spontaneously or in response toan auditory cue. Next, we investigated the
involvement of the higher motor cortex (M2) andprimary motor cortex (M1) in these tasks after training
the
mice,
by
inhibiting
neuralactivity
pharmacologically and optogenetically. When we
consistently suppressed activity in both M2 and M1,
the success rate decreased regardless of whether the
movement was internally generated or externallytriggered. However, when suppression was transient
after movement initiation, only inhibition of M1
caused motor dysfunction. These results suggest thatboth M2 and M1 are necessary for task execution, but
after movement initiation, the motor executionfunction shifts to M1, indicating that these two areas
may be hierarchically processing information.
Next, to understand what information isrepresented in neural activity, we conducted calcium
imaging with two-photon microscopy. To clarify how
M2 and M1 interact, it is important to simultaneously
measure neural activity in both areas. Our laboratory
previously developed microscopy called the'wide-field two-photon microscopy', which allows
sequential measurement of neural activity in separateareas
atsingle-cellresolutionusingacustom-developed miniaturized optical element. In
this study, we further improved this microscopy,nearly doubling the image acquisition speed fromabout 6 frames per second to approximately 10 frames
per second, enabling the capture of more detailed
activity changes.
Using this microscopy to examine theactivities in the superficial layers of M2 and M1, we
confirmed the presence of neural activities responding
to the differences in start signals between internallygenerated and externally triggered movements. To
further investigate the information transmitted
between areas, we also imaged axons projecting fromthe thalamus, located beneath the cerebral cortex, toM2, from M2 to M1, and corticospinal tract neurons
in the deep layer of M1, conducting comprehensive
measurements from M2 input to M1 output. Usingmachine learning-based decoding analysis, wequantified the context dependency, i.e., whether the
movement initiation was internally generated or
externally triggered, at the group level for eachstructure. As a result, while the superficial layer of M2
always showed high context dependency, and thecorticospinal tract neurons in M1 always showed low
context dependency, the context dependency of axons
projecting from M2 to M1 and neurons in the
superficial layer of M1 varied significantly between
days and animals. Further analysis revealed that thehigher the context dependency in both structures, thebetter the task performance, such as success rate andresponse time to the sound cue. Additionally, thehigher the context dependency in the superficial layerof M1, the better the motor proficiency, such as
lever-pulling speed, duration, and reproducibility oflever trajectory.
At the individual cell level, when motor
proficiency was high, the number of cells in the
superficial layer of M1 with both high context
information and high motor information increased,suggesting that the increase in context dependency
and motor proficiency at the group level wasinterconnected. Even when this reorganization ofactivity occurred in the superficial layer of M1, there
were no significant differences in information

30

representation at the group or individual cell levels inthe superficial layer of M2. It is considered that highmotor function was realized by reorganizing cellgroups that generate motor commands specialized foreach context downstream (see Figure below).

The finding in this study that therelationshipbetweenthereorganizationofcontext-dependent neural activity and motor
proficiency varies greatly depending on the region andlayer within the frontal cortex, and that the neuralnetwork between context input and motor output
dynamically changes, demonstrates the highly
adaptive information processing ability of the cerebral
cortex. Further research may contribute to thedevelopmentof
high-performance
artificial
intelligence algorithms that mimic the brain.
Additionally, elucidating the mechanisms of internallygenerated and externally triggered movements isimportant for understanding Parkinson's disease andholds promise for the development of new treatments.
(2) Development of a bleed-free multi-site
automated injection robot for accurate, fast, anddense viral delivery to mouse and marmoset brains
Minimizing invasiveness to the living body is an
undoubtedly important issue in biomedical science.
Robotics provide one answer to this challenge:
automation, and it is awaited especially in theneuroscience and neurosurgical fields, since a brain is
one of the most delicate and three-dimensionallycomplex organs. In the preceding automations, such as
craniotomy,
patch-clamping,andelectrode
implantation, are mainly focused on precision ofrobotic manipulation, which could reduce tissue
damage by limiting unexpected movement of surgeons.
However, surgical planning is mostly decided byhuman, and its automation is still in its infancy.
Here, we developed ARViS: an Automated Robotic

Virus injection System. An infrared sensor was used toaccurately scan the three-dimensional brain surface
with the skull removed. Based on the scanning data,
we applied a neural network for retinal vessel
segmentation to extract the brain vasculature structure,
which were recognized up to 14 µm with 100%
accuracy, and optimized the locations of more than
100 injection sites without hitting any blood vessels
by developing an original algorithm. Then, acommercially accessible 6-DOF robot precisely
moved the needle to each injection site and inserted it
to the specified depth. The injection site could beplaced as close as 60 µm from vessels and the actual
injection depth could only deviate by about ±50 µm
from the target. Furthermore, because the soft tissuechanges shape during needle insertion and because
blood vessels run vertically in the brain, the needle
angle was aligned perpendicular to the surface, which
also contributed to improved accuracy and reduced
invasiveness.
As a proof-of-concept experiment, adenoassociated virus (AAV) expressing a Ca2+ indicator
was injected into over 120 sites of the whole dorsal
cerebral cortex of mouse and 266 sites of common
marmoset. The risk of major bleeding was only 0.73%
in mice (2333 sites) and none was observed inmarmoset (266 sites). It took only approximately 20
seconds to change the needle position and angle from
one target to another. We clearly detected uniform
florescence expression over the broad areas of 8 × 8mm2 in the mouse, which covers from the prefrontal tovisual cortex in both hemisphere, and 8 ×14 mm2 inthe marmoset, ranging from area PE to A8.
Furthermore, in the mouse, in vivo Ca2+ signals from
more than 10,000 neurons were simultaneously
recorded under an epifluorescence microscope. Thus,
ARViS enables bleed-free muti-site automatedinjection for accurate, fast, and dense virus delivery.
This research provides a new solution for
micron-order control of minimally invasive needle
insertion into delicate three-dimensional structures
avoiding high-risk areas on the surface. It paves theway to the ultra-minimal invasive drug delivery orbiopsy targeting at sub-milli order cell aggregation in
the future by combining the existing imaging
technology such as MRI or CT, which can be applied
to a wide range of clinical medicine, from early

31detection of breast cancer through biopsies of verysmall tumors to gene therapy by injecting viral
vectors.
(From an abstract in the BIO UT 2022)

References
1.

2.

Terada S., Kobayashi K., and Matsuzaki M.
Transitionof
distinct
context-dependent
ensembles from secondary to primary motor
cortex in skilled motor performance. Cell Reports
41, 111494, 2022.
Terada S., and Matsuzaki M. (News and Views)
Silent microscopy to explore a brain that hears
butterflies’ wings. Light: Science & Applications
11, 140, 2022.

32

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 fellow, 7 graduate students,and 5 technicians. We teach neurophysiology for
medical undergraduates and students in the Master andPh.D. courses. Our research aims at elucidating
cellular and molecular mechanisms underlying theregulation of synaptic transmission and postnatal
development of neuronal circuits.

Teaching activities
We teach neurophysiology to 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 sensorimotor 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 neurophysiology
experiments. First, students make intracellular
recordings from frog skeletal muscle fibers andexamine the endplate potential for understanding thebasic properties of synaptic transmission. Second,
students record an electromyogram (EMG) fromhuman gastrocnemius muscles and learn how thestretch reflex works.
We accept Free-Quarter students. Students areencouraged to experience patch-clamp recordings
from neurons either in brain slices or in dissociatedcultures, or to experience recordings of neuronal
activities from living animals.
For the training of Master and Ph.D. course students,
we have a weekly conference to discuss 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 brain function, it is necessary to elucidate
mechanisms of synaptic transmission and thoseunderlying changes in synapses related todevelopment, learning, and memory (synaptic
plasticity). We take various methodologicalapproaches
includingelectrophysiology,
pharmacology, morphology, and genetic engineeringof mice. We particularly focus on observing neuronal
activities in real-time in intact neurons. We use
whole-cell patch clamp recording, calcium imaging,and two-photon imaging and their combinations invarious preparations (cultured neurons, brain slices,

33

and intact animals) and investigate molecularmechanisms of synaptic transmission and plasticity.
The main subjects of our research are as follows(1) Refinement of synaptic organization during
cerebellar development:
In early postnatal days, all Purkinje cells in the
cerebellum are innervated by multiple climbing fibers.
These surplus climbing fibers are eliminatedeventually with the progress of postnatal development,
and most Purkinje cells become innervated by single
climbing fibers by the end of the third postnatal weekin mice. We investigate the mechanisms of 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
activity-dependent manner, act retrogradely onto
presynaptic cannabinoid receptors, and suppress
transmitter release. Since then, we have been
investigating the mechanisms of this retrograde
modulation. We are also interested in elucidating thephysiological significance of this phenomenon
including learning and memory, addiction, andanxiety.
(3) Neural Activity and its function in intact animals:
To understand the representation of information by
specific neurons and their functions in vivo, we recordand regulate neural activity in intact animals during
behavioral tasks by using two-photon microscopy,
miniaturized microscopy, and optogenetics. Alongsidethese, we are also developing various techniques tofacilitate these in vivo experiments.

References(1) Itami C, Uesaka N, Huang JY, Lu HC, Sakimura K,
Kano M, Kimura F. Endocannabinoid-dependent
formation of columnar axonal projection in themouse cerebral cortex. Proc Natl Acad Sci USA.
2022 Sep 13;119(37):e2122700119. doi: 10.1073/
pnas.2122700119. Epub 2022 Sep 6.

(2) Harbers M, Nakao H, Watanabe T, Matsuyama K,
Tohyama S, Nakao K, Kishimoto Y, Kano M, Aiba
A. mGluR5 is substitutable for mGluR1 in
cerebellar Purkinje cells for motor coordination,
developmental synapse elimination, and motor
learning. Cells. 2022 Jun 23;11(13):2004. doi:
10.3390/cells11132004.
(3) Sakamoto M, Inoue M, Takeuchi A, Kobari S,
Yokoyama T, Horigane SI, Takemoto-Kimura S,
Abe M, Sakimura K, Kano M, Kitamura K, Fujii H,
Bito H. A Flp-dependent G-CaMP9a transgenic
mouse for neuronal imaging in vivo. Cell Rep
Methods. 2022 Feb 14;2(2):100168. doi: 10.1016/
j.crmeth.2022.100168. eCollection 2022 Feb 28.
(4) Sugaya Y, Kano M. Endocannabinoid-mediatedcontrol of neural circuit excitability and epileptic
seizures. Front Neural Circuits. 2022 Jan 3;15:
781113. doi: 10.3389/fncir.2021.781113. eCollection
2021.

Functional Biology
2. Pharmacology

35

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

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

Assistant Professor
Hirokazu Sakamoto, Ph. D.

Homepage

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

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

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

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

1) Development of high-performance fluorescenceprobes for visualizing neurotransmitters
Imaging techniques which visualize neurotransmittersin living neurons are powerful methods to understandthe mechanism underlying synaptic transmission inneuronal circuits. To facilitate this process, wedeveloped a high-throughput screening system basedon 96-well plate format protocol. After screening, we
obtained high-performance glutamate probes showing
large fluorescence changes upon glutamate binding.
This result indicates that our screening system should
be applicable to develop fluorescence probes for
signaling molecules other than glutamate in shortperiods.
2) Study of the mechanism underlying the exocytosisof neurotransmitterFor understanding of regulation mechanism
underlying neuronal circuit in mammalian central
nervous system, elucidation of the neurotransmitter
release machinery is indispensable. Aiming at imaging
neurotransmitter glutamate, we developed a novel
optical glutamate probe by our high-throughput
screening system as described above. Using this probe,
we successfully visualized presynaptically released
glutamate with a single synapse resolution in cultured
hippocampal neurons. We quantitatively analyzed
released glutamate at individual synapses and revealed36that single hippocampal synapses contain several
release units. Furthermore, we have succeeded in
imaging spatiotemporal dynamics of glutamate in theextrasynaptic space in brain slices and in vivo. This
study demonstrated that bursting synaptic activities
cause glutamate spillover from the synaptic cleft toactivate perisynaptic metabotropic glutamate receptors,
and will provide a basis for the research of
extrasynaptic glutamate transmission that is involvedin many important brain functions. These results
indicate that our glutamate probe is useful to directly
assess synaptic functions including presynaptic
modulation and plasticity.
3) Analysis of supra-molecular assemblies ofsynaptic molecules in central synapse
Recently, nanoscale molecular distribution in synapses
is suggested to be a key determinant of synaptic
function. To reveal the relationship between the nanoscale molecular assemblies and synaptic functions, weare trying to perform a super resolution microscopic
analysis in combination with glutamate imaging.
These advanced imaging techniques revealed thatdynamics of neurotransmitter release is precisely
controlled by the highly coordinated nanoscale
molecular assemblies of presynaptic molecules. We
are also trying to identify the functional changes innanoscale molecular assemblies in psychiatric diseasemodel.

References
1. Miyano, R., Sakamoto, H., Hirose, K., & Sakaba,
T. (2022). RIM-BP2 regulates Ca2+ channel
clustering and neurotransmitter release athippocampal mossy fiber terminals. bioRxiv,
2022-08.
2. Sakamoto, H., Kimpara, N., Namiki, S., Hamada,S., Ohtsuka, T., & Hirose, K. (2022). Synapse
type-specific molecular nanoconfigurations of thepresynaptic active zone in the hippocampus
identified by systematic nanoscopy. bioRxiv,
2022-03.

37

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

Project Associate Professor
Yoichi Minami, Ph.D.

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

Project Lecturer
Akifumi Kishi, Ph.D.

Research Associate
Daisuke Tone, Ph.D.

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

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

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

Research activities
Department of systems pharmacology is conducting

research to establish organism-level systems biology
and pharmacology using sleep-wake cycle as a model
system, which is common to organisms with a central
nervous system and one of the main factors that
dictate the dynamics of social behavior. With ourmembers from different backgrounds, we would liketo realize systems biology at the organism level
including human, leading to greater understanding andeven control of organismal pathophysiology. To thisend, we specifically focus on the cellular circuits
controlling the sleep/wake cycle and address thehourglass mechanism of sleep, a homeostatic- andcircadian-dependent regulation of sleep amount andtiming. We are also planning on multi-scale research
activities covering a series of length scales;
molecule-to-cell, cell-to-tissue, and tissue-to-organism
to envision such complicated underlying mechanism.
We have been devoting our research to twotechnological challenges; 1) next-generation mammalian reverse genetics, where we can produce

38

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, weinvestigate 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

39

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 thefact that each animal spices shows characteristic
different sleep duration. However, detailed molecularmechanisms underlying the control of sleep durationin mammals are still elusive. Using triple-target
CRISPR, SSS, and CUBIC techniques together with acomputational model that simulates the membranepotential of cortex neuron regulated by a group of ionchannels, we have discovered and proposed that
Ca2+-dependent neuronal hyperpolarization pathway
affects sleep duration in mammals (Sunagawa et al.,Cell Reports 2016; Tatsuki et al., Neuron 2016;
Yoshida et al. PNAS 2019; Yamada et al., iScience2022).
We have further been investigating molecules that
regulate the transition and consolidation of sleep andawake phases. In this regard, we have reported aphenotype of Chrm1 and Chrm3 double-knockout
mice produced by triple-CRISPR technology, whichshowed a complete loss of REM sleep (Niwa et al.,Cell Rep. 2018; Yamada and Ueda, Front. Neurosci.
2020). These results were the first report of essential
genes of REM sleep. This study also indicated that
REM sleep, defined through EEG-EMG recordings, is
not critical for the survival of animals.
In the process of investigating the relationshipbetween Ca2+-dependent regulation of neuronal
activity and sleep, we discovered CaMKIIα/β as thefirst sleep-inducing protein kinase in mammals(Tatsuki et al., Neuron 2016). Since then, therelationship between protein phosphorylation andsleep regulation has been suggested by multiple
genetic and biochemical findings—leading to the
proposal of phosphorylation hypothesis of sleep (Odeand Ueda, Front. Psychol. 2021). Phosphorylation/dephosphorylation-mediatedproteinregulation
represents a promising target in sleep–wake regulation
because it can occur on variable dynamics and timescale from minutes to hours (Sugai et al., Cell Rep.
2017; Yamaguchi et al., iScience 2021). Furthermore,
we analyzed the mouse sleep phenotype induced bycomprehensive mutagenesis of CaMKIIβ at all

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

References1.

Dean B, Bakker G, Ueda HR, Tobin AB, Brown
A, Kanaan RAA. A growing understanding of therole of muscarinic receptors in the molecular

40

2.

3.

4.

5.

6.

pathology and treatment of schizophrenia. Front.
Cell Neurosci. 17, 1124333 (2023)
Ishii S, Chino H, Ode KL, Kurikawa Y, Ueda HR,
Matsuura A, Mizushima N, Itakura E. CCPG1
recognizes ER luminal proteins for selective
ER-phagy. Mol. Biol. Cell 34, ar29 (2023)
Wang Y, Minami Y, Ode KL, Ueda HR. The roleof calcium and CaMKII in sleep. Front. Syst.
Neurosci. 16, 1059421 (2022)
Tone D, Ode KL, Zhang Q, Fujishima H, Yamada
RG, Nagashima Y, Matsumoto K, Wen Z,
Yoshida SY, Mitani TT, Arisato Y, Ohno RI,
Ukai-Tadenuma M, Yoshida Garçon J, Kaneko M,
Shi S, Ukai H, Miyamichi K, Okada T,
Sumiyama K, Kiyonari H, Ueda HR. Distinct
phosphorylation states of mammalian CaMKIIβcontrol the induction and maintenance of sleep.
PLOS Biol. 20, e3001813 (2022)
Sakamaki JI, Ode KL, Kurikawa Y, Ueda HR,
Yamamoto H, Mizushima N. Ubiquitination ofphosphatidylethanolamineinorganellar
membranes. Mol. Cell 82, 3677-3692 (2022)
Takahashi K, Abe K, Kubota SI, Fukatsu N,
Morishita Y, Yoshimatsu Y, Hirakawa S, Kubota
Y, Watabe T, Ehata S, Ueda HR, Shimamura T,
Miyazono K. An analysis modality for vascular
structures combining tissue-clearing technology
and topological data analysis. Nat. Commun. 13,5239 (2022)

Pathology, Immunology andMicrobiology
1. Pathology

42

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
Daizo Koinuma, M.D., Ph.D. (Aug 1~)
Aya Shinozaki-Ushiku, M.D., Ph.D. (Division of Integrative Genomics)

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

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

Research Associate
Ryohei Kuroda, M.D., Ph.D., Hirofumi Rokutan, M.D., Ph.D.,
Masaki Suzuki, Munetoshi Hinata, M.D., Ph.D.,
Noritaka Kudo (~ Jun 30) (Department of Pathology, Hospital)
Akiko Iwasaki, M.D., Ph.D., Mayu Hakozaki, M.D., Ph.D., Atsushi Kondo, M.D., Ph.D.
Yoichi Yasunaga, M.D., Ph.D. (~Jul 31, Aug 1~ Department of Pathology, Hospital)

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
Department of Pathology of the University Hospital.
Our aim is to perform pathology as an important partof clinical medicine as well as to establish “nextgeneration pathology” incorporating cutting-edge
science and technology.
Dr. Yamazawa took a leave of absence on March
31, 2022, and left for the United States to engage inmedical research. Drs. Kudo (Department of
Pathology, Hospital) and Kondo (Department of43

Pathology and Diagnostic Pathology) became research
associates on Apr 1. Dr Kudo moved to Toranomon
Hospital on Jul 1. Dr Koinuma joined as an associate
professor on Aug 1 and Dr. Yasunaga moved to the
Department of Pathology of the hospital.
Two postgraduate students (Yamamoto andKashima) finished the course and received Ph.D. In
the new fiscal year, 2023, three new students willenter the postgraduate course, and there will be 13
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. Okabe, thedean of Graduate School. The program has been
adopted as one of Activation Program of Basic
Researcher Training of the Ministry of Education,
Culture, Sports, Science and Technology. During four
years between FY2018 and FY2021, 13 postgraduate
students were trained to be specialized in "deathinvestigation, remote pathology diagnosis, andgenomic medicine" with the training system oriented
to region support by rotating among universities. We
hope the students who joined this program will be
future leaders in pathology and forensic medicine. We
also hold an annual seminar to recruit high school
students who aim to be pathologists and forensic
scientists.

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

Research activities
We explore the diagnosis and pathogenesis of disease,especially focusing on gastrointestinal oncogenesis.
Ongoing project includes exploration of highly
aggressive type of gastric cancer with fetal phenotype(e.g. AFP-producing gastric cancer) to clarify its
pathogenesis, genomic abnormalities and to findtherapeutic targets (Drs. Koinuma, Shinozaki-Ushiku,
Kunita, Rokutan, Kuroda, Iwasaki and Kondo). We
are also working on research projects of digestivesystemcancers,
such
ascancerimmunemicroenvironment, Epstein-Barr virus-positive gastriccancer, hereditary gastric tumors, duodenal cancer,
and pancreatobiliary cancers.
Our department has pathologists with different
expertise, and they are engaged in specific research
projects. The research covers brain tumors andneurodegenerative disease (Drs. Ikemura and
Hakozaki), Epstein-Barr virus-associated neoplasms(Drs. Shinozaki-Ushiku, Abe and Hinata), liver andpancreatobiliary tumors (Drs. Tanaka and Yasunaga),
and lung cancer (Dr. Suzuki). We also collaborate withother laboratories in and outside the University todevelop new technologies such as AI, tissue clearing
technique, and tissue processing robots in pathology
practice (Drs. Abe and Hinata).

44

References
1.

2.

3.

4.

5.

6.

Abe H, Kurose Y, Takahama S, Kume A, Nishida
S, Fukasawa M, Yasunaga Y, Ushiku T,
Ninomiya Y, Yoshizawa A, Murao K, Sato S,
Kitsuregawa M, Harada T, Kitagawa M,
Fukayama M, JP-AID/NII Study Group for
Gastric Biopsy Pathology. Development andmulti-institutional validation of an artificial
intelligence-based diagnostic system for gastricbiopsy. Cancer Science. 2022;113(10):36083617.
Adachi Y, Ueda K, Nomura S, Ito K, Katoh M,
Katagiri M, Yamada S, Hashimoto M, Zhai B,
Numata G, Otani A, Hinata M, Hiraike Y, Waki
H, Takeda N, Morita H, Ushiku T, Yamauchi T,
Takimoto E, Komuro I. Beiging of perivascularadipose tissue regulates its inflammation andvascular remodeling. Nat Commun. 2022;13:
5117.
Ishii T, Mimura I, Nagaoka K, Naito A,
Sugasawa T, Kuroda R, Yamada D, Kanki Y,
Kume H, Ushiku T, Kakimi K, Tanaka T,
Nangaku M. Effect of M2-like macrophages of
the injured-kidney cortex on kidney cancer
progression. Cell Death Discovery 2022;8:480.
Ito T, Kudoh S, Fujino K, Sanada M, Tenjin Y,
Saito H, Nakaishi-Fukuchi Y, Kameyama H,
Ichimura T, Udaka N, Kudo N, Matsuo A, Sato Y.
Pulmonary neuroendocrine cells and small celllung carcinoma: immunohistochemical study
focusing on mechanisms of neuroendocrine
differentiation. Acta Histochemica et Cytochemica.
2022;3:75–83.
Kashima J, Hashimoto T, Yoshida A, Goto Y,
Ushiku T, Ohe Y, Watanabe SI, Yatabe Y.
Insulinoma-associated-1 (INSM1) expression inthymic squamous cell carcinoma. Virchows Arch.
2022;481(6):893-901.
Kato H, Tateishi K, Fujiwara H, Nakatsuka T,
Yamamoto K, Kudo Y, Hayakawa Y, Nakagawa
H, Tanaka Y, Ijichi H, Otsuka M, Iwadate D,
Oyama H, Kanai S, Noguchi K, Suzuki T, Sato T,
Hakuta R, Ishigaki K, Saito K, Saito T, Takahara
N, Kishikawa T, Hamada T, Takahashi R,
Miyabayashi K, Mizuno S, Kogure H, Nakai Y,
Hirata Y, Toyoda A, Ichikawa K, Qu W,

Morishita S, Arita J, Tanaka M, Ushiku T,
Hasegawa K, Fujishiro M, Koike K.
MNX1-HNF1B Axis Is Indispensable for
Intraductal Papillary Mucinous Neoplasm
Lineages. Gastroenterology. 2022;162(4):12721287.
7. Kishino Y, Matsukawa K, Matsumoto T,
Miyazaki R, Wakabayashi T, Nonaka T,
Kametani F, Hasegawa M, Hashimoto T,
Iwatsubo T. Casein kinase 1δ/ε phosphorylates
fused in sarcoma (FUS) and ameliorates
FUS-mediated neurodegeneration. J Biol Chem.
2022;298(8):102191.
8. Ko T, Nomura S, Yamada S, Fujita K, Fujita T,
Satoh M, Oka C, Katoh M, Ito M, Katagiri M,
Sassa T, Zhang B, Hatsuse S, Yamada T, HaradaM, Toko H, Amiya E, Hatano M, Kinoshita O,
Nawata K, Abe H, Ushiku T, Ono M, Ikeuchi M,
Morita H, Aburatani H, Komuro I. Cardiac
fibroblasts regulate the development of heart
failure via Htra3-TGF-β-IGFBP7 axis. Nat
Commun. 2022;13:3275.
9. Kume A, Shinozaki-Ushiku A, Kunita A, Kondo
A, Ushiku T. Enhanced PD-L1 Expression in
LMP1-positive
Cells
of
Epstein-Barr
Virus-associated Malignant Lymphomas andLymphoproliferative Disorders: A Single-cell
Resolution
Analysis
With
Multiplex
Fluorescence Immunohistochemistry and In Situ
Hybridization. Am J Surg Pathol. 2022;46(10):1386-1396.
10. Liu B, Katoh H, Komura D, Yamamoto A, Ochi
M, Onoyama T, Abe H, Ushiku T, Seto Y, Suo J,
Ishikawa S. Functional genomics screening
identifies aspartyl-tRNA synthetase as a novel
prognostic marker and a therapeutic target for
gastric cancers. J Pathol. 2022;258(2):106-120.
11. Liu PY*, Fukuma N*, Hiroi Y*, Kunita A*,
Tokiwa H*, Ueda K, Kariya T, Numata G,
Adachi Y, Tajima M, Toyoda M, Li Y, Noma K,
Harada M, Toko H, Ushiku T, Kanai Y,
Takimoto E, Liao JK, Komuro I(*; equal
contributor). Tie2-Cre–Induced Inactivation of
Non-Nuclear Estrogen Receptor-α Signaling
Abrogates Estrogen Protection Against Vascular
Injury. JACC: Basic to Translational Science.
2022;8(1):55-67.

45

12. Miyashita H, Taoka K, Kume A, Ushiku A,
Ushiku T, Toyama K, Kurokawa M. Clinicalusefulness of a novel classification of T cell
distribution patterns in the tumor microenvironment of follicular lymphoma to detect
transformation. Ann Hematol. 2022;101(11):2477-2483.
13. Naito Y, Notohara K, Omori Y, Aishima S, Itoi T,
Ohike N, Okabe Y, Kojima M, Tajiri T, Tanaka
M, Tsuneki M, Nakagohri T, Norose T,
Hirabayashi K, Fukumura Y, Mitsuhashi T,
Yamaguchi H, Fukushima N, Furukawa T.
Diagnostic Categories and Key Features for
Pathological
Diagnosis
ofEndoscopic
Ultrasound-Guided Fine Needle Aspiration
Biopsy Samples of Pancreatic Lesions: A
Consensus Study. Pancreas. 2022;51(9):11051111.
14. Saito N, Sato Y, Abe H, Wada I, Kobayashi Y,
Nagaoka K, Kushihara Y, Ushiku T, Seto Y,
Kakimi K. Selection of RNA-based evaluation
methods for tumor microenvironment bycomparing with histochemical and flow
cytometric analyses in gastric cancer. Sci Rep.
2022;12:8576.
15. Takahashi K, Podyma-Inoue KA, Saito M,
Sakakitani S, Sugauchi A, Iida K, Iwabuchi S,
Koinuma D, Kurioka K, Konishi T, Tanaka S,
Kaida A, Miura M, Hashimoto S, Okada M,
Uchihashi T, Miyazono K, Watabe T. TGF-β
generates a population of cancer cells residing in
G1 phase with high motility and metastatic
potential via keratin-associated protein 2-3. Cell
Reports. 2022;40:111411.
16. Tanaka M, Kunita A, Yamagishi M, Katoh H,
Ishikawa S, Yamamoto H, Abe J, Arita J,
Hasegawa K, Shibata T, Ushiku T. KRAS
mutation in intrahepatic cholangiocarcinoma:
Linkage with metastasis-free survival andreduced E-cadherin expression. Liver Int. 2022;
42(10):2329-2340.
17. Yamazawa S, Ushiku T. Carcinosarcoma of thestomach: four cases that expand the morphologic
spectrum of gastric cancer with a primitive
phenotype. Virchows Arch. 2022;480(5):10511062.

46

Department of MolecularPathology
Professor
Yasuhiro Yamada, M.D.,Ph.D.

Assistant professors
Sho Ohta, Ph.D., Nao Sankoda, M.D., Ph.D.

Homepage

http://molpathology2.m.u-tokyo.ac.jp/home_E/index.html

Introduction and Organization
The Department of Molecular Pathology has a historyof more than 120 years, originating from the Second
Department of Pathology, of which the first professor
was Dr Katsusaburo Yamagiwa, who succeeded in
inducing artificial cancer by applying coal tar to rabbit
ears. In November 2022, Yasuhiro Yamada wastransferred from the Institute of Medical Science,
University of Tokyo, to succeed Professor Kohei
Miyazono, who retired in March 2022. The department
has been conducting basic research on cancer at theorganismal level as well as research on tissue
regeneration and aging. As of the end of March 2023,
the department comprised one professor and two
assistant professors, in addition to two researchers, ten
postgraduate students and two technical experts.

Teaching activities
Our department takes responsibility for lectures on“General Pathology” for undergraduate students of theFaculty of Medicine in collaboration with the
Department of Human Pathology. Since we believe it isvery important for medical students to study basic
oncology, we teach basic tumor biology in our lectures
on General Pathology. Given that the function of
oncogenes and cancer-suppressor genes, themechanismofviral
carcinogenesis,
cancerepidemiology, cancer genetics, the mechanism ofcancer invasion and metastasis as well as cancer
epigenetics are important issues in cancer biology, we

give intensive lectures on these topics. Practicaltraining included experiments on immunostaining oftumor tissue. During systematic lectures on oncology,
we hope that undergraduate students will get an
overview of cancer biology. We also supervise theresearch activities of the graduate students of thedepartment.
Our laboratory is located on the 11th floor of the
Research Building of the Graduate School of Medicine.
The Department of Molecular Pathology holds weekly
progress meetings in the department and a weekly
journal club to provide research guidance to students.

Research activities
Epigenetic regulation plays a critical role in cell fatespecification during normal development and stable
maintenance of somatic cell fate. Impairment in
epigenetic regulation is often associated with various
diseases such as cancer. Recent studies also imply thataltered epigenetic regulation is involved in cells ofaged organisms. Together, maintaining proper
epigenetic regulation is crucial for the healthy life oforganisms.
The development of reprogramming technologies, as
represented by iPS cell derivation, has enabled tocontrol of somatic cell fate. The reprogramming
process involves dynamic changes in epigenetic
modifications. Taking advantage of reprogramming
technology, we have devised reprogrammable mouse47

models in which epigenetic regulation and eventuallycell fate can be altered in vivo. By inducing
perturbation of epigenetic regulation and a cellular
identity at the organismal level, we aim to elucidate theimpact of epigenetic regulation on pathogenesis andaging. Finally, we aim to develop a means for disease
treatment, tissue regeneration, and rejuvenation
through epigenetic regulation with reprogramming
technologies.
Our effort should promote interdisciplinary researchthat connects a wide range of research fields, which
eventually contributes to the development of novel
strategies to control the detrimental effects of diseases
and aging in humans.
From 2017, our research has been supported by a
CREST program “Clarification of the Mechanism of
Individual’s Functional Impairment over the Entire
Life Course” from Japan Agency for Medical Researchand Development (AMED) (22gm1110004h9906).
From 2022, our research is also supported by a Projectfor Promotion of Cancer Research and Therapeutic
Evolution (P-PROMOTE) (22ama221201h0001) andby a Research Center Network for Realization ofRegenerative Medicine (22bm1223002h0001), bothfrom AMED.
Followings are research projects conducted at ourlaboratory in 2022.
1) Dissecting cancer biology with reprogramming
technology
Epigenetic regulation plays a critical role in the cellulardifferentiation, the stable maintenance of cellular
identity,
andthereprogramming
process.
Accumulating evidence suggests that epigenetic
abnormalities represented by abnormal DNA
methylation have been involved in various diseases. We
are interested in unveiling epigenetic regulation incellular differentiation, the maintenance of cellular
identity, and the pathogenesis including cancer. Taking
advantage of reprogramming technology, we havedevised reprogrammable mouse models in which
epigenetic regulation and eventually cell fate can bealtered in vivo. By analyzing in vivo reprogramming
process, we aim to uncover the epigenetic regulation incancer development, cancer cell maintenance, andprogression. Finally, we will try to develop a novel
approach targeting epigenetic regulation to treat cancer
patients.
2) In vivo reprogramming for tissue regeneration andrejuvenation
We have devised in vivo reprogramming systems(Reprogrammable Mouse) in which iPS cells can be
induced in living mice. Recent analyses of
Reprogrammable Mice have revealed unappreciatedmechanisms regarding senescence, tissue regeneration,and rejuvenation. By analyzing the response to cell fateperturbations at the organismal level, we aim to clarify
the molecular basis of aging and tissue regeneration.
Furthermore, we apply these reprogramming systems
to develop innovative strategies for tissue regeneration
and rejuvenation.
3) Expansion of mature islet cells as a regenerative
strategy targeting diabetes
We showed that a MYCL-mediated reprogramming
expands functional islet cells. We aim to apply thesemethods to islet transplantation therapy throughamplification of cadaveric islet cells in vitro. We also
try to induce the proliferation of mature islet cells invivo by gene therapy. The goal of our study is todevelop regenerative medicine and restore the functionof aging pancreatic islets using reprogramming
technology.

References
1

2

Hirano M, So Y, Tsunekawa S, Kabata M, Ohta S,
Sagara H, Sankoda N, Taguchi J, Yamada Y, Ukai
T, Kato M, Nakamura J, Ozawa M, Yamamoto T
and Yamada Y. MYCL-mediated reprogramming
expands pancreatic insulin-producing cells.
Nature Metabolism 2022 doi:10.1038/s42255022-00530-y
Ito K, Nagata K, Ohta S, Matsuda Y, Ukai T,
Yasuda I, Ota A, Kobayashi R, Kabata M, Sankoda
N, Maeda T, Woltjen K, Yang L, Maruyama R,
Katayama R, Yamamoto T and Yamada Y. The
oncogene-dependent resistance to reprogramming
unveils cancer therapeutic targets. Cell Reports
2022 doi:10.1016/j.celrep.2022.110721

48

3

4

Shimada-Takayama Y, Yasuda T, Ukai T, Taguchi
J, Ozawa M, Sankoda N, Ohta S and Yamada Y
Generation of mice for evaluating endogenous
p16Ink4a protein expression. Biochem. Biophys.
Res. Commun. 2022 9;599:43-50 doi:10.1016/j.
bbrc.2022.02.005
Oka K, Fujioka S, Kawamura Y, Komohara Y,
Chujo T, Sekiguchi K, Yamamura Y, Oiwa Y,
Omamiuda-Ishikawa N, Komaki S, Sutoh Y,
Sakurai S, Tomizawa K, Bono H, Shimizu A,
Araki K, Yamamoto T, Yamada Y, Oshiumi H and
Miura K. Resistance to chemical carcinogenesis
induction via a dampened inflammatory response
in naked mole-rats. Commun. Biol. 2022 5(1):287.
doi:10.1038/s42003-022-03241-y.

Pathology, Immunology andMicrobiology
2. Microbiology

50

Department of Microbiology
Professor
Makoto Takeda, M.D.,Ph.D.

Associate Professor
Hiroshi Katoh, Ph.D.

Associate
Yukiko Akahori, Ph.D

Homepage

http:// microbiology.labby.jp

Introduction and Organization
Following the retirement of Professor Masanori
Hatakeyama, who served as department head until
March 2022, Professor Makoto Takeda assumed theposition in September 2022. Currently, one professor(Takeda), one associate professor (Katoh), and one
assistant professor (Akahori) are engaged in researchand educational activities.

Teaching activities
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 activities
Our laboratory mainly studies respiratory RNA viruses,
such as paramyxoviruses, coronaviruses, and influenza
viruses. Our goal is to contribute to society by
elucidating molecular mechanisms of diseases causedby these viruses. We also aim to contribute to modern
medicine by developing new technologies forrecombinant viruses. In our research on themechanisms of paramyxovirus replication andpathogenesis, we search for host factors required forparamyxoviruses such as measles virus and mumps
virus to multiply in cells and study the pathogenic
mechanisms by clarifying their interactions with viralproteins. In the study of the activation mechanism of
respiratory viruses by host proteases, we have revealed
that membrane fusion proteins of various respiratory
viruses, including the novel coronavirus SARS-CoV-2,
are activated by a protease called TMPRSS2 in the hostcell. In addition, we have been researching thedevelopment of viral vectors and their application tovaccine development, making full use of theparamyxovirus gene manipulation technology we havestudied over the years.
Role of host protease TMPRSS2 in novel
coronavirus SARS-CoV-2 infection
In cultured cells, SARS-CoV-2 infects cells by
multiple pathways using different host proteases. We
have shown that the infection pathway using furin and
TMPRSS2 (early entry pathway) is particularly
important for SARS-CoV-2 infection. However, recent
studies have reported that the early entry pathway is notessential for the infection of the Omicron variant,which has recently become a significant epidemicstrain, and that the cathepsin-dependent pathway inendosomes (late entry pathway) is the primary route.
Our study also confirmed that the Omicron variant incultured cells is mainly infected using the late entry

51

pathway. However, in the airways of TMPRSS2
knockout mice, Omicron variant infection was also
severely restricted, as was the case with other variant
strains and the Wuhan strain in the early stages of theepidemic. Thus, in vivo, transmission of the Omicron
variant was confirmed to utilize the TMPRSS2dependent early entry pathway. In conclusion, the early
entry pathway using TMPRSS2 was shown to be
critically important for the infection of SARS-CoV-2,
including the Omicron variant.
Demonstration of bacterium-free very rapid reverse
genetics system using mumps virus
Mononegaviruses(non-segmented
negativestranded RNA viruses) include many medicallyimportant viruses such as measles virus, mumps virus,
and RS virus. In the study of mononegaviruses, genetic
engineering techniques for producing recombinantviruses are essential, however, in conventional methods,
the full-length genome of the virus must be introduced
into a plasmid and amplified in E. coli, which is timeconsuming and introduces mutations in E. coli. Thus,
we attempted to develop an E. coli-free full-length
genome construction of mumps virus, as an example ofmononegaviruses.
We succeeded in constructing a full-length genome bylinking and amplifying the mumps virus genome,
which was divided into four fragments, by PCR or the
OriCiro Cell-Free Cloning System. The full-lengthviral genomic DNA was transfected into BHK cells
expressing T7 polymerase together with helperplasmids, and then the cells were co-cultured with Verocells. Importantly, the virus was rescued in a shortertime with this method than with the conventional
plasmid-based method. Our newly developed rapid
genome construction method without using E. coli isuseful for genetic manipulation of mononegaviruses.
SNARE protein USE1 is involved in theglycosylation and the expression of mumps virus
fusion protein and important for viral propagation
We searched for host factors involved in the
propagation of mumps virus, which is a causative agentof mumps, using a proximity-labeling method. The
biotin ligase TurboID was split into N-terminal and Cterminal domains and introduced into the cytoplasmic
regions of two membrane proteins (F and HN proteins,respectively) of mumps virus. The two membraneproteins were co-expressed in cells and biotin wasadded. The resulting biotinylated proteins were
purified with streptavidin and identified by mass
spectrometry, resulting in the identification of 638
proteins as host factors localized close to thecytoplasmic regions of F and HN proteins. Gene
ontology and interactome analyses showed that thefactors categorized in "Vesicle transport" formed thelargest cluster. Next, 26 proteins were selected from thefactors classified as "Vesicle transport" based on the
results of mass spectrometry analysis, and siRNAtargeting for each factor was transfected into A549 cells.
Forty-eight hours after transfection, the cells were
infected with the AcGFP-expressing mumps virus, andthe effect on viral growth was examined using thebrightness of AcGFP. The results showed that theknockdown of 6 out of 26 factors significantly
suppressed viral growth. Among them, we focused on
USE1, a SNARE subfamily protein that interacts withF proteins in the ER, and analyzed its role in mumps
virus infection. The results of the fusion assay andendoglycosidase assay indicated that USE1 is a hostfactor that contributes to the stability and glycosylationof F protein by regulating the transport of F protein
between ER and Golgi.

References
1. Bae C, Katoh H, Wakata A, Sakata M, Kato F,
Takeda M: Demonstration of bacterium-free very
rapid reverse genetics system using mumps virus.
Microbiol Immunol 67:44-47, 2023.
2. Takashita E, Fujisaki S, Morita H, Nagata S, Miura
H, Nagashima M, Watanabe S, Takeda M,
Kawaoka Y, Hasegawa H: Assessment of thefrequency of SARS-CoV-2 Omicron variant escapefrom RNA-dependent RNA polymerase inhibitorsand 3C-like protease inhibitors. Antiviral Res
216:105671, 2023.
3. Ono T, Hashimoto K, Kume Y, Chishiki M, Okabe
H, Sato M, Norito S, Aso J, Sada M, Mochizuki I,
Mashiyama F, Ishibashi N, Suzuki S, Sakuma H,
Suwa R, Kawase M, Takeda M, Shirato K, Kimura
H, Hosoya M: Molecular Diversity of Human
Respiratory Syncytial Virus before and during the
COVID-19 Pandemic in Two Neighboring52

Japanese Cities. Microbiol Spectr 11:e0260622,
2023.
4. Takahashi T, Akagawa M, Kimura R, Sada M,
Shirai T, Okayama K, Hayashi Y, Kondo M,
Takeda M, Ryo A, Kimura H: Molecular
evolutionary analyses of the fusion protein gene inhuman respirovirus 1. Virus Res 333:199142, 2023.
5. Miyano S, Vynnycky E, Pattamavone C, Ichimura
Y, Mori Y, Nouanthong P, Phounphenghack K,
Tengbriacheu C, Khamphaphongphane B, Franzel
L, Yang TU, Raaijimarkers H, Komada K, Ota T,
Funato M, Takeda M, Hachiya M: Comparison of
population-based measles-rubella immunoglobulin
G antibody prevalence between 2014 and 2019 in
Lao People's Democratic Republic: Impacts of thenational immunization program. Int J Infect Dis
129:70-77, 2023.
6. Okura T, Tahara M, Otsuki N, Sato M, Takeuchi K,
Takeda M: Generation of a photocontrollable
recombinant bovine parainfluenza virus type 3.
Microbiol Immunol 67:204-209, 2023.
7. Kidokoro M, Shiino T, Yamaguchi T, Nariai E,
Kodama H, Nakata K, Sano T, Gotou K, Kisu T,
Maruyama T, Kuba Y, Sakata W, Higashi T, Kiyota
N, Sakai T, Yahiro S, Nagita A, Watanabe K,
Hirokawa C, Hamabata H, Fujii Y, Yamamoto M,
Yokoi H, Sakamoto M, Saito H, Shibata C, Inada
M, Fujitani M, Minagawa H, Ito M, Shima A,
Murano K, Katoh H, Kato F, Takeda M, Suga S;
Surveillance Team for Mumps Virus in Japan:
Nationwide
andlong-term
molecular
epidemiologic studies of mumps viruses thatcirculated in Japan between 1986 and 2017. Front
Microbiol 13:728831, 2022.
8. Iwata-Yoshikawa N, Kakizaki M, Shiwa-Sudo N,
Okura T, Tahara M, Fukushi S, Maeda K, Kawase
M, Asanuma H, Tomita Y, Takayama I, Matsuyama
S, Shirato K, Suzuki T, Nagata N, Takeda M:
Essential role of TMPRSS2 in SARS-CoV-2
infection in murine airways. Nat Commun 13:6100,
2022.
9. Seki F, Takeda M: Novel and classicalmorbilliviruses: Current knowledge of three
divergent morbillivirus groups. Microbiol
Immunol 66:552-563, 2022.
10. Wakata A, Katoh H, Kato F, Takeda M: Nucleolar
protein Treacle is important for the efficient growthof mumps virus. J Virol 96:e0072222. doi: 10.1128/
jvi.00722-22.
11. Liu Y, Katoh H, Sekizuka T, Bae C, Wakata A, Kato
F, Sakata M, Yamaji T, Wang Z, Takeda M: SNARE
protein USE1 is involved in the glycosylation andthe expression of mumps virus fusion protein andimportant for viral propagation. PLoS Pathog
18:e1010949, 2022.
12. Mori Y, Sakata M, Sakai S, Okamoto T, Nakatsu Y,
Taguwa S, Otsuki N, Maeda Y, Hanada K,
Matsuura Y, Takeda M: Membrane sphingomyelin
in host cells is essential for nucleocapsid
penetration into the cytoplasm after hemifusion
during rubella virus entry. mBio 13:e0169822.
13. Shirato K, Matsuyama S, Takeda M: Less frequent
sequence mismatches in variants of concern (VOCs)of SARS-CoV-2 in the real–time RT–PCR assays
developed by the National Institute of Infectious
Diseases, Japan. Jpn J Infect Dis 75:96-101, 2022.
14. Takashita E, Yamayoshi S, Fukushi S, Suzuki T,
Maeda K, Sakai-Tagawa Y, Ito M, Uraki R,
Halfmann P, Watanabe S, Takeda M, Hasegawa H,
Imai M, Kawaoka Y: Efficacy of Antiviral Agentsagainst the Omicron Subvariant BA.2.75. N Engl J
Med 387:1236-1238.
15. Takashita E, inoshita N, Yamayoshi S, SakaiTagawa Y, Fujisaki S, Ito M, Iwatsuki-Horimoto K,
Halfmann P, Watanabe S, Maeda K, Imai M,
Mitsuya H, Ohmagari N, Takeda M, Hasegawa H,
Kawaoka Y: Efficacy of antiviral agents against the
SARS-CoV-2 Omicron BA.2 variant. N Engl J Med
386:1475-1477, 2022.
16. Takashita E, Kinoshita N, Yamayoshi S, SakaiTagawa Y, Fujisaki S, Ito M, Iwatsuki-Horimoto K,
Chiba S, Halfmann P, Nagai H, Saito M, Adachi E,
Sullivan D, Pekosz A, Watanabe S, Maeda K, Imai
M, Yotsuyanagi H, Mitsuya H, Ohmagari N, Takeda
M, Hasegawa H, Kawaoka Y: Efficacy of antibodies
and antivirals against a SARS-CoV-2 omicron
variant. N Engl J Med 386:995-998, 2022.
17. Kitai Y, Sato K, Shirato K, Ohmiya S, Watanabe O,
Kisu T, Ota R, Takeda M, Kawakami K, Nishimura
H: Variation in thermal stability among respiratorysyncytial virus clinical isolates under non-freezing
conditions. Viruses 14:679, 2022.
18. Shirato K, Kakizaki M, Tomita Y, Kawase M,
Takeda M: Detection of the ORF1 gene is an53

indicator of the possible isolation of severe acuterespiratory syndrome coronavirus-2. Pathogens
11:302, 2022.
19. Saso W, Yamasaki M, Nakakita S, Fukushi S,
Tsuchimoto K, Watanabe N, Sriwilaijaroen N,
Kanie O, Muramatsu M, Takahashi Y, Matano T,
Takeda M, Suzuki Y, Watashi K: Significant role ofhost sialylated glycans in the infection and spreadof severe acute respiratory syndrome coronavirus
2. PLOS Pathog 18:e1010590, 2022.
20. Kanai M, Kamiya H, Okuno H, Sunagawa T,
Tanaka-Taya K, Matsui T, Oishi K, Kitajima H,
Takeda M, Mori Y: Epidemiology of congenital
rubella syndrome related to the 2012-2013 rubella
epidemic in Japan. J Pediatric Infect Dis Soc.
29:400-403, 2022.
21. Okura T, Shirato K, Kakizaki M, Sugimoto S,
Matsuyama S, Tanaka T, Kume Y, Chishiki M, Ono
T, Moriishi K, Sonoyama M, Hosoya M,
Hashimoto K, Maenaka K, Takeda M:
Hydrophobic alpha-helical short peptides inoverlapping reading frames of the coronavirus
genome. Pathogens 11:877, 2022.

54

Department of Infection Control
and Prevention
Professor
Takeya Tsutsumi, M.D., Ph.D.

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

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

Research Associate
Mayo Tsuboi, M.D., Ph.D.
Daisuke Ohki, M.D., Ph.D.
Ryu Yoneda, M.D., 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55

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.
4.

Research activities
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) Mechanisms and molecular epidemiology ofmulti-drug resistant microorganisms
4) Clinical characteristics and molecular epidemiology
of hypervirulent Klebsiella pnemoniae infection
5) Prevention and therapy for COVID-19
6) Epidemiology of Clostridioides difficile infection7) Molecular epidemiological analysis of MRSA
8) Prevention of endoscope-related infection9) Usefulness of environmental monitoring

5.

6.

Publications
1.

2.

3.

Takashita E, Yamayoshi S, Halfmann P, Wilson N,
Ries H, Richardson A, Bobholz M, Vuyk W,
Maddox R, Baker DA, Friedrich TC, O'Connor
DH, Uraki R, Ito M, Sakai-Tagawa Y, Adachi E,
Saito M, Koga M, Tsutsumi T, IwatsukiHorimoto K, Kiso M, Yotsuyanagi H, Watanabe S,
Hasegawa H, Imai M, Kawaoka Y. In Vitro
Efficacy of Antiviral Agents against Omicron
Subvariant BA.4.6. N Engl J Med. 2022;387:
2094.
Adachi E, Saito M, Koga M, Tsutsumi T,
Yotsuyanagi H. Favorable Outcome Following
Sotrovimab Monoclonal Antibody in a Patientwith Prolonged SARS-CoV-2 Omicron Infection
with HIV/AIDS. Intern Med. 2022;61:3459
Yamaoka Y, Sasai M, Suehiro Y, Hashimoto S,
Goto A, Yamamoto N, Suzuki N, Higaki S, Fujii I,
Suzuki C, Matsumoto T, Hoshida T, Koga M,
Tsutsumi T, Lim LA, Matsubara Y, Tomochika S,

7.

8.

Yoshida S, Hazama S, Yotsuyanagi H, Nagano H,
Sakaida I, Takami T, Yamasaki T. Comparison of
two primer-probe sets of Fusobacterium
nucleatum using droplet digital polymerase chain
reaction for the detection of colorectal neoplasia
from faecal samples. Ann Clin Biochem. 2022;
59:396.
Nagai H, Saito M, Adachi E, Sakai-Tagawa Y,
Yamayoshi S, Kiso M, Kawamata T, Koga M,
Kawaoka Y, Tsutsumi T, Yotsuyanagi H.
Casirivimab/Imdevimab for Active COVID-19
Pneumonia Which Persisted for Nine Months in a
Patient with Follicular Lymphoma during
Anti-CD20 Therapy. Jpn J Infect Dis. 2022;75:
608.
Mizutani T, Ishizaka A, Koga M, Tsutsumi T,
Yotsuyanagi H. Role of Microbiota in Viral
Infections and Pathological Progression. Viruses.
2022;14:950.
Halfmann PJ, Kuroda M, Armbrust T, Theiler J,
Balaram A, Moreno GK, Accola MA,
Iwatsuki-Horimoto K, Valdez R, Stoneman E,
Braun K, Yamayoshi S, Somsen E, Baczenas JJ,
Mitamura K, Hagihara M, Adachi E, Koga M,
McLaughlin M, Rehrauer W, Imai M, Yamamoto
S, Tsutsumi T, Saito M, Friedrich TC, O'Connor
SL, O'Connor DH, Gordon A, Korber B,
Kawaoka Y. Characterization of the SARS-CoV-2
B.1.621 (Mu) variant. Sci Transl Med. 2022;14:
eabm4908.
Uraki R, Kiso M, Iida S, Imai M, Takashita E,
Kuroda M, Halfmann PJ, Loeber S, Maemura T,
Yamayoshi S, Fujisaki S, Wang Z, Ito M, Ujie M,
Iwatsuki-Horimoto K, Furusawa Y, Wright R,
Chong Z, Ozono S, Yasuhara A, Ueki H,
Sakai-Tagawa Y, Li R, Liu Y, Larson D, Koga M,
Tsutsumi T, Adachi E, Saito M, Yamamoto S,
Hagihara M, Mitamura K, Sato T, Hojo M,
Hattori SI, Maeda K, Valdez R; IASO study
team; Okuda M, Murakami J, Duong C, Godbole
S, Douek DC, Maeda K, Watanabe S, Gordon A,
Ohmagari N, Yotsuyanagi H, Diamond MS,
Hasegawa H, Mitsuya H, Suzuki T, Kawaoka Y.
Characterization and antiviral susceptibility of
SARS-CoV-2 Omicron BA.2. Nature. 2022;607:
119.
Adachi E, Nagai E, Saito M, Isobe M, Konuma T,

56

9.

10.

11.

12.

13.

14.

Koga M, Tsutsumi T, Nannya Y, Yotsuyanagi H.
Anti-spike protein antibody titer at the time ofbreakthrough infection of SARS-CoV-2 omicron.
J Infect Chemother. 2022;28:1015.
Mizutani T, Ishizaka A, Koga M, Ikeuchi K, Saito
M, Adachi E, Yamayoshi S, Iwatsuki-Horimoto K,
Yasuhara A, Kiyono H, Matano T, Suzuki Y,
Tsutsumi T, Kawaoka Y, Yotsuyanagi H.
Correlation Analysis between Gut Microbiota
Alterations and the Cytokine Response inPatients with Coronavirus Disease during
Hospitalization. Microbiol Spectr. 2022;10:e0168921.
Adachi E, Saito M, Nagai H, Ikeuchi K, Koga M,
Tsutsumi T, Yotsuyanagi H. Transient depletionof T cells during COVID-19 and seasonal
influenza in people living with HIV. J Med Virol.
2022;94:1789
Koga M, Senkoji T, Kubota M, Ishizaka A,
Mizutani T, Sedohara A, Ikeuchi K, Kikuchi T,
Adachi E, Saito M, Koibuchi T, Hosomichi K,
Ohashi J, Kawana- Tachikawa A, Matano T,
Tsutsumi T (corresponding author), Yotsuyanagi
H. Predictors associated with a better response to
the Japanese aluminum-free hepatitis A vaccine,
Aimmugen®, for people living with HIV.
Hepatol Res. 2022;52:227
Ikeuchi K, Okushin K, Saito M, Adachi E,
Tsutsumi T, Takura T, Yotsuyanagi H. Prevalenceof HIV infection among non-elderly individuals
with hepatitis C in Japan: a population-based
cohort study using a health insurance claim data.
BMC Infect Dis. 2022;22:167.
Sekiba K, Otsuka M, Funato K, Miyakawa Y,
Tanaka E, Seimiya T, Yamagami M, Tsutsumi T,
Okushin K, Miyakawa K, Ryo A, Koike K.
HBx-induced degradation of Smc5/6 complex
impairs homologous recombination-mediatedrepair of damaged DNA. J Hepatol. 2022;76:53.
Yamaguchi R, Okamoto K, Yamamoto T, Harada
S, Tanaka T, Suzuki H, Moriya K. Impact oftargeted intervention using a collaborative
approachfororalthird-generation
cephalosporins: An interrupted time-series
analysis. Antimicrob Steward Healthc Epidemiol.
2022;2:e115.

15. Kurano M, Jubishi D, Okamoto K, Hashimoto H,
Sakai E, Morita Y, Saigusa D, Kano K, Aoki J,
Harada S, Okugawa S, Doi K, Moriya K, Yatomi
Y. Dynamic modulations of urinary sphingolipid
and glycerophospholipid levels in COVID-19 andcorrelations with COVID-19-associated kidney
injuries. J Biomed Sci. 2022;29:94.
16. Kurano M, Okamoto K, Jubishi D, Hashimoto H,
Sakai E, Saigusa D, Kano K, Aoki J, Harada S,
Okugawa S, Doi K, Moriya K, Yatomi Y.
Dynamic modulations of sphingolipids andglycerophospholipids in COVID-19. Clin Transl
Med. 2022;12:e1069.
17. Ohama Y, Nomura Y, Mizoguchi M, Higurashi Y,
Okamoto K, Harada S. Accurate Identification of
Klebsiella variicola by MALDI-TOF Mass
SpectrometryinClinicalMicrobiology
Laboratories. Microbiol Spectr. 2022;10:e0284422.
18. Hoashi K, Hayama B, Suzuki M, Sakurai A,
Takehana K, Enokida T, Takeda K, Ohkushi D,
Doi Y, Harada S. Comparison of the Treatment
Outcome of Piperacillin-Tazobactam versus
Carbapenems for Patients with Bacteremia
Caused by Extended-Spectrum β-LactamaseProducing Escherichia coli in Areas with Low
Frequency of Coproduction of OXA-1: aPreliminary Analysis. Microbiol Spectr. 2022 31;
10:e0220622.
19. Jubishi D, Okamoto K, Hamada K, Ishii T,
Hashimoto H, Shinohara T, Yamashita M,
Wakimoto Y, Otani A, Hisasue N, Ikeda M,
Harada S, Okugawa S, Moriya K, Yanagimoto S.
The association between adverse reactions andimmune response against SARS-CoV-2 spike
protein after vaccination with BNT162b2 among
healthcare workers in a single healthcare system:a prospective observational cohort study. Hum
Vaccin Immunother. 2022 30;18:2048559.
20. Jin C, Wakimoto Y, Ikeda M, Ohama Y, Ri M,
Yamashita H, Ohtani A, Yamashita M, Shinohara
T, Jubishi D, Kanno Y, Okamoto K, Higurashi Y,
Harada S, Okugawa S, Seto Y, Moriya K. Humanabdominal abscess caused by Necropsobacterrosorum and tips for its identification: A casereport. J Infect Chemother. 2022;28:833.

57

21. Morita Y, Kurano M, Jubishi D, Ikeda M,
Okamoto K, Tanaka M, Harada S, Okugawa S,
Moriya K, Yatomi Y. Urine sediment findings
were milder in patients with COVID-19associated renal injuries than in those with nonCOVID-19-associated renal injuries. Int J InfectDis. 2022;117:302.
22. Hoshi K, Ikebe T, Ota Y, Kishimoto H, Kurata T,
Kurita H, Sakamaki K, Takenobu T, Harada S,
Ogasawara T, Tei K, Kirita T. Guide for surgicalprocedures in oral and maxillofacial areas during
coronavirus disease 2019 pandemic. J Oral
Maxillofac Surg Med Pathol. 2022;34:294
23. Nakamura M, Satoh N, Horita S, Nangaku M.
Insulin-inducedmTOR
signaling
andgluconeogenesis in renal proximal tubules: A
mini-review of current evidence and therapeuticpotential. Front Pharmacol. 2022;13:1015204.
24. Mizuno T, Satoh N, Horita S, Tsukada H, Takagi
M, Sato Y, Kume H, Nangaku M, Nakamura M.
Oxidized alkyl phospholipids stimulate sodiumtransport in proximal tubules via a nongenomic
PPARγ-dependent pathway. J Biol Chem. 2022;
298:101681.
25. Okushin K, Tateishi R, Takahashi A, Uchino K,
Nakagomi R, Nakatsuka T, Minami T, Sato M,
Fujishiro M, Hasegawa K, Eguchi Y, Kanto T,
Kubo S, Yoshiji H, Miyata H, Izumi N, Kudo M,
Koike K. Current status of primary liver cancer
and decompensated cirrhosis in Japan: launch ofa nationwide registry for advanced liver diseases(REAL). J Gastroenterol. 2022;57:587.
26. Saito K, Shimamoto T, Takahashi Y, Okushin K,
Takahashi M, Masuda Y, Nishikawa T,
Kakushima N, Wada R, Yamamichi N.
Gender-specific factors contributing to visceralobesity including the sleep-obesity relationship: alarge-scale cross-sectional study from East Asia.
Sci Rep. 2022;12:20318.
27. Yamamichi N, Shimamoto T, Okushin K,
Nishikawa T, Matsuzaki H, Yakabi S, Takahashi
M, Wada R, Koike K, Fujishiro M. Fibrosis-4
index efficiently predicts chronic hepatitis andliver cirrhosis development based on alarge-scale data of general population in Japan.
Sci Rep. 2022;12:20357.

28. Kawamura S, Matsushita Y, Kurosaki S, Tange
M, Fujiwara N, Hayata Y, Hayakawa Y, Suzuki
N, Hata M, Tsuboi M, Kishikawa T, Kinoshita H,
Nakatsuka T, Sato M, Kudo Y, Hoshida Y,
Umemura A, Eguchi A, Ikenoue T, Hirata Y,
Uesugi M, Tateishi R, Tateishi K, Fujishiro M,
Koike K, Nakagawa H. Inhibiting SCAP/SREBP
exacerbates liver injury and carcinogenesis inmurine nonalcoholic steatohepatitis. J Clin Invest.
2022;132:e151895.
29. Ohki D, Tsuji Y, Shinozaki T, Sakaguchi Y,
Mizutani H, Nagao S, Miura Y, Fukagawa K,
Tamura N, Yakabi S, Yamamichi N, Fujishiro M.
Long-term prognosis after endoscopic resectionof T1a-MM/T1b-SM1 esophageal squamous cell
carcinoma. Medicine. 2022;101:e32115.
30. Hisada H, Tsuji Y, Obata M, Cho R, Nagao S,
Miura Y, Mizutani H, Ohki D, Yakabi S,
Takahashi Y, Sakaguchi Y, Kakushima N,
Yamamichi N, Fujishiro M. The impact ofsarcopenia on short- and long-term outcomes ofendoscopic submucosal dissection for earlygastric cancer. J Gastroenterol. 2022;57:952.
31. Kubota D, Takahashi Y, Yamamichi N, Matsui
M, Shimamoto T, Minatsuki C, Nakagawa H,
Mizutani S, Tsuji Y, Sakaguchi Y, Tamura N,
Yakabi S, Ohki D, Mizutani H, Niimi K, Wada R,
Fujishiro M. Analysis of Barrett's Esophagus and
Its Risk Factors: A Cross-Sectional Study of
10,122 Subjects at a Japanese Health
Examination Center. Digestion. 2022;103:411.
32. Ohki D, Tsuji Y, Tanaka M, Ushiku T, Fujishiro
M. A case of a tiny neuroendocrine carcinoma ina large flat-elevated rectal tumor causing multiple
liver metastases. Clin J Gastroenterol. 2022;15:
1078.
33. Ohki D, Tsuji Y, Cho R, Obata M, Mizutani H,
Sakaguchi Y, Fujishiro M. Management of
intraoperative giant perforation of colorectal
endoscopic submucosal dissection. Endoscopy.
2022;54(S 02):E995.
34. Hisada H, Sakaguchi Y, Oshio K, Mizutani S,
Nakagawa H, Sato J, Kubota D, Obata M, Cho R,
Nagao S, Miura Y, Mizutani H, Ohki D, Yakabi
S, Takahashi Y, Kakushima N, Tsuji Y,
Yamamichi N, Fujishiro M. Endoscopic

58

35.

36.

37.

38.

39.

Treatment of Superficial Gastric Cancer: Present
Status and Future. Curr Oncol. 2022;29:4678.
Tamura N, Sakaguchi Y, Furutani W, Matsui M,
Nagao S, Sakuma N, Fukagawa K, Miura Y,
Mizutani H, Ohki D, Kataoka Y, Saito I, Ono M,
Minatsuki C, Tsuji Y, Ono S, Kodashima S, Abe
H, Ushiku T, Yamamichi N, Koike K, Fujishiro
M. Magnifying endoscopy with narrow-band
imaging is useful in differentiating gastric cancerfrom matched adenoma in white light imaging.
Sci Rep. 2022;12:8349.
Ohki D, Yamamichi N, Sakaguchi Y, Takahashi
Y, Kageyama-Yahara N, Yamamichi M,
Takeuchi C, Tsuji Y, Sakai Y, Sakurai K, Tomida
S, Koike K, Fujishiro M. Transcriptome ofsessile serrated adenoma/polyps is associatedwith MSI-high colorectal cancer and decreased
expression of CDX2. Cancer Med. 2022;11:5066.
Hisada H, Tamura N, Tsuji Y, Nagao S,
Fukagawa K, Miura Y, Mizutani H, Ohki D,
Yakabi S, Minatsuki C, Takahashi Y, Sakaguchi
Y, Yamamichi N, Fujishiro M. The impact ofsarcopenia on adverse events associated withgastric endoscopic submucosal dissection. Surg
Endosc. 2022;36:6387.
Fujimoto A, Saito Y, Abe S, Hoteya S, Nomura
K, Yasuda H, Matsuo Y, Uraoka T, Kuribayashi
S, Tsuji Y, Ohki D, Maehata T, Kato M, Yahagi
N. Clinical usefulness of red dichromatic imaging
in hemostatic treatment during endoscopic
submucosal dissection: First report from amulticenter, open-label, randomized controlled
trial. Dig Endosc. 2022;34:379.
Ikeyama S, Kanda S, Sakamoto S, Sakoda A,
Miura K, Yoneda R, Nogi A, Ariji S, Shimoda M,
Ono M, Kanda S, Yokoyama S, Takahashi K,
Yokoyama Y, Hattori M. A case of early onset
cystinuria in a 4-month-old girl. CEN Case Rep.
2022;11:216.

Pathology, Immunology andMicrobiology
3. Immunology

60

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

Associate Professor
Takeshi Nitta, Ph.D.

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

Homepage

http://www.osteoimmunology.com/

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

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

generation of scientists. Undergraduate students of thefaculty take part in departmental class work throughlectures on immunobiology, immunochemistry andmolecular immunology as well as practical training by
way of laboratory courses on basic immunology
experimental techniques. The education of graduate
students is based on weekly seminars where students
present the progress of their own research projects,
discuss the future directions of their research and theresearch of others, and are exposed to the latest
cutting-edge questions confronting the research fieldof immunology. We also offer a special training course(called ‘free quarter’) of basic and advanced
biological and immunological techniques to medical
students. We are also accepting undergraduate
students as Medical Scientist Training Program infaculty of medicine. In fiscal year 2022, special
lectures for undergraduate students were given byinternationally recognized scientists, Dr. Shimon
Sakaguchi (Osaka Univ.), Dr. Hisashi Arase (Osaka
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61

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

activated T cells c1 (NFATc1) as a master regulator for
osteoclast differentiation (Takayanagi et al., Dev Cell,
2002; Asagiri et al., J. Exp. Med., 2005). We also
identified an ITAM-harboring co-receptor for RANK
(Koga et al., Nature, 2004) and the importance ofbridging signal cascade between RANK and ITAM
via Btk for RANK dependent osteoclastogenesis(Shinohara et al., Cell, 2008; Shinohara et al., Bone,2014). Our recent proteomic analysis identified
multiple target proteins phosphorylated upon
differentiation of osteoclasts (Sumiya et al., Biochem
Biophys Res Commun., 2015).
Furthermore, we have revealed the roles of
Semaphorin4D
onosteoblast
differentiation(Negishi-Koga et al., Nature Med. 2011) andSemaphorin3A on inhibition of bone resorption as
well as promotion of bone formation (Hayashi et al.,Nature, 2012; Hayashi et al., Cell Metab., 2019). We
also found that immune complexes in serum activate
osteoclastogenesis and cause bone loss throughbinding to Fc receptors (Negishi-Koga et al., Nat
Commun., 2015). To understand the precise
mechanisms underlying cell fate specification duringosteoclast differentiation, we performed single-cell
RNA sequencing (scRNA-seq) analysis on the in vitro
osteoclast culture system, and provided acomprehensive picture of molecular processes
underlying osteoclastogenesis (Tsukasaki et al., Nat
Metab., 2020, Tsukasaki et al., Inflamm Regen., 2022).
We also reported that, using a bone-fracture model inmouse, the cytokine IL-17 promotes bone fracture
healing via osteoblastic bone formation and that Tcells are the major source of IL-17 produced in thebone injury site (Ono et al., Nat Commun., 2016).
Although it has been known that IL-17 enhancesosteoclastic bone resorption in certain pathologicalsituations, our current results clearly show thepromoting 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

62

products. Second, they inhibit bacterial dissemination
by removing the tooth. Thus, exFoxp3Th17 cells playa beneficial role in the host defense against oral
bacteria. This investigation highlighted the notion that
T-cell-mediated bone damage, which was considered
to be an adverse consequence of inflammation, may
have developed to contribute to host defense against
oral bacteria (Tsukasaki et al., Nat Commun., 2018).
An anti-RANKL neutralizing antibody has been
introduced for the treatment of osteoporosis,
skeletal-related events by bone metastasis and bone
destruction in rheumatoid arthritis. We havedemonstrated that oral administration of the novel
small-molecule inhibitor against RANKL suppressedbone metastasis using the mouse models, indicating
the great efficacy of RANKL inhibition with asmall-molecule compound in bone metastasis (Nakai
et al., Bone Res., 2019). RANKL is synthesized asmembrane-bound molecule, and cleaved into its
soluble form by proteases. We have reported thatsoluble RANKL is dispensable for physiologicalregulation of bone and immune systems, but has adistinct and pivotal role in the promotion of bonemetastasis (Asano et al., Nat Metab., 2019). TheRANKL system plays a central role in bone andimmune homeostasis, but the source of OPG, thedecoy receptor for RANKL, has long been unknown.
We generated OPG-floxed mice and showed that
locally produced OPG, but not circulating OPG, has a
crucial function in the thymus, bone, and intestine(Tsukasaki et al., Cell Rep., 2020). The periosteum, amembranous tissue covering the outer surface ofbones, has been considered to be involved only inintramembranous bone formation at the cortex. We
revealed that stem cells residing in the periosteum
control the homeostasis of growth plate and bonemarrow by secreting soluble factor Ihh, highlighting
the importance of the periosteum as the key player inthe osteoimmue system (Tsukasaki et al., Nature
Commun., 2022). 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 thethymus is mainly composed of thymic epithelial cells
that regulate selections of developing T cells.
Recently, we focused on thymic fibroblasts, astromal cell type with uncharacterized function in thethymus, and established a method to isolate the thymic
fibroblast subsets, capsular fibroblasts and medullary
fibroblasts. Our results demonstrated that medullary
fibroblasts contribute to the induction of T cell
self-tolerancebyproducingauniquesetofself-antigens (Nitta et al, Nat Immunol., 2020; Nitta etal, Immunol Rev., 2021; Nitta, Inflamm Regen., 2022).
Fibroblasts have been attracting much attention inrecent years due to their functional diversity indifferent organs and their ability to control various
biologicalresponses

throughinteractions

withimmune cells. It is expected that our findings
contribute to the elucidation of the functions ofvarious types of fibroblasts in vivo. In addition, we
reported that the transcription factor Sox4 is required
for the development of thymic tuft cells, a subset ofterminally differentiated medullary thymic epithelial
cells (mTECs) （Mino et al, Int Immunol 2022）. Ourfindings suggest that mTECs employ the sametranscription programs as peripheral epithelial cells to‘project’ an immunological self within the thymus forthe establishment of central self-tolerance.
We have reported that the genetic variations ofhuman PSMB11 gene, which encodes 5t, a thymusspecific proteasome subunit, affected the MHC class
I-bound peptide repertoire in the thymus and positive
selection of CD8 T cells (Nitta et al., Sci Immunol.,2017). One of the PSMB11 polymorphisms, G49S,
detected in the Japanese population at a highfrequency, was associated with a higher risk of
Sjögren’s syndrome. These results suggested that, in
addition to the MHC haplotype, genetic variations ofproteasome influence T cell repertoire selection andsusceptibility to autoimmunity. Elucidation of theprinciples of T-cell repertoire selection is one of most

63

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 (Muroet 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 amarked reduction of V5V1 T cells in the thymus
and skin, but had normal development of other Tcell subsets and leukocytes. This study indicates an
exclusive function of Skint family genes in thedevelopment of V5V1 T cells and provides auseful animal model to analyze the mechanism forthymic education of T cells.
Much attention has been paid to the development
and function of the gut-associated lymphoid tissues(GALTs) and the symbiotic relationship between thegut microbiota and host immune system. We
identified a previously unrecognized subset ofmesenchymal cells in the subepithelial dome of
GALTs (Nagashima et al., Nat Immunol., 2017).
These cells expressed high levels of RANKL anddirectly interacted with the gut epithelium to induce
microfold (M) cell differentiation and CCL20
expression. The deletion of RANKL in mesenchymal
cells impaired M cell-dependent antigen sampling,which resulted in a reduction in IgA production and adecrease in microbial diversity, indicating thatsubepithelial RANKL-expressing mesenchymal cells(M cell inducer (MCi) cells) are key players in themaintenance of host-microbe symbiosis. Furthermore,
we reported that Col6a1-Cre driver mice are useful tostudy the function of MCi cells (Nagashima et al.,Biochem Biophys Res Commun., 2017). Manipulationof MCi cells may provide a molecular basis for novel
treatments of intestinal diseases such as inflammatory
bowel disorders and infectious diseases.
We have recently found that protein arginine

methylation, a post-translational modification, is an
essential regulator of T cell maintenance. T
cell-specificdeficiency
ofthearginine
methyltransferase PRMT5 led to a decrease in thenumber of peripheral CD4, CD8 and regulatory T cells,
and an almost complete loss of iNKT cells.
PRMT5-mediated arginine methylation was essential
for the expression of the cytokine-signal-transducing
components, the common cytokine receptor γ-chain(γc) and JAK3, which are required for thedevelopment of iNKT cells and the proliferation andsurvival of peripheral T cells. PRMT5 induced thearginine methylation of the spliceosomal component
SmD3 that promoted the splicing of pre-mRNA
encoding γc and JAK3. In recent years, Jak inhibitors
have attracted attention as potential agents for the
autoimmune diseases such as rheumatoid arthritis.
This study presented an entirely new regulatory
mechanism governing γc family cytokine-Jak3
signaling in T cells (Inoue et al., Nat Immunol., 2018).
3) Mechanism of autoimmune disease
The IL-17 producing helper T cell subset (Th17cell) plays critical roles in several autoimmune diseasemodels such as collagen induced arthritis (CIA) andexperimental encephalomyelitis (EAE). We haveidentified 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 thatrobustly produces IL-17 and RANKL and exacerbates
both inflammation and bone destruction in CIA mice.
Interestingly these Th17 cells are the progeny of CD4
T cells expressing Foxp3, a master regulator for
immunosuppressive Treg cells (Komatsu et al., Nat
Med., 2014). We also reported that RANKL producedby synovial fibroblasts is primarily responsible for theformation of bone-destructive osteoclasts in inflammatory arthritis (Danks et al., Ann Rheum Dis., 2016).
We identified that the transcription factor ETS1 iscritical for polarization of tissue-destructive synovial
fibroblasts by upregulating both RANKL and MMP
expression (Yan et al., Nat Immunol., 2022).
Periarticular bone loss is one of the earliest indices ofRA, often preceding the onset of clinical symptoms
via largely unknown mechanisms. We found that bone

64

marrow plasma cells promote periarticular bone loss
as RANKL-expressing osteoclast inducer cells(Komatsu et al., J Clin Invest., 2021). These results
taken together propose the importance of theimmune-fibroblast-bone triad in autoimmune arthritis
and suggest that the targeting pathogenic cells and/or
molecules could be effective in preventing bone
destruction in RA (Komatsu and Takayanagi, Nat Rev
Rheumatol. 2022).
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 etal., Immunity, 2015).
We have also been studying the mechanism of T
cell tolerance induction, because a breakdown of T
cell tolerance induces autoimmune diseases. Selftolerance of T cells is primarily established during
their development in the thymic medulla, wheremTECs
ectopically
expressavarietyoftissue-restricted antigens (TRAs) and thereby
TRA-reactive immature T cells are deleted. It has
been known that expression of a set of TRAs isregulated by the transcriptional regulator Aire,although how the remaining TRAs are regulated has
been unclear. We identified a novel key transcription
factor Fezf2, which is highly expressed in mTECs andcontrols the expression of a large fraction of
Aire-independent TRAs (Takaba et al., Cell, 2015).
Mice lacking Fezf2 in mTECs exhibited severe
autoimmune disorders in peripheral organs, and thespectrum of autoimmunity in Fezf2-deficient micediffered from that in Aire-deficient mice. These
results indicate that two independent factors, Fezf2
and Aire, play non-redundant and mutually complementary roles in the TRA expression to ensure T cell
tolerance induction. In addition, we identified Chd4 as
chromatin remodeler interacting with Fezf2. Chd4
works with not only Fezf2 but Aire to promote
promiscuous TRA expression in mTECs, mediating

central immune tolerance (Tomofuji et al., Nat
Immunol., 2020). Thus, these studies represented
important advance in our understanding of themechanisms underlying the immune tolerance andautoimmune diseases.

References
Nitta et al., Fibroblasts as a source ofself-antigens for central immune tolerance. Nat
Immunol., 21: 1172–1180. (2020)
2. Nitta et al., The fibroblast: an emerging key
player in thymic T cell selection. Immunol Rev,
302: 68-85. (2021)
3. Mino et al., The Transcription Factor Sox4 is
Required for Thymic Tuft Cell Development. Int
Immunol., 34: 45-52. (2022)
4. Yan M et al., ETS1 governs pathological tissueremodeling programs in disease-associatedfibroblasts. Nat Immunol. 23(9):1330-1341.
(2022)
5. Komatsu et al., Plasma cells promoteosteoclastogenesis and periarticular bone loss in
autoimmune arthritis. J Clin Invest., 131:
e143060. (2021)
6. Komatsu N and Takayanagi H Mechanisms ofjoint destruction in rheumatoid arthritis—immune system–fibroblast–bone interactions
Nat Rev Rheumatol. 18(7):415-429. (2022)
7. Tomofuji et al., Chd4 choreographs self-antigen
expression for central immune tolerance. Nat
Immunol., 21: 892–901. (2020)
8. Nitta, Mesenchymal stromal cells in the thymus.
Inflamm Regen., 42:33. (2022)
9. Tsukasaki et al., Periosteal stem cells control
growth plate stem cells during postnatal skeletal
growth. Nature Communications 13:4166.
(2022)
10. Tsukasaki et al., Osteoclast biology in the
single-cell era. Inflamm Regen., 42:27. (2022)
1.

Radiology and Biomedical
Engineering
1. Radiology

66

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

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

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

Project Lecturer
Mami Ogita, M.D., Ph.D., Eisuke Shibata, M.D., Ph.D.

Assistant Professor
Nawa Yobu, Ph.D., Koichiro Yasaka, M.D., Ph.D., Yusuke Watanabe, M.D., Ph.D., Yudai
Nakai, M.D., Ph.D., Takatoshi Kubo, M.D., Ph.D., Ryo Kurokawa, M.D., Ph.D., Masafumi
Kaiume, M.D., Ph.D., Subaru Sawayanagi, M.D., Yosuke Miki, M.D., Ph.D., Ryu Miyagawa,
Ph.D.

Project Assistant Professor
Shohei Inui, M.D., Ph.D., Saori Koshino, M.D. Takeshi Ohta, R.T., Ph.D., Hisaichi Shibata,Ph.D., Tomomi Takenaga, R.T., Ph.D., Yuki Nozawa, M.Sc.

Homepage

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

Introduction and Organization

Clinical activities

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 2 assistant professor) positions. In addition, Department ofRadiology mainly takes care of radiation protection
and radiation safety in the hospital.

Clinical services on Diagnostic Radiology,
Nuclear Medicine, and Radiation Oncology areprovided in the Radiology Center 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

67

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.
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 Inpatient Building A, there
are 12 beds in the Radiology ward, which areusually used for oncology patients receiving
radiation therapy and chemotherapy. Some of them
are sometimes used for patients receiving invasive
diagnostic procedures such as interventional
radiology (IVR), angiography and myelography.
There are two special beds for radionuclide (RN)
therapy in the same floor. In addition, four beds areallotted to terminal care ward located in the 14th
floor.

Education
Lectures are given to the fourth-, fifth- andsixth-year students to provide fundamental
knowledge of diagnostic radiology, radiation
oncology, and nuclear medicine. Professor,
associate professors and lecturers as well as
specialists assigned as part time lecturers take partin the education. A series of lectures about
fundamentals of radiology and related sciences are
given to the fourth-year students. As bed-sidelearning (Clinical Clerkship, CC) curriculum, small
groups of the sixth-year students are taking part inmini-lectures and practice to learn basics ofdiagnostic radiology, advanced medical techniquesof Radiation Oncology and Nuclear Medicine. They
will learn detailed principles of image constructions
in various kinds of imaging modalities andtechnology in radiation therapy against cancer.
Postgraduate students are also welcome to each ofsubspecialties of radiology according to theirinterests.

ResearchResearch activities in our department include
clinical research, animal experiments, and develop-

ment 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- or four-dimensional(3D, 4D) fashion. Using the data acquired by
MDCT, various kinds of diseases in almost all partsof the body, from cerebral to musculoskeletal
diseases, can be displayed in 3D or time-resolved
3D images. New 3D software developed in our
departments is now widely used in the field of thegastrointestinal tract, lung, and central nervous
system. In addition, we have opened a newlaboratory section named Image Computing andAnalysis Laboratory with invitation of experts ofengineering. 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, structural and functional MRI,
perfusion and diffusion imaging are the researchesof interest. 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 for68metastatic 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,such as head and neck cancer, prostate cancer, rectal
cancer and lung cancer, has been investigated in
combination with 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 underinvestigation in collaboration 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.

Conclusion
Diagnostic radiology, radiotherapy and nuclear
medicine are the three pillars that support radiology.
Mutual cooperation among these three fields, which
are divided by modality, is the basis forcomprehensive
diagnostic
imagingandmultidisciplinary treatment, and our department has
been working vigorously toward its realization. In
the future, there is a strong need to train more
field-oriented radiologists who have cross-cutting
knowledge, experience, and research achievementsin each field.

Publications
One hundred and twenty-six, 137, and 83 English
original articles have been published from ourdepartment in 2022, 2021, and 2020. respectively.
Please refer to our homepage, http://www.utradiology.umin.jp/publication/2022.html.

Radiology and Biomedical
Engineering
2. Biomedical Engineering

70

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

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

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

Introduction and Organization
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 cellular sensing
and response mechanisms to mechanical stimuli. The
main theme of our work is the relationships between
shear stress or cyclic strain, which are hemodynamic
forces generated by blood flow, and their target cells,
vascular endothelial cells (ECs). This would be of
benefit not only to understanding blood flow-mediatedregulation of vascular functions but also to theelucidation of clinically important problems such as
angiogenesis, vascular remodeling, atherogenesis, anddevelopment 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 areanalyzed 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
6. Hemodynamic force-induced changes in plasma
membrane cholesterol levels

71

1. Cell responses to hemodynamic forces
Our studies have demonstrated that ECs havefunctional responses to hemodynamic forces, shear
stress and cyclic strain. When a cultured EC monolayer
was partially denuded, surrounding cells migrated andproliferated in the denuded area, and covered thedenuded area. Shear stress enhanced the regenerative
functions of ECs. Shear stress increased the productionof nitric oxide, a potent vasodilator, in ECs in a dosedependent manner. Shear stress also increased theexpression of thrombomodulin, an antithrombotic
molecule, in ECs. In contrast, it decreased theexpression of vascular cell adhesion, which leads to theinhibition of leukocyte adhesion to vascular celladhesion molecule-1 (VCAM-1). It was shown thatshear stress increases the levels of adrenomedulin andC-type natriuretic peptide mRNA which havevasodilating effects in addition to nitric oxide, and thatit also augmented the expression of lectin like low
density lipoprotein receptor (LOX-1) at the protein andmRNA 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 Gprotein coupled receptor was cloned. We showed thatthe transcription factor SP1 is involved in the shear
stress-induced down-regulation of P2X4 (an ATP-gatedcation channel) gene expression in ECs. We also
revealed that endothelial genes are differentiallyregulated by laminar and turbulent shear stress.
Laminar shear stress decreases the gene expression of
urokinase plasminogen activator (uPA), which plays arole in fibrinolysis and vascular remodeling, via both
GATA6-mediateddown-regulationofgene

transcription and an acceleration of mRNA degradation,
while turbulent shear stress increases the uPA gene
expression through mRNA stabilization. We
demonstrated that shear stress up-regulates the gene
expression of plasminogen activator inhibitor-1 (PAI1) through activation of transcription factors Sp-1 andEts-1 in human hepatocytes. We developed a compliant
tube-type flow-loading device that allows simultaneous
application of physiological levels of shear stress andcyclic strain to cultured cells and observed that the
response of endothelial genes to shear stress or cyclicstrain depends on whether the two 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 the arterial
EC marker ephrinB2 in EPCs, while it decreased thegene 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 for use
in regenerative medicine. Embryonic cells are exposed
to fluid-mechanical forces, including shear stress andthe cyclic strain generated by beating heart during theprocess of embryonic development. We found thatshear stress induces the differentiation of murine ES
cells into vascular EC lineage in vitro; cyclic strain
induces the differentiation into vascular smooth muscle
cell (SMC) lineage. Differentiation into the EC lineage
and differentiation into SMC lineage are mediated byligand-independent phosphorylation of vascularendothelial growth factor receptor 2 (VEGFR2) andplatelet derived growth factor receptor (PDGFR),
respectively. Moreover, our study has shown that shear
stress increases expression of ephrinB2 in murine ES
cells via the VEGF-Notch signaling pathways,
suggesting that shear stress can also affect the arterialvenous differentiation of ES cells. Based on thesefindings, in a collaborative study, a new hybrid type of
artificial blood vessel, in which ES cells were cultured

72

on the surface of polymer tubes and exposed topulsatile 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 thecell 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 andpropagate throughout the entire cell in the form of aCa2+ wave. The initiation locus corresponded precisely
to caveolae rich cell edges. We found that a subtype of
ATP-gated cation channel, the P2X4 receptor, isexpressed 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 human pulmonary
artery ECs were exposed to controlled levels of shear
stress in a flow-loading device and the changes in the
mitochondrial ATP levels were examined by real-time
imaging using a fluorescence resonance energy
transfer-based ATP biosensor. Immediately upon the
exposure of the cells to flow, the mitochondrial ATP
levels increased, which was both reversible anddependent on the shear stress intensity. Inhibitors of themitochondrial electron transport chain and ATP
synthase, as well as knockdown of caveolin-1, a major
structural protein of the caveolae, abolished the shearstress-induced mitochondrial ATP generation, resulting

in the loss of the ATP release and influx of Ca2+ into thecells. These results suggest the novel role of themitochondria in transducing the shear stress into ATP
generation: the ATP generation leads to ATP release in
the caveolae, triggering purinergic Ca2+ signaling. Thus,
exposure of ECs to shear stress seems to activate
mitochondrial ATP generation through caveola- or
caveolin-1- mediated 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 orderand decreased membrane fluidity. A similar increase inlipid order occurred when the artificial lipid bilayer
membranes of giant unilamellar vesicles were
stimulated by shear stress by using a flow-loading
apparatus or stretched by hypotonic swelling,
indicating that mechanical force-mediated responses oflipid 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 thesechanges in the membrane lipid order by depleting
membrane cholesterol with methyl--cyclodextrin or
by adding cholesterol resulted in a marked inhibition of
the EC response specific to shear stress and stretch, i.e.,
phosphorylation of VEGFR2 and phosphorylation of
PDGFR, respectively. These findings indicate that EC
plasma membranes differently respond to shear stressand stretch by changing their lipid order, fluidity, andcholesterol content in opposite directions and that thesechanges in membrane physical properties are involvedin the mechanosensing mechanisms and the mechanotransduction that activates membrane receptors specificto each force.

5. Shear stress-induced mitochondria oxidative
phosphorylation
Vascular endothelial cells (ECs) sense andrespond to hemodynamic shear stress, which is
critical for circulatory homeostasis and thepathophysiology of vascular diseases. The

73

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 stress rapidly decreases
cholesterol in the plasma membrane, thereby
activating mitochondrial ATP production. Imaging
using D4 mutant-derived cholesterol biosensors
showed that the application of shear stress tocultured ECs markedly decreased cholesterol levels
in both the outer and inner plasma membrane
bilayers. Flow cytometry showed that the cholesterollevels in the outer bilayer began to decrease within 3
min after the onset of shear stress, reached aminimum (around 60% of the control level) at 10
min, and plateaued thereafter. After the shear stressceased, the decreased cholesterol levels returned tothose seen in the control. A biochemical analysis
showed that shear stress caused both the efflux andthe internalization of plasma membrane cholesterol.
ATP biosensor imaging demonstrated that shear
stress significantly increased mitochondrial ATP
production. Similarly, the treatment of cells withmethyl--cyclodextrin (MCD), a membranecholesterol-depleting agent, increased mitochondrial
ATP production. The addition of cholesterol to cells
inhibited the increasing effects of both shear stressand MCD on mitochondrial ATP production in adose-dependent manner. These findings indicate thatplasma membrane cholesterol dynamics are closely
coupled to mitochondrial oxidative phosphorylationin ECs.

decreases cholesterol in the plasma membrane,
thereby activating mitochondrial ATP production.
Imaging using D4 mutant-derived cholesterol biosensors showed that the application of shear stress tocultured ECs markedly decreased cholesterol levels
in both the outer and inner plasma membrane bilayers. Flow cytometry showed that the cholesterollevels in the outer bilayer decreased rapidly after the
onset of shear stress, reached a minimum (around
60% of the control level) at 10 min, and plateaued
thereafter. After the shear stress ceased, the decreased cholesterol levels returned to those seen in
the control. A biochemical analysis showed thatshear stress caused both the efflux and the internalization of plasma membrane cholesterol. ATP biosensor imaging demonstrated that shear stress significantly increased mitochondrial ATP production.
Similarly, the treatment of cells with methyl--cyclodextrin (MCD), a membrane-cholesterol-depleting agent, increased mitochondrial ATP production.
The addition of cholesterol to cells inhibited the increasing 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 tomitochondrial oxidative phosphorylation in ECs.

References
1.

2.

6. Hemodynamic force-induced changes inplasma membrane cholesterol levels
Vascular endothelial cells (ECs) sense and respondto hemodynamic shear stress, which is critical for
circulatory homeostasis and the pathophysiology ofvascular diseases. The mechanisms of shear stressmechanotransduction, however, remain elusive. We
previously demonstrated a direct role of mitochondria in the purinergic signaling of shear stress: shear
stress increases mitochondrial ATP production, triggering ATP release and Ca2+ signaling via EC purinoceptors. Here, we showed that shear stress rapidly

3.

4.

J. Ando and K. Yamamoto. Hemodynamic forces,
endothelial mechanotransduction, and vasculardiseases. Magn. Reson. Med. Sci., 21(2), 258-266(2022).
I. Ono, Y. Abekura, A. Kawashima, M. Oka, A.
Okada, S. Hara, S. Miyamoto, H. Kataoka, A. Ishii,
K. Yamamoto, T. Aoki, Endothelial Cell Malfunction in Unruptured Intracranial Aneurysm Lesions
Revealed Using a 3D-Casted Mold, J. Neuropathol. Exp. Neurol. 82(1), 49-56 (2022).
K. Yoshida, S. Tanihara, Y. Miyashita, K.
Obayashi, M. Ito, K. Yamamoto, T. Imai, and I.
Matsuoka, P2X4 receptor stimulation enhances
MrgprB2-mediated mast cell activation and pseudoallergic reactions in mice. Sci. Rep., 12, Article
number: 18613 (2022).
K. Obayashi, K. Yoshida, M. Ito, T. Mori, K.
Yamamoto, T. Imai, I. Matsuoka, Synergistic

74

cytokine production by ATP and PGE2 via P2X4
and EP3 receptors in mouse bone marrow-derived
mast cells. Cells. 11 (4), 616 (2022).

75

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

Associate Professor
Ryosuke Kojima, Ph.D.

Assistant Professor
Kyohhei Fujita, 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 2 postdoctoral
researcher, 7 PhD students, 4 master course students, 1
undergraduate student, and 2 guest researchers, as of
FY2022.

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
In our laboratory, we conduct research aimed atdeveloping various fluorescence imaging probes andtheir biological and medical applications. In fiscal
year 2022, we reported on the development ofmethods for quantifying intracellular pH byfluorescent lifetime imaging, a Raman probe that canbe activated by red light, and a fluorescent probe thatcan visualize thymoma and thymic carcinoma, etc.

Details are as follows.
Intracellular organelles such as endosomes andlysosomes strictly regulate their pH levels.
Disruptions of this balance correlate with diseases
such as cancer and Alzheimer's, hence accuratequantification and understanding of its dynamics andcontrol mechanisms are vital. Existing fluorescentprobes that enable monitoring of intracellular pH oftenchange their ON/OFF fluorescence in response to pHchanges. However, the intensities of these signals are
directly influenced by the amount of probe, which is adrawback for the precise detection of intracellular pH.
We developed a novel method to quantify intracellular
pH by fluorescent lifetime imaging, focusing on thefact that fluorescence lifetime is not affected by theamount of probe. Specifically, we developed a probe,
m-DiMeNAF488, which has a large fluorescence
lifetime change, 4.38 ns for the protonated form and0.58 ns for the deprotonated, indicating a pKa of 4.58
(optimal to visualize intracellular acidic organelles
around pH5). Using this, we successfully captured theacidification of phagosomes during phagocytosis inreal time (Publication 1).
Photoactivatable fluorescent probes are useful for
pulse labeling and tracking various biomolecules andcells, but because fluorescence has a broad spectral
width, there is a limit to the multiplicity when
distinguishing different samples in multiple colors. We

76

focused on Raman imaging with excellent multiplex
detection capabilities and developed an activatable
Raman probe that can photoactivate Raman signals.
Specifically, we designed and developed a new Ramanprobe, 9CN-diMeJTeP, which induces a strong Raman
signal by pre-resonance Raman due to a significant
redshift of the absorption wavelength associated withphotooxidation. We achieved photoactivation of its
Raman signal by irradiating red light under amicroscope (Publication 2, collaborative research with
Prof. Mayuko Kamaya @ Tokyo Institute ofTechnology, Prof. Yasuyuki Ozeki, Faculty ofEngineering, The University of Tokyo).
In recent years, thoracoscopic and robotic surgeries
have become possible for the treatment of thymomas
and thymic carcinoma. The ability to accurately
distinguish major areas is important for improving
treatment outcomes. We examined the discrimination
ability of the green fluorescent probe gGlu-HMRG,
which
can
monitortheactivityof
γ-glutamyltransferase (GGT) known to be highly
expressed in multiple types of cancer, for thymomas
and thymic carcinoma. Imaging was conducted in acomparative manner between major areas andsurrounding normal tissues in 22 cases of clinicalspecimens of thymomas and thymic carcinoma. It was
found that thymomas and thymic cancers could be
visualized with a sensitivity of 77.3% and specificityof 100%. These results suggest that gGlu-HMRG
could be useful for accurately removing the major
areas without leaving any residual tissue inthoracoscopic surgery, etc. (Publication 3)
In addition, we conducted and presented several joint
research projects with researchers from within andoutside the university (Publications 4-7).

References(1) Koda, K.; Keller, S.; Kojima, R.; Kamiya, M.;
Urano, Y. Measuring the PH of Acidic Vesicles inLive Cells with an Optimized Fluorescence
Lifetime Imaging Probe. Anal. Chem. 2022, 94,
11264–11271.
(2) Kawatani, M.; Spratt, S. J.; Fujioka, H.; Shou, J.;
Misawa, Y.; Kojima, R.; Urano, Y.; Ozeki, Y.;
Kamiya,M.
9-Cyano-10-Telluriumpyronin
Derivatives as Red-Light-Activatable Raman

(3)

(4)

(5)

(6)

(7)

Probes. Chem. Asian J. 2023, 18, e202201086.
Yoshida, D.; Kamiya, M.; Kawashima, S.;
Yoshioka, T.; Hino, H.; Abe, A.; Fujita, K.;
Kojima, R.; Shinozaki-Ushiku, A.; Urano, Y.;
Nakajima, J. Rapid Imaging of Thymoma andThymic Carcinoma with a Fluorogenic Probe
Targeting γ-Glutamyltranspeptidase. Sci. Rep.
2023, 13, 3757.
Tsuyama, Y.; Xu, B.; Hattori, K.; Baek, S.;
Yoshioka, Y. A 50 Μm Acoustic Resonator
Microchannel Enables Focusing 100 Nm
Polystyrene Beads and Sub-Micron Bioparticles.
Sens. Actuators B Chem. 2023, 376, 132918
Hirata, H.; Kamohara, A.; Murayama, M.;
Nishioka, K.; Honda, H.; Urano, Y.; Soejima, H.;
Oki, S.; Kukita, T.; Kawano, S.; Mawatari, M.;
Kukita, A. A Novel Role of Helix-Loop-Helix
Transcriptional Factor Bhlhe40 in Osteoclast
Activation. J. Cell. Physiol. 2022, 237, 3912–
3926.
Tang, X.; Nishimura, A.; Ariyoshi, K.; Nishiyama,K.; Kato, Y.; Vasileva, E. A.; Mishchenko, N. P.;
Fedoreyev, S. A.; Stonik, V. A.; Kim, H.-K.; Han,J.; Kanda, Y.; Umezawa, K.; Urano, Y.; Akaike,T.; Nishida, M. Echinochrome Prevents Sulfide
Catabolism-Associated Chronic Heart Failure
after Myocardial Infarction in Mice. Mar. Drugs
2023, 21, 52.
Hattori, K.; Goda, Y.; Yamashita, M.; Yoshioka,
Y.; Kojima, R.; Ota, S. Droplet Array-Based
Platform for Parallel Optical Analysis of
Dynamic Extracellular Vesicle Secretion fromSingle Cells. Anal. Chem. 2022, 94, 11209–
11215.

77

Department of Biosystem
Construction & Control
Lecturer
Takashi Isoyama, Ph.D.
※The following information is the same as that of the previous year for certain reasons.

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

78

engineers and clinical engineers is another importantrole of our laboratory.

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

79

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 thecomponents 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

80

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

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

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

Activities
Teaching activities
We teach the 3rd year medical students (M1) about
genomics, genomic medicine, and genetic counselingas part of “General Pathology” and “Medical
Engineering Lectures”. For M4 medical students whocome to the Department of Clinical Genomics for aone-month rotation in fiscal year, we give lectures andopportunities to participate in genetic counseling andmolecular tumor board (Expert Panels) undercollaboration with “Next-Generation Precision
Medicine Development Laboratory”, “Department of
Pathology”, “Department of Clinical Laboratory”, andmany other related clinical departments. As for PhD
students, our laboratory take part in the lecture of“Clinical Oncology”.
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).

81

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”
This study assesses the efficacy of olaparib
maintenance monotherapy in high-grade and stage
IIIC/IV ovarian cancer patients (including patientswith primary peritoneal and / or fallopian tube cancer)
with “BRCA-related biomarker” that is predicted bywhole-exome sequencing of fresh-frozen tumor
samples.

3.

4.

5.

6.

(3) Enrollment to the prospective trial of patientproposed healthcare services with multiple targeted
agent based on the result of gene profiling by
multigene panel test. (BELIEVE) : jRCTs031190104
Clinical activities are described in the section of“Department of Clinical Genomics”.

7.

Publications
1.

2.

Tanaka M, Shinozaki-Ushiku A, Kunita A,
Yasunaga Y, Akamatsu N, Hasegawa K, Ushiku
T: High-grade transformation of pancreatic
neuroendocrine tumor associated with TP53
mutations: A diagnostic pitfall mimicking
neuroendocrine carcinoma. Pathol Int. 2022
Aug;72(8):411-418.
Kage H, Kohsaka S, Tatsuno K, Ueno T, Ikegami
M, Zokumasu K, Shinozaki-Ushiku A, Nagai S,
Aburatani H, Mano H, Oda K: Tumor mutationalburden measurement using comprehensive
genomic profiling assay. Jpn J Clin Oncol. 2022
Aug 5;52(8):925-929.

8.

9.

Taguchi A, Rokutan H, Oda K, Tanikawa M,
Tanimoto S, Sone K, Mori M, Tsuruga T,
Kohsaka S, Tatsuno K, Shinozaki-Ushiku A,
Miyagawa K, Mano H, Aburatani H, Ushiku T,
Osuga Y: Genetic diagnosis of pseudomyxoma
peritonei originating from mucinous borderline
tumor inside an ovarian teratoma. BMC Med
Genomics. 2022 Mar 7;15(1):51.
Ando T, Kage H, Shinozaki-Ushiku A, Tatsuno
K, Tsutsumi S, Nagayama K, Nakajima J,
Kohsaka S, Miyagawa K, Aburatani H, Mano H,
Nagase T: Composite Clonal Analysis Reveals
Transition of NSCLC Subtypes ThroughAccumulation of Gene Mutations: A Case Report.
JTO Clin Res Rep. 2022 Jan 10;3(2):100277.
Tian D, Shiiya H, Sato M, Shinozaki-Ushiku A,
Yan HJ, Nakajima J: Pathological tumor long-toshort axis ratio as a prognostic factor in patientswith thymic epithelial tumors. Thorac Cancer.
2022 Sep;13(17):2489-2498.
Kume A, Shinozaki-Ushiku A, Kunita A, Kondo
A, Ushiku T: Enhanced PD-L1 Expression in
LMP1-positive Cells of Epstein-Barr Virusassociated
MalignantLymphomas
andLymphoproliferative Disorders: A Single-cell
Resolution
Analysis
With
Multiplex
Fluorescence Immunohistochemistry and In Situ
Hybridization. Am J Surg Pathol. 2022 Oct
1;46(10):1386-1396.
Tian D, Shiiya H, Takahashi M, Terasaki Y,
Urushiyama H, Shinozaki-Ushiku A, Yan HJ,
Sato M, Nakajima J: Noninvasive monitoring of
allograft rejection in a rat lung transplant model:
Application of machine learning-based 18Ffluorodeoxyglucose positron emission tomography
radiomics. J Heart Lung Transplant. 2022
Jun;41(6):722-731.
Nakazaki K, Yoshida M, Masamoto Y,
Shinozaki-Ushiku A, Ikemura M, Hisamoto T,
Yasunaga M, Sato S, Kurokawa M: Discordant
lymphomas of classic Hodgkin lymphoma andperipheral
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Uchino M, Tsuruga T, Osuga Y: Recurrent
malignant melanoma of the uterine cervix treatedwith anti-PD-1 antibodies and anti-CTLA-4
antibodies: A case report. Mol Clin Oncol. 2022
Mar;16(3):63.
10. Takano H, Yasunaga M, Yamazaki I, Nishikawa
M, Masamoto Y, Shinozaki-Ushiku A,
Kawakami M, Yatomi Y, Kurokawa M:
Degenerated mitochondria in leukemic blast
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11. Tanaka R, Kaburaki T, Taoka K, Karakawa A,
Tsuji H, Nishikawa M, Yatomi Y, ShinozakiUshiku A, Ushiku T, Araki F: More Accurate
Diagnosis of Vitreoretinal Lymphoma Using a
Combination of Diagnostic Test Results: A
Prospective Observational Study. Ocul Immunol
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12. Shiiya H, Sato M, Shinozaki-Ushiku A, Konoeda
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Chest after Lung Transplantation. Ann Thorac
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13. Toyohara Y, Sone K, Noda K, Yoshida K,
Kurokawa R, Tanishima T, Kato S, Inui S, Nakai
Y, Ishida M, Gonoi W, Tanimoto S, Takahashi Y,
Inoue F, Kukita A, Kawata Y, Taguchi A,
Furusawa A, Miyamoto Y, Tsukazaki T,
Tanikawa M, Iriyama T, Mori-Uchino M,
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Osuga Y. Development of a deep learning
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14. Kukita A, Sone K, Kaneko S, Kawakami E, Oki
S, Kojima M, Wada M, Toyohara Y, Takahashi
Y, Inoue F, Tanimoto S, Taguchi A, Fukuda T,
Miyamoto Y, Tanikawa M, Mori-Uchino M,
Tsuruga T, Iriyama T, Matsumoto Y, Nagasaka
K, Wada-Hiraike O, Oda K, Hamamoto R, Osuga
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Tsuchimochi S, Taguchi A, Miyamoto Y, Sone K,
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Neuroscience
1. Basic Neuroscience85

Department of Neuropathology
Professor
Takeshi Iwatsubo, M.D., Ph.D.

Lecturer
Tomoki Kuwahara, Ph.D.

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

Homepage

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

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

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

86

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

lesions, and has characterized a wide spectrum of
α-synuclein
pathologies
inneurodegenerative
disorders.
3. Identification of a non-Aβ Alzheimer amyloid plaquecomponent CLAC, and its precursor CLAC-P
The major component of Alzheimer’s amyloid
plaques is Aβ, although there are a number of non-Aβ
components that potentially affect fibrillization anddegradation of amyloid deposits. Among these, there
has been an enigmatic “missing piece” protein ofmolecular masses of 50/100 kDa. Dr. Iwatsubo’sgroup raised a monoclonal antibody against amyloid
fraction that recognizes this protein, and using thisantibody as a probe, they conducted a thoroughbiochemical purification of these antigens and finallycloned a cDNA coding for the precursor of this protein.
This protein turned out to be a novel class ofmembrane-bound collagen, which was named CLAC
(collagen-like Alzheimer amyloid plaque component)
and its precursor CLAC-P (Hashimoto et al. EMBO J
2002). This finding had an immense impact both on
fields of AD research as well as on general biology as
a first discovery of neuron-specific collagen harboringa unique membrane-spanning structure. CLAC has
been highlighted as a protein that may affectfibrillization of Aβ and contribute to amyloid plaqueformation. Indeed, he has recently shown that CLACpositive senile plaques constitute a unique subset ofplaques distinct from the classical, β-sheet-richamyloid deposits, underscoring the pathobiologicalrole of CLAC in amyloid formation, and that CLAC
inhibits fibrillization of Aβ in vitro. Knockout micestudies have confirmed the role of CLAC inneuromuscular development (Munezane et al. Cell
Reports, 2019).
4. Glymphatic system and tau clearance
Accumulation of tau has been implicated invariousneurodegenerative
diseasestermedtauopathies. Tau is a microtubule-associated protein
but is also actively released into the extracellular
fluids including brain interstitial fluid andcerebrospinal fluid (CSF). However, it remained
elusive whether clearance of extracellular tau impacts
tau-associated neurodegeneration. We showed thataquaporin-4 (AQP4), a major driver of the glymphatic
clearance system, facilitates the elimination of

87

extracellular tau from brain to CSF and subsequently
to deep cervical lymph nodes. Strikingly, deletion of
AQP4 not only elevated tau in CSF but also markedly
exacerbated phosphorylated tau deposition andassociated neurodegeneration in the brains oftransgenic mice expressing P301S mutant tau. We thus
identified the clearance pathway of extracellular tau in
the central nervous system, suggesting that glymphatic
clearance of extracellular tau is a novel regulatory
mechanism whose impairment contributes to tau
aggregation and neurodegeneration.
5. Japanese ADNI and development of diseasemodifying therapies against AD
Basic studies on the pathomechanism of AD haveboosted the development of mechanism-based drugs
for AD, whereas the bottleneck has been the lack ofsurrogate biomarkers that represent the progression of
AD pathology and are useful in the clinical trial of
disease-modifying drugs. In close collaboration with
Drs. Mike Weiner and Ron Petersen of US-ADNI, Dr.
Iwatsubo has initiated the Japanese ADNI as theprincipal investigator on 2006, recruiting 38 clinicalsites nationwide, and preparing all the infrastructures
required for the large-scale clinical study. The J-ADNI
group recruit 537 individuals in total, and all the data
derived from the J-ADNI study have been made inpublic from the National Bioscience Database Center
for research use. Recently, the J-ADNI group has
demonstrated the similarity between MCI due to AD
in Asian and Caucasian populations by comparing theclinical and biomarker features of J-ADNI and ADNI
participants, supporting the feasibility of global
clinical trials of disease-modifying therapies for AD.
Recently, his group is leading the “Japanese
Trial-Ready cohort for prevention of AD (J-TRC).
These efforts have led to the successful developmentof anti-amyloid antibody therapies against AD in
2023.

2)

3)

4)

5)

6)

7)

References
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An H, Litscher G, Watanabe N, Wei W,
Hashimoto T, Iwatsubo T, Buchman VL,
Shelkovnikova T: ALS-linked cytoplasmic FUS
assemblies are compositionally different fromphysiological stress granules and sequester

8)

hnRNPA3, a novel modifier of FUS toxicity.
Neurobiol Dis 162:105585, 2022
Kazawa K, Akishita M, Ikeda M, Iwatsubo T,
Ishii S: Experts’ perception of support for people
with dementia and their families during the
COVID-19 pandemic. Geriatr Gerontol Int 22:
26-31, 2022
Rotstein A, Levine SZ, Samara M, Yoshida K,
Goldberg Y, Cipriani A, Iwatsubo T, Leucht S,
Furawaka TA: Cognitive impairment networks in
Alzheimer’s disease: Analysis of three doubleblind randomized, placebo-controlled, clinical
trials of donepezil. Eur Neuropsychopharmacol
57:50-58, 2022
Levine SZ, Goldberg Y, Yoshida K, Efthimiou O,
Samara M, Cipriani A, Iwatsubo T, Leucht S,
Furawaka TA: Early- and subsequent- responseof cognitive functioning in Alzheimer’s disease:
Individual-participant data from five pivotal
randomized clinical trials of donepezil. J
Psychiatr Res 148:159-164, 2022
Ishida K, Yamada K, Nishiyama R, Hashimoto T,
Nishida I, Abe Y, Yasui M, Iwatsubo T:
Glymphatic system clears extracellular tau andprotectfromtau
aggregation
andneurodegeneration. J Exp Med 219:e20211275,
2022
Kaneshiro N, Komai M, Imaoka R, Ikeda A,
Kamikubo Y, Hashimoto T, Iwatsubo T, Sakurai T,
Uehara T, Takasugi N: Lipid flippase dysfunction
as a novel therapeutic target for endosomal
anomalies in Alzheimer’s disease. iScience 25:
103869, 2022
Haeberlein SB, Aisen PS, Barkhof F, Chalkias S,
Chen T, Cohen S, Dent G, Hansson O, Harrison
K, von Hehn C, Iwatsubo T, Mallinckrodt C,
Mummery CJ, Muralidharan KK, Nestorov I,
Nisenbaum L, Rajagovindan R, Skordos L, TianY, van Dyck CH, Vellas B, Wu S, Zhu Y,
Sandrock A: Two randomized phase 3 studies toevaluate aducanumab in early Alzheimer disease.
J Prev Alzheimers Dis 9:197-210, 2022
Tsujikawa K, Hamanaka K, Riku Y, Hattori Y,
Hara N, Iguchi Y, Ishigaki S, Hashizume A,
Miyatake S, Mitsuhashi S, Miyazaki Y, Kataoka
M, Jiayi L, Yasui K, Kuru S, Koike H, Kobayashi
K, Sahara N, Ozaki N, Yoshida M, Kakita A,

88

Saito Y, Iwasaki Y, Miyashita A, Iwatsubo T,
Ikeuchi T, Miyata T, Sobue G, Matsumoto N,
Sahashi K, Katsuno M: Actin-1 binding protein
filamin-A drives tau aggregation and contributes
to progressive supranuclear palsy pathology. Sci
Adv 8:eabm5029, 2022
9) Sato K, Niimi Y, Mano T, Iwata A, Iwatsubo T:
Time to onset of drug-induced parkinsonism:
Analysis using a large Japanese adverse event
self-reporting database. Biosci Trends 16:151157, 2022
10) Sato K, Niimi Y, Mano T, Iwata A, Iwatsubo T:
Automated evaluation of conventional clockdrawing test using deep neural network: potential
as a mass screening tool to detect individuals
with cognitive decline. Front Neurol 13:896403,
2022
11) Kishino Y, Matsukawa K, Matsumoto T,
Wakabayashi T, Nonaka T, Kametani F,
Hasegawa M, Hashimoto T, Iwatsubo T: Casein
kinase 1 phosphorylates fused in sarcoma(FUS) and ameliorates FUS-mediated neurodegeneration. J Biol Chem 298: 102191, 2022
12) Poulakis K, Pereira JB, Muehlboeck J-S,
Wahlund L-O, Smedby Ö, Volpe G, Masters CL,
Ames D, Niimi Y, Iwatsubo T, Ferreira D,
Westman E: Stage vs. Subtype hypothesis in
Alzheimer’s disease: a multi-cohort andlongitudinal Bayesian clustering study. Nat
Commun 13:4566, 2022
13) Kasuga K, Kikuchi M, Tsukie T, Suzuki K, Ihara
R, Iwata A, Hara N, Miyashita A, Kuwano R,
Iwatsubo T, Ikeuchi T: Characterization of ATN
profile classified using two different N markers
in CSF. BMJ Neurol Open 4:e000321, 2022
14) Sato K, Niimi Y, Iwatsubo T, Ishii S: Change inlong-term care service usage in Japan following
the COVID-19 pandemic: a survey using anationwide statistical summary in 2018–2021.
Geriatr Gerontol Int 22:803-809, 2022
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Seshadri S, Carrillo M, Sagar R, Huang Y,
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Akinyemi R, Prasad K, D’Avossa G, GonzalezAleman G, Hosseini A, Vavougios GD, Sachdev
P, Bankart J, Ole Mors NP, Lipton R, Katz M,
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Mavreas V, Blangero J, Cruchaga C, Krishna M,
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89

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

Lecturer
Hajime Fujii, Ph.D.

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

Homepage

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

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

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

wing of the third building of the Medical School. The
Department currently enrolls one professor, one
lecturer, two assistant professors, two postdoctoral
scholars, one technical staff, seven Ph.D. graduate
students, one research student, one technical assistantand 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;
Fujii et al., Neurosci Res. 2022). We also applied the
CaMKII FRET probe to elucidate the molecularmechanisms of intellectual disability caused by
CAMK2A mutations and found a candidate
therapeutic (Fujii et al., Front. Mol. Neurosci. 2022).
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). We also developed knock-in mice expressingthese novel Ca2+ indicators (Sakamoto et al., Cell
Reports Methods 2022; Sakamoto et al., STAR
Protocol, 2022).
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.

93

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(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 2022- December 2022)
1.

Hashizume R, Fujii H, Mehta S, Ota K, Qian Y,
Zhu W, Drobizhev M, Nasu Y, Zhang J, Bito H,

94Campbell RE. A genetically encoded far-red
fluorescent calcium ion biosensor derived from abiliverdin-binding protein. Protein Sci. 31(10),e4440, 2022 doi: 10.1002/pro.4440.
2. Fujii H, Kidokoro H, Kondo Y, Kawaguchi M,
Horigane SI, Natsume J, Takemoto-Kimura S,
Bito H. Förster resonance energy transfer-based
kinase mutation phenotyping reveals an aberrant
facilitationofCa2+/calmodulin-dependent
CaMKIIα activity in de novo mutations related tointellectual disability. Front Mol Neurosci. 15,
970031, 2022, doi: 10.3389/fnmol.2022.970031.
3. Manita S, Shigetomi E, Bito H, Koizumi S,
Kitamura K. In Vivo Wide-Field and Two-Photon
Calcium Imaging from a Mouse using a Large
Cranial Window. J Vis Exp. (186), e64224, 2022,
doi: 10.3791/64224.
4. Ago K, Nagoshi N, Imaizumi K, Kitagawa T,
Kawai M, Kajikawa K, Shibata R, Kamata Y,
Kojima K, Shinozaki M, Kondo T, Iwano S,
Miyawaki A, Ohtsuka M, Bito H, Kobayashi K,
Shibata S, Shindo T, Kohyama J, Matsumoto M,
Nakamura M, Okano H. A non-invasive system
to monitor in vivo neural graft activity after
spinal cord injury. Commun Biol. 5(1):803, 2022,
doi: 10.1038/s42003-022-03736-8.
5. Sakamoto M, Ota K, Kondo Y, Okamura M, Fujii
H, Bito H. In utero electroporation and cranial
window implantation for in vivo wide-field
two-photon calcium imaging using G-CaMP9atransgenic mice. STAR Protoc. 3(2):101421,
2022, doi: 10.1016/j.xpro.2022.101421.
6. Sakamoto M, Inoue M, Takeuchi A, Kobari S,
Yokoyama T, Horigane SI, Takemoto-Kimura S,
Abe M, Sakimura K, Kano M, Kitamura K, Fujii
H, Bito H.
A Flp-dependent G-CaMP9a transgenic mouse forneuronal imaging in vivo. Cell Rep Methods.
2(2):100168, 2022, doi: 10.1016/j.crmeth.2022.
100168.
7. Fujii H, Bito H., Deciphering Ca2+-controlled
biochemical computation governing neuralcircuit dynamics via multiplex imaging.
Neurosci Res. 179:79-90, 2022, doi: 10.1016/j.
neures.2022.04.004.
8. Wang C, Horigane SI, Wakamori M, Ueda S,
Kawabata T, Fujii H, Kushima I, Kimura H,

9.

Ishizuka K, Nakamura Y, Iwayama Y, Ikeda M,
Iwata N, Okada T, Aleksic B, Mori D, Yoshida T,
Bito H, Yoshikawa T, Takemoto-Kimura S, Ozaki
N. Identification of ultra-rare disruptive variants
in voltage-gated calcium channel-encoding genes
in Japanese samples of schizophrenia and autism
spectrum disorder. Transl Psychiatry. 12(1):84,
2022, doi: 10.1038/s41398-022-01851-y.
Goto F, Kiyama Y, Ogawa I, Okuno H, Ichise T,
Ichise H, Anai M, Kodama T, Yoshida N, Bito H,
Manabe T. Gastrin-releasing peptide regulates
fear learning under stressed conditions via
activation of the amygdalostriatal transition area.
Mol Psychiatry. 27(3):1694-1703, 2022, doi:
10.1038/s41380-021-01408-3.

Neuroscience
2. Integrative Medical Neuroscience96

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

Homepage

http://childpsy.umin.jp/

Introduction and Organization

Research activities

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.

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 2022 are as follows:

Teaching activities
In the year of 2022, we had 6 graduate students (1 inmaster course and 5 in doctor course). In addition toresearch training, educational program includingcase conference was implemented with further
improvement.

・Epidemiological, behavior phenotype, neuropsychological, and treatment study of Tourette
syndrome (chronic tic disorder with multiple motor
tics and one or more vocal tics) and child &adolescent OCD
We are evaluating tics, obsessive-compulsive
symptoms, and premonitory urges in Tourette
syndrome and child & adolescent OCD to examine
their relationship to each other, as well as
investigating situation and needs for treatment andsupport to improve them.
We are following a clinical cohort of patients with
Tourette syndrome and are also investigating theimpact of the COVID-19 pandemic. We are examining
the neuropsychology of Tourette syndrome and theeffectiveness of the Comprehensive Behavioral
Intervention for Tics (CBIT). We have developed
internet-based psychoeducational materials that will

97

lead to CBIT, and have begun investigating theireffectiveness. We are also trying to develop an
objective assessment of tics.
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.
We are also continuing to analyze the findings of oursurvey of tics and related behaviors in community
preschoolers.
・Brain-imaging study of ASD, ADHD and Tourette
syndrome by structural-MRI, functional-MRI andnear-infrared spectroscopy (NIRS)
We continue to examine morphological and functional
brain imaging in adults with ASD.
・Development of predictor of parent training for
ADHD
We are examining what aspects of children with
ADHD and their caregivers are affected by parent
training. In addition to focusing on the relationshipbetween parent training and attachment, we also aim
to examine the relationship between brain function as
measured by fMRI and these factors.
・Effectiveness of psychological support for ASD
We are examining effectiveness of early intervention
for autistic preschoolers in terms of theircommunication behaviors and parental stress. We arealso examining support for their transition fromkindergarten and preschool to elementary school.
Furthermore, effectiveness of a program of groupcognitive behavior therapy for adults withhigh-functioning ASD is investigated in a randomized
control trial.
・Investigation on clinical evaluation and psychological education for adults with developmental
disorders
We are collecting and analyzing data obtained through“inpatient assessment on developmental disorders”
program, in which adult patients with suspecteddevelopmental disorders undergo detailed clinicalassessment, including symptoms of ASD and ADHD,
and receive psychoeducation based on thisassessment.

References
1.

2.

3.

4.

Kuroda M, Kawakubo Y, Kamio Y, Yamasue H,
Kono T, Nonaka M, Matsuda N, Kataoka M,
Wakabayashi A, Yokoyama K, Kano Y, Kuwabara
H. Preliminary efficacy of cognitive-behavioral
therapy on emotion regulation in adults with
autism spectrum disorder, A pilot randomized
waitlist-controlled study. PLoS One, 17(11):e0277398, 2022.
Tanaka M, Kanehara A, Morishima R, Yousuke
Kumakura Y, Okouchi N, Nakajima N, Hamada J,
Ogawa T, Tamune H, Nakahara M, Jinde S, Kano
Y, Kasai K. Educational challenges for 22q11.2
deletion syndrome in Japan: Findings from amixed methods survey. J Appl Res Intellect
Disabil, 36(3): 558-570, 2023.
Ishikawa N, Ishizuka Y, Kano Y, Iida J,
Yamamoto J. Exploring factors of successfultransition to elementary school among children
with autism spectrum disorder in Japan: a focus
group
study,
International
JournalofDevelopmental Disabilities, 1-10, 2022.
Suzuki A, Yamaguchi R, Kim L, Kawahara T,
Ishii-Takahashi A. Effectiveness of mockscanners and preparation programs for successful
magnetic resonance imaging: a systematic review
and meta-analysis. Pediatr Radiol, 53(1): 142-158,
2023.

Neuroscience
3. Clinical Neuroscience99

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

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

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

Lecturer
Shinsuke Kondo, M.D., Ph.D.

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

Research Associate
Kayo Ichihashi, M.D.

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

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

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

Tempei Ikegame, M.D., Ph.D.

Susumu Morita, M.D., Ph.D.

Mao Fujioka, M.D., Ph.D.

Taku Kiuchi, M.D., Ph.D.

Hiroshi Azuma, M.D.

Homepage

http://npsy.umin.jp/

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

Clinical activities
For our clinical services, we have more than 15
staff psychiatrists, 5 clinical psychologists and 2 psy-

chiatric social workers. In 2022, approximately 680
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 319 patientswith various psychiatric disorders were admitted in
2022. 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. Most of the patients are
schizophrenia, mood disorder and the psychosis basedon the somatic diseases. Modified electro-convulsive
therapy was performed for approximately 300 patients
per year.
We established the day care unit for outpatientswith schizophrenia in 1974, and the patients areengaged in rehabilitation and re-work programs.

Education
For psychiatric residents, we have provided: 1)
clinical meetings on patients (every morning); 2) case100

conferences 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.

2.

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

3.

4.

5.

6.

7.

Publications
1.

Furukawa Y, Oguro S, Obata S, Hamza T,
Ostinelli Edoardo G , Kasai K: Optimal dose of
brexpiprazole for augmentation therapy of

8.

antidepressant-refractory
depression:asystematic review and dose-effect meta-analysis.
Psychiatry and Clinical Neurosciences. 2022;
76(9):416-422.
Furukawa Y, Hamza T, Cipriani A, Furukawa TA,
Salanti G, Ostinelli EG. Optimal dose ofaripiprazole for augmentation therapy ofantidepressant-refractory depression: preliminary
findings based on a systematic review anddose-effect meta-analysis. Br J Psychiatry. 2022;
221(2):440-447.
Kirihara K, Fujioka M, Suga M, Kondo S,
Ichihashi K, Koshiyama D, Morita K, Ikegame T,
Tada M, Araki T, Jinde S, Taniguchi K,
Hosokawa T, Sugishita K, Dogan S, Marumo K,
Itokawa M, Kasai K: Betaine supplementation
improves positive symptoms in schizophrenia.
Schizophrenia Research. 2022. PMID: 36401992
Koshiyama D, Miyakoshi M, Tanaka-Koshiyama
K, Sprock J, Light GA. High-power Gamma
related Delta Phase Alteration in Schizophrenia
Patients at Rest. Psychiatry Clin Neurosci 76:
179-186, 2022.
Sakakibara E. On the nature, pathology, andetiology of delusions: comments on Miyazono’s
delusions and beliefs. Asian Journal of
Philosophy 1(1) 32.
Yamagishi M, Satomura Y, Sakurada H,
Kanehara A, Sakakibara E, Okada N, Koike S,
Yagishita S, Ichihashi K, Kondo S, Jinde S,
Fukuda M, Kasai K: Retrospective Chart
Review-based Assessment Scale for Adverse
Childhood Events and Experiences. Psychiatry
and Clinical Neurosciences Reports 1: e58, 2022.
Usui K, Kirihara K, Tada M, Fujioka M,
Koshiyama D, Tani M, Tsuchiya M, Morita S,
Kawakami S, Kanehara A, Morita K, Satomura Y,
Koike S, Suga M, Araki T, Kasai K: The
association between clinical symptoms and later
subjective quality of life in individuals withultra-high risk for psychosis and recent-onset
psychotic disorder: A longitudinal investigation.
Psychiatry Clin Neurosci. 2022. PMID:
35352436
Usui K, Kirihara K, Tada M, Fujioka M,
Koshiyama D, Tani M, Tsuchiya M, Morita S,
Kawakami S, Kanehara A, Morita K, Satomura Y,

101

9.

10.

11.

12.

13.

Koike S, Suga M, Araki T, Kasai K: The
association between clinical symptoms and later
subjective quality of life in individuals withultra-high risk for psychosis and recent-onset
psychotic disorder: A longitudinal investigation.
Psychiatry Clin Neurosci. 2022. PMID:
35352436
Kiyono T, Ando S, Morishima R, Fujikawa S,
Kanata S, Morimoto Y, Endo K, Yamasaki S,
Usami S, Hiraiwa-Hasegawa M, Nishida A,
Kasai K: Sex-based differences in thelongitudinal association between autistic traits
andpositive
psychotic
experiencesinadolescents: A population-based cohort study.
Schizophrenia Research. 2022; 246:1-6.
Morishima R, Koike H, Kanehara A, Usui K,
Okada N, Ando S, Kasai K: Implementation of
online classes during national school closure due
to COVID-19 and mental health symptoms ofadolescents: A cross-sectional survey of 5000
students. Psychiatry and Clinical Neurosciences
Reports. 2022.
Nagaoka D, Tomoshige N, Ando S, Morita M,
Kiyono T, Kanata S, Fujikawa S, Endo K,
Yamasaki S, Fukuda M, Nishida A, HiraiwaHasegawa M, Kasai K: Being praised for
prosocial behaviors longitudinally reduces
depressive symptoms in early adolescents: A
population-based cohort study. Front Psychiatry,2022; 13:865907.
Morishima R, Usami S, Ando S, Kiyono T,
Morita M, Fujikawa S, Araki T, Kasai K:
Trajectory and course of problematic alcohol use
after the Great East Japan Earthquake: Eight-year
follow-up of Higashi-Matsushima cohort study.
Alcoholism: Clinical and Experimental Research.
2022; 46(4):570-580.
Ichihashi K, Kyou Y, Hasegawa N,
Yasui-Furukori N, Shimizu Y, Hori H, Hashimoto
N, Ide K, Imamura Y, Yamada H, Ochi S, Iga J,
Takaesu Y, Ohi K, Tsuboi T, Iida H, Yamagata H,
Hishimoto A, Horai T, Usami M, Makinodan M,
Nagasawa T, Komatsu H, Kido M, Muraoka H,
Atake K, Takeshima M, Kubota C, Inagaki T,
Tamai S, Kishimoto T, Furihata R, Matsumoto J,
Miura K, Inada K, Watanabe K, Kasai K,
Hashimoto R: The characteristics of patients

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receiving psychotropic pro re nata medication atdischarge for the treatment of schizophrenia andmajor depressive disorder: A nationwide survey
from the EGUIDE project. Asian Journal of
Psychiatry . 2022; 69:103007.
Kanehara A, Koike H, Fujieda Y, Yajima S,
Kabumoto A, Kumakura Y, Morita K, Miyamoto
Y, Nochi M, Kasai K: Culture-dependent anduniversal constructs and promoting factors for theprocess of personal recovery in users of mental
health services: Qualitative findings from Japan.
BMC Psychiatry. 2022; 22(1):105.
Morishima R, Kumakura K, Usami S, Kanehara
A, Tanaka M, Okochi N, Nakajima N, Hamada J,
Ogawa T, Ando S, Tamune H, Nakahara M, Jinde
S, Kano Y, Tanaka K, Hirata Y, Oka A, Kasai K:
Medical, welfare, and educational challenges andpsychological distress in parents caring for anindividual with 22q11.2 deletion syndrome: A
cross-sectional survey in Japan. American
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188(1):37-45.
Koike S, Sakakibara E, Satomura Y, Sakurada H,
Yamagishi M, Matsuoka J, Okada N, Kasai K:
Shared functional impairment in the prefrontal
cortex affects symptom severity acrosspsychiatric disorders. Psychol Med 2022; 52(13):2661-70.
Kasai K, Kumagaya S, Takahashi Y, Sawai Y,
Uno A, Kumakura Y, Yamagishi M, Kanehara A,
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Kasai K, Yagishita S, Tanaka SC, Koike S, Murai
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Kanehara A, Morita K, Kumakura Y, Takahashi Y,
Sawai Y, Uno A, Sakakibara E, Okada N,
Okamoto Y, Nochi M, Kumagaya SI, Fukuda M:
Personalized values in life as point of interaction
with the world: Developmental/neurobehavioral
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Koike S, Uematsu A, Sasabayashi D, Maikusa N,
Takahashi T, Ohi K, Nakajima S, Noda Y, Hirano
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MRI studies in schizophrenia through the life
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2022;21(4):539-52.
20. Koshiyama D, Miura K, Nemoto K, Okada N,
Matsumoto J, Fukunaga M, Hashimoto R.
Neuroimaging studies within Cognitive Genetics
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Brain Mapp 43:182–193, 2022.

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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.
Akatsuki Kubota, M.D., Ph.D.

Associate
Meiko Maeda, M.D., PhD., Takashi Matsukawa, M.D., PhD.,
Satoshi Kodama, M.D., Ph.D., Toshiyuki Kakumoto M.D., Ph.D., Atsushi Sudo M.D., Ph.D.

Homepage

http://www.utokyo-neurology.org

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

Clinical activities
We offer clinical services in the field of
Neurology. We are putting our effort to provide thepatients with highly advanced clinical practice as wellas on clinical activities connected to postgraduate
education of Neurology.
We have outpatient clinics covering the broad
fields of Neurology. Furthermore, we also provide
clinics specialized to movement disorders anddementia (Dementia center).
In the in-patient ward, we offer programs forpostgraduate education including the program for the
first stage postgraduate education. We also offer the
excellent training program with the goal to get theboard of Neurologist. In 2005, we initiated deep brain
stimulation for the treatment of movement disorders incooperation with Department of Neurosurgery.

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

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clinical practice at the affiliated hospitals where richexperience is obtained for numerous cases in Clinical
Neurology.
In Graduate School, we offer highly advanced
research activities based on the interest of graduate
students.

Research activities
Our research field covers broad fields related toneurological diseases, with the goals to elucidate themechanisms of neurological diseases, and to eventually develop new therapeutic strategies. Our research
activities include molecular genetics, developmental
biology, cell biology, pharmacology, pathology, andphysiology. We aim to integrate these broad research
fields to better contribute to clinical neurology.
In the development of molecular therapeutics thatameliorate α-dystroglycan (α-DG)-associated diseases,
we identified the glycan unit ribitol 5-phosphate(Rbo5P) in α-DG and showed that enzyme activitiesof α-DG-associated diseases are involved in thesynthesis of tandem Rbo5P. We also found that FKTN
and FKRP can transfer GroP to O-mannosyl glycans
by using CDP-glycerol (CDP-Gro) as a donor
substrate. The analysis of mouse models of
α-DG-associateddiseasesindicatedthat
spatiotemporalpersistenceoffunctionallyglycosylated α-DG may be crucial for brain
development. These findings provide insight into
pathogenesis
andtherapeuticstrategies
inα-DG-associated diseases. In addition, a First In
Human clinical trial of a novel antisense nucleic acid
NS-035 in Fukuyama-type congenital muscular
dystrophy, which is common in Japan due todystroglycanopathy is currently underway. (Toda, T.,
Kanagawa, M., Kobayashi, K., Sudo, A., Fujino, G.,
Kitamura, A., Takahashi, A.)
We perform case-control association studies in
Parkinson disease (PD) employing whole-exome
sequence analysis to discover rare PD susceptibility
variants. Employing a novel bioinformatics approach
using GWAS loci in PD along with in vitro functional
studies and MPTP mouse model analysis, we
identified a novel drug candidate for the prevention ofneurodegeneration in PD. We also identified genetic
factors responsible for the individual difference of theeffects of zonisamide by using GWAS andtranscriptome analysis. (Toda, T., Satake, W., Uenaka,
T., Cha, P.C., Fujino, G., Naito, T.)
In the field of molecular genetics, we havedeveloped the Genomic Medicine Research Support
Center, and introduced next-generation sequencers to
conduct comprehensive genome analyses to elucidate
molecular bases of various neurological diseases.
Regarding monogenic neurologic diseases, we
conduct pedigree analyses in various neurologicaldiseases including epilepsy, multiple system atrophy,
amyotrophic lateral sclerosis, hereditary spastic
paraplegia,
spinocerebellar
atrophy,andadrenoleukodystrophy. As for sporadic neurologic
diseases, we perform case-control association studies
in multiple system atrophy and amyotrophic lateralsclerosis to identify genetic factors underlying these
diseases. On the basis of the findings that mutations in
COQ2 are associated with familial as well as sporadic
multiple system atrophy, we are conducting an
investigator-initiated clinical trial using coenzyme
Q10 for patients with multiple system atrophy.
Genetic study on benign adult familial myoclonus
epilepsy (BAFME), neuronal intranuclear inclusion
disease (NIID), oculopharyngeal myopathy withleukoencephalopathy(OPML),
andoculopharyngodistal myopathy type 1 (OPDM1) are
performed, which have been revealed to be caused byexpasions of noncoding repeats at our department. We
reported safety and efficacy of hematopoietic stem
cell transplantation for adolescent-/adulthood-onset
cerebral form/cerebello-brainstem form of adrenoleukodystrophy. We are now studying a biomarker for
adrenoleukodystrophy. (Toda, T., Tsuji, S., Mitsui, J.,
Ishiura, H., Matsukawa, T., Naruse, H., Kakumoto, T.,
Nagasako, Y., Hao, A., Shinmi, J, Mitsue, A.,
Mitsutake, A., Yamaguchi, N., Almansour, M. A.,
Porto, K. J. L., Orimo, K.)
The human neurophysiology section specializes
in studying the physiology of the human motor andsensory systems in awake healthy volunteers and thepathophysiology of neurological disorders using
several non-invasive physiological methods, such as
TMS, EEG, MEG, fMRI, NIRS and EOG. Our final
goal is to devise new therapeutic techniques for
intractable neurological disorders. To this end, thework extends from the study of spinal systems to basal

105

ganglia and cerebral cortex. We are interested inmismatch negativity changes in ataxic syndrome aswell as basalganglia disorders and entrainment ofneuronal oscillation by peripheral nerve stimulation,
sensor-oriented and sensor-free motion measurements
in Parkinson disease, network analysis in patient withepilepsy using MEG, fMRI of spinal cord andneuronal excitability changes in dystonic patients.
(Hamada, M., Shirota, Y., Kodama, S., Kainaga M,
Seto E, Katsuse K, Tokimura R, and Miyano R.)
In the field of neuromuscular diseases, we
provide pathological diagnosis of biopsied materials
from patients with myopathy or neuropathy. We also
provide autoantibody testing for anti-gangliosideantibodies, and muscle specific antibodies. In research
field, using biopsied muscles and collected serum
samples, we have been studying the mechanisms ofinflammatory myopathies from the view points ofpathological changes, myositis specific autoantibodies,
serum cytokines, and expression profiling of muscle
samples. Our aim is to increase understanding of the
etiology and pathogenesis of neuromuscular diseases.
(Shimizu, J., Kubota A., Maeda M., Kitamura A.).
In the biochemistry laboratory, autopsy brain
analysis of Alzheimer's disease and Lewy bodydisease was performed, and a new gene involvement
was discovered. Chronic cerebral hypoperfusion
model mouse was created and its characteristics wereanalyzed, the technology was applied to analyze
amyloid β metabolism under chromic hypoperfusion.
On the other hand, we analyzed J-ADNI cohort data.
Comparison
with
US-ADNIdata
revealed
compatibility between the two cohorts. The influenceof sex difference and education level, and theinfluence of serum calcium level was discovered. We
analyzed the database of adverse drug reactions to
COVID-19 vaccine and dementia drugs. Other
activities include development of new imaging
techniques using Raman microspectroscopy. We
recently invented a novel high-sensitivity lipid
imaging methodology using delipidation technique forsample preconditioning before Raman observation,
which successfully determined spatial distribution ofminor lipid species in porcine nerve and muscle
tissues. We also developed a new optical sensor chip
detecting biomarkers for Alzheimer’s disease using
nanoimprint lithography (NIL)-based two-dimensional

photonic crystal (2D-PhC), which achieved thesensitivity surpassing ELISA. We newly developed adetection device for our sensor chip, realizing
automated, high-throughput measurement. (YuNagashima, Ryo Ohtomo, Tatsuo Mano, Taro Bannai,
Takeyuki Tsuchida, Kensuke Hamada, Kagari Mano,
Gaku Ohtomo, Kenichiro Sato, Masanori Kurihara)
Neuroimmunology section is focused onunderstanding inflammatory disease of the CNS:
namely multiple Sclerosis and neuromyelitis optica.
Through application of both conventional and more
contemporary immunological methods (FACS, ELISA,
cell culture and NGS analysis), we aim to reveal
disease-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.

Kubota A, Shimizu J, Unuma A, Maeda M,
Shirota Y, Kadoya M, Uchio N, Sakiyama Y, AraiN, Shiio Y, Uesaka Y, Hashida H, Iwata NK,
Goto J, Nakashima R, Mimori T, Toda T. Alaninetransaminase is predominantly increased in theactive phase of anti-HMGCR myopathy.
Neuromuscul Disord. 2022 Jan;32(1):25-32. doi:
10.1016/j.nmd.2021.10.007.
Sato K, Iwata A, Kurihara M, Mano T, Toda T.
Stress cardiomyopathy (Takotsubo syndrome) inpatients who received adrenergic agonist drugs: A
pharmacovigilance study using the JapaneseAdverse Drug Event Report (JADER) database. J
Cardiol. 2022 Jan; 79(1):36-41. doi: 10.1016/
j.jjcc.2021.08.019.
Kono M, Komai T, Yuki H, Hanata N, Kakumoto
T, Kubota A, Hashimoto Maeda M, Toda T,
Shoda H, Fujio K. Anti-Ku antibody-positive
myositis presenting as a wide range of axial
myopathies and myocarditis: A case report andreview of the literature. Mod Rheumatol Case
Rep. 2022 Jan 7;6(1):64-68. doi: 10.1093/mrcr/
rxab024.
Aizawa H, Kato H, Oba K, Kawahara T, Okubo Y,
Saito T, Naito M, Urushitani M, Tamaoka A,
Nakamagoe K, Ishii K, Kanda T, Katsuno M,
Atsuta N, Maeda Y, Nagai M, Nishiyama K,
Ishiura H, Toda T, Kawata A, Abe K, Yabe I,

106

Takahashi-Iwata I, Sasaki H, Warita H, Aoki M,
Sobue G, Mizusawa H, Matsuyama Y, Haga T,
Kwak S. Randomized phase 2 study of
perampanel for sporadic amyotrophic lateralsclerosis. J Neurol. 2022 Feb;269(2):885-896.
doi: 10.1007/s00415-021-10670-y.
5. Kubota A, Ishiura H, Porto KJL, Tanaka M,
Mitsui J, Unuma A, Maki H, Komuro I, Tsuji S,
Shimizu J, Toda T. DMD exon 2 duplication due
to a complex genomic rearrangement isassociatedwithasomatic
mosaicism.
Neuromuscul Disord. 2022 Mar;32(3):263-269.
doi: 10.1016/j.nmd.2021.12.004.
6. Ueda M, Katsuse K, Kakumoto T, Kobayashi S,
Ishiura H, Mitsui J, Toda T. A Case of Copper
Deficiency in Wilson's Disease with a Normal
Zinc Value. Internal med.. 2022 Apr.1; 62(7):1073-1076. doi.10.2169/internalmedicine.936622.
7. Koto S, Chihara N, Akatani R, Nakano H, Hara A,
Sekiguchi K, Matsumoto R, Toda T.
Transcription
Factorc-Maf
Promotes
Immunoregulation of Programmed Cell Death 1–
Expressed CD8<sup>+</sup> T Cells in Multiple
Sclerosis.
NeurolNeuroimmunol
Neuroinflamm. 2022 Apr.5;9(4): e1166. doi.
10.1212/nxi.0000000000001166
8. Tokuoka H, Imae R, Nakashima H, Manya H,
Masuda C, Hoshino S, Kobayashi K, Lefeber DJ,
Matsumoto R, Okada T, Endo T, Kanagawa M,
Toda T. CDP-ribitol prodrug treatment
ameliorates ISPD-deficient muscular dystrophy
mouse model. Nat Commun. 2022 Apr 14;13(1):1847. doi: 10.1038/s41467-022-29473-4.
9. Akamatsu M, Yamashita T, Teramoto S, Huang Z,
Lynch J, Toda T, Niu L, Kwak S. Testing of thetherapeutic efficacy and safety of AMPA receptor
RNA aptamers in an ALS mouse model. Life Sci
Alliance. 2022 Jan 12;5(4):e202101193. doi:
10.26508/lsa.202101193.
10. Kitagawa K, Arima H, Yamamoto Y, Ueda S,
Rakugi H, Kohro T, Yonemoto K, Matsumoto M,
Saruta T, Shimada K; Recurrent Stroke
Prevention Clinical Outcome (RESPECT) Study
Group. Intensive or standard blood pressure
control in patients with a history of ischemic
stroke: RESPECT post hoc analysis. Hypertens

11.

12.

13.

14.

15.

Res. 2022 Apr;45(4):591-601. doi: 10.1038/
s41440-022-00862-y
Yamaguchi N, Matsuda S, Matsumoto J, Ugawa
Y, Shimizu J, Toda T, Sonoo M, Yoshizawa T.
Rippling Muscle Disease with Irregular Toe Jerks
and Anti-acetylcholine Receptor Antibodies:
Remission after Extended Thymectomy. Intern
Med. 2022 May 1;61(9):1439-1442. doi:
10.2169/internalmedicine.8146-21.
Naito T, Satake W, Cha PC, Kobayashi K, Murata
M, Toda T. Comparative whole transcriptome
analysis of Parkinson's disease focusing on theefficacy of zonisamide. J Neurol Neurosurg
Psychiatry. 2022 May;93(5):509-512. doi:
10.1136/jnnp-2021-328742.
Egawa N, Izumi Y, Suzuki H, Tsuge I, Fujita K,
Shimano H, Izumikawa K, Takahashi N, Tsukita
K, Enami T, Nakamura M , Watanabe A, Naitoh
M, Suzuki S, Seki T, Kobayashi K, Toda T, KajiR, Takahashi R, Inoue H. TDP-43 regulatescholesterol biosynthesis by inhibiting sterol
regulatory element-binding protein 2. Sci Rep.
2022May14; 12(1) :7988. doi.10.1038/s41598022-12133-4.
Tokimura R, Hashimoto M, MitsutakeA, Sakai S,
Suzuki F, Sugasawa K, Fujimoto C, Ishiura H,
Toda T. Isolated Paravermal Hyperintensities in
Neuronal Intranuclear Inclusion Disease.
Neurology ,2022May31;98(22) :938-939. doi.10.
1212/WNL.0000000000200590
Oki R, Izumi Y, Fujita K, Miyamoto R, Nodera H,
Sato Y, Sakaguchi S, Nokihara H, Kanai K,
Tsunemi T, Hattori N, Hatanaka Y, Sonoo M,
Atsuta N, Sobue G, Shimizu T, Shibuya K, Ikeda
K, Kano O, Nishinaka K, Kojima Y, Oda M,
Komai K, Kikuchi H, Kohara N, Urushitani M,
Nakayama Y, Ito H, Nagai M, Nishiyama K,
Kuzume D, Shimohama S, Shimohata T, Abe K,
Ishihara T, Onodera O, Isose S, Araki N, Morita
M, Noda K, Toda T, Maruyama H, Furuya H,
Teramukai S, Kagimura T, Noma K, Yanagawa H,
Kuwabara S, Kaji R; Japan Early-Stage Trial of
Ultrahigh-Dose Methylcobalamin for ALS(JETALS) Collaborators. Efficacy and Safety of
Ultrahigh-Dose Methylcobalamin in Early-Stage
Amyotrophic Lateral Sclerosis: A Randomized
Clinical Trial. JAMA Neurol. 2022 Jun 1; 79(6):

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16.

17.

18.

19.

20.

21.

575-583. doi: 10.1001/jamaneurol.2022.0901.
Itamiya T, Komai T, Kanda H, Nagafuchi Y,
Chang H, Shibata S, Ishiura H, Shoda H, Toda T,
Fujio K. Efficacy of canakinumab on AA
amyloidosis in late-onset NLRP3-associatedautoinflammatory disease with an I574F somatic
mosaic mutation. Clin Rheumatol. 2022July1;
41(7): 2233-2237 . doi.10.1007/s10067-02206130-1.
Kurihara M, Sugiyama Y, Tanaka M, Sato K,
Mitsutake A, Ishiura H, Kubota A, Kaori K,
Hayashi T, Iwata A, Shimizu J, Murayama K,
Tsuji S, Toda T. Diagnostic Values of Venous
Peak Lactate, Lactate-to-pyruvate Ratio, and Fold
Increase in Lactate from Baseline in Aerobic
Exercise Tests in Patients with Mitochondrial
Diseases, Intern Med. 2022July1; 61(13): 19391946 . doi.10.2169/internalmedicine.8629-21.
Kikkawa Y, Matsunuma M, Kan R, Yamada Y,
Hamada K, Nomizu M, Negishi Y, Nagamori S,
Toda T, Tanaka M, Kanagawa M. Laminin
α5_CD239_Spectrin is a candidate associationthat compensates the linkage between thebasement membrane and cytoskeleton in skeletal
muscle fibers. Matrix Biol Plus. 2022Aug;15:
100118-100118.
doi.10.1016/j.mbplus.2022.
100118.
Uchigami H, Sato K, Samejima N, Watanabe A,
Kuwana N, Tsuchida T, Toda T, Saito M.
Preoperative factors associated with shunt
responsiveness in patients with idiopathic
normal-pressure hydrocephalus. Clinical Neurol
Neurosurg. 2022 Aug28;222:107425-107425.
doi.10.1016/j.clineuro.2022.107425.
Harada R, Taniguchi-Ikeda M, Nagasaka M,
Nishii T, Inui A, Yamamoto T, Morioka I, Kuroda
R, Iijima K, Nozu K, Sakai Y, Toda T.
Assessment of the upper limb muscles in patientswith Fukuyama muscular dystrophy: Noninvasive
assessment using visual ultrasound muscle
analysis and shear wave elastography,
Neuromuscul Disord. 2022 Sep;32(9):754-762.
doi,10.1016/j.nmd.2022.05.004.
Katsuse K, Kenichiro Sato K, Nobuyuki Tanaka
N, Idai Uchida I, Tatsushi Toda T, Takashi Mikata
T, Yasufumi Motoyoshi Y. Predicting the CTG
Repeat Size from a Single Spirometry Test

22.

23.

24.

25.

26.

27.

Performed at Any Time during the Disease
Course of Myotonic Dystrophy Type 1. Intern
Med. 2022;61(15): 281-2286. doi.org/10.2169/
internalmedicine.8633-21.
Sekiya H, Suji A, Hashimoto Y, Takata M, Koga
S, Nishida K, Futamura N, Kawamoto M, Kohara
N, Dickson DW, Kowa H, Toda T. Discrepancy
between
distributionofalpha-synuclein
oligomers and Lewy-related pathology in
Parkinson's disease. Acta Neuropathol Commun.
2022Sep.06;10(1): 133-133. doi10.1186/s40478022-01440-6
Bujo S, Amiya E, Hashimoto-Maeda M, Ishida J,
Hatano M, Ishizuka M, Uehara M, Oshima T,
Kojima T, Nakanishi K, Daimon M, Shimizu J,
Toda T, Komuro I. The effect of
immunosuppressive
therapyon
cardiacinvolvements in anti-mitochondrial antibodypositive myositis. ESC Heart Fail. 2022Sep.06;
9(6): 4112-4119. doi.10.1002/ehf2.14138.
Miller TM, Cudkowicz ME, Genge A, Shaw PJ,
Sobue G, Bucelli RC, Chiò A, Van Damme P,
Ludolph AC, Glass JD, Andrews JA, Babu S,
Benatar M, McDermott CJ, Cochrane T, Chary S,
Chew S, Zhu H, Wu F, Nestorov I, Graham D,
Sun P, McNeill M, Fanning L, Ferguson TA,
Fradette S; VALOR and OLE Working Group.
Trial of Antisense Oligonucleotide Tofersen for
SOD1 ALS.N Engl J Med. 2022 Sep 22; 387(12):1099-1110. doi: 10.1056/NEJMoa2204705.
Hara R, Mano T, Yano S, Toda T. Isolated
Abducens Nerve Palsy Caused by Anterior
Inferior Cerebellar Artery Compression. Intern
Med. 2022.Oct1;61(19)2991-2992. doi: 10.2169/
internalmedicine.9294-21.
Seki Y, Yamada T, Kiyosue A, Kimura K, Uehara
M, Hatano M, Sasako T, Shirota Y, Sudo A,
Ishiura H, Toda T, Yamauchi T, Komuro I.
Asymptomatic myocardial infarction in a patientwith myotonic dystrophy type 1. J Cardiology
Cases. 2022 Oct;26(4):248-251. doi.10.1016/j.
jccase.2022.05.004.
Ando T, Riku Y, Akagi A, Miyahara H, Hirano M,
Ikeda T, Yabata H, Koizumi R, Oba C, Morozumi
S, Yasui K, Goto A, Katayama T, Sakakibara S,
Aiba I, Sakai M, Konagaya M, Mori K, Ito Y,
Yuasa H, Nomura M, Porto KJL, Mitsui J, Tsuji S,

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28.

29.

30.

31.

32.

33.

Mimuro M, Hashizume Y, Katsuno M, Iwasaki Y,
Yoshida M. Multiple system atrophy variant withsevere hippocampal pathology. Brain Pathol.
2022 Jan;32(1):e13002. doi: 10.1111/bpa.13002.
Koh K, Tsuchiya M, Ishiura H, Shimazaki H,
Nakamura T, Hara H, Suzuyama K, Takahashi M,
Tsuji S, Takiyama Y; Japan Spastic Paraplegia
Research Consortium. Chédiak-Higashi syndrome
presenting as a hereditary spastic paraplegia. J
Hum Genet. 2022 Feb;67(2):119-121. doi:
10.1038/s10038-021-00977-z.
Kokubo Y, Morimoto S, Sasaki R, Hasegawa M,
Ishiura H, Tsuji S, Yoshida M, Yamazoe N,
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9;12(1):9543. doi: 10.1038/s41598-022-13580-9.
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F, Takahashi A, Kunita A, Ishiura H, Shin M,
Nakatomi H, Nagao T, Goto H, Takahashi SI,
Ushiku T, Ishikawa S, Okazaki M, Morishita S,
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Department of Neurosurgery
Professor
Nobuhito Saito, M.D., Ph.D.

Lecturer
Shota Tanaka, M.D.,Ph.D. Naoto Kunii, M.D., Ph.D.
Satoru Miyawaki, M.D., Ph.D.

Specially Appointed Lecturer
Shunsaku Takayanagi, M.D., Ph.D.

Asssistant Professor
Shunsaku Takayanagi, M.D., Ph.D. Hirokazu Takami, M.D., Ph.D.
Seijiro Shimada, M.D., Ph.D.

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

Satoshi Koizumi, M.D.

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

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

Taijun Hana, M.D., Ph.D.

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

Yuki Shinya, M.D.

Motoyuki Umekawa, M.D.

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

Homepage

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

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

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

Clinical activities
General outpatient clinic including new patient clinic
is open every weekday and subspecialty clinic is open
three days a week (Monday and Friday). The latter isopen for patients with brain tumor, pituitary disease,spinal disease, cerebrovascular disease, endovascularintervention, epilepsy, and gamma knife treatment.
From April 2022 to March 2023, 18,537 patients weretreated at the outpatient clinics.

112

The neurosurgery ward has approximately 40 beds on
the seventh floor of the hospital building opened in
September 2001. In 2022, 947 patients were admitted
to the neurosurgery ward. 449 surgical procedures and
205 gamma knife procedures were performed in 2022.
Our practice covers a wide variety of neurosurgicaldiseases including malignant and benign brain tumors,hemorrhagic and thromboembolic cerebrovasculardiseases, spinal disorders, pediatric diseases, epilepsy,
pain and movement disorders.
Intraoperative functional monitoring in brain tumor
surgery and pre- and intra-operative functional mapping in epilepsy surgery are frequently used 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 32 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 6 in 2021, 12 in 2022, and 4 in 2023 in
our neurosurgical residency program. These residents
are trained in the university hospital and affiliatedhospitals to experience every aspect of neurosurgicalpractice for five years on average. Our residency
training is finalized after the sixth year, when thefinishing 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.

1132) Genetic analyses of cerebrovascular diseases andbenign brain tumors
We are conducting genetic analysis research for
cerebrovascular diseases and benign brain tumors withthe aim of identifying molecular markers with highclinical significance and elucidating the pathogenic
mechanism.
Specially, genes such as RNF213 in moyamoya
disese, NF2 in meningioma and schwannoma, CCM in
cerebral cavernous malformation were analyzed. In
addition, comprehensive genetic analyses, including
analysis of whole exome sequences, were performed to
identify novel disease-related genes..
In the field of cerebrovascular disease, analysis of
the RNF213 gene revealed that RNF213 variant isassociated with not only moyamoya disease but also
various intracranial artery stenosis. Furthermore,genome wide association study of intracranial arterystenosis was performed, and diseae related gene
polymorphisms were clarified. In addition, we haveidentified
disease-relatedgeneinvenousmalformations that occur in the head and conducting
functional analysis.
In the field of benign brain tumors, we improved the
diagnostic
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 include 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.
Furthermore, we are at the frontier in the field of
pediatric brain tumor research, especially on CNS germ
cell tumors. We have been publishing important articles
regarding basic, translational and clinical research.
Multi-omics genomic investigation into thepathogenesis and clinical trials are ongoing.
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

114

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 threedimensional computer graphics for neurosurgery
Our department intensively utilizes various kinds offunctional and metabolic imaging modalities including
magnetoencephalography, functional MRI, and diffusion tensor imaging-based tractography for presurgicalbrain mapping. Combining the results of 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.

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10.1007/s00701-021-04999-6
Hasegawa H., Saito N. [Surgical Site Infection
Following Craniotomies]. No Shinkei Geka
50(5):1008-1016, 2022
doi: 10.11477/mf.
1436204660

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6.

Hasegawa H., Shin M., Kawagishi J., Jokura H.,
Hasegawa T., Kato T., Kawashima M., Shinya Y.,
Kenai H., Kawabe T., Sato M., Serizawa T.,
Nagano O., Aoyagi K., Kondoh T., Yamamoto M.,
Onoue S., Nakazaki K., Iwai Y., Yamanaka K.,
Hasegawa S., Kashiwabara K., Saito N. A
Practical Grading Scale for Predicting Outcomesof Radiosurgery for Dural Arteriovenous Fistulas:JLGK 1802 Study. Journal of stroke 24(2):278287, 2022 doi: 10.5853/jos.2021.03594
7. Hasegawa H., Shin M., Niwa R., Koizumi S.,
Yoshimoto S., Shono N., Shinya Y., Takami H.,
Tanaka S., Umekawa M., Amemiya S., Kin T.,
Saito N. Revisitation of imaging features of skull
base chondrosarcoma in comparison to chordoma.
J Neurooncol 159(3):581-590, 2022
doi:
10.1007/s11060-022-04097-2
8. Hirano Y., Shinya Y., Aono T., Hasegawa H.,
Kawashima M., Shin M., Takami H., Takayanagi
S., Umekawa M., Ikemura M., Ushiku T., Taoka
K., Tanaka S., Saito N. The Role of Stereotactic
Frame-Based Biopsy for Brainstem Tumors in the
Era of Molecular-Based Diagnosis and Treatment
Decisions. Current oncology (Toronto, Ont)
29(7):4558-4565, 2022 doi: 10.3390/curroncol
29070360
9. Hirata T., Miyawaki S., Koizumi S., Teranishi Y.,
Ishikawa O., Saito N. Spontaneous regression of asymptomatic developmental venous anomaly withcapillary stain. Interventional neuroradiology :journal of peritherapeutic neuroradiology,
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28(3):257-261, 2022 doi: 10.1177/15910199211
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[Molecular Pathogenesis of Cerebral Cavernous
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11. Ishigami D., Koizumi S., Miyawaki S., Hongo H.,
Teranishi Y., Mitsui J., Saito N. Symptomatic andStenotic Developmental Venous Anomaly with
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journal 9:139-144, 2022 doi: 10.2176/jns-nmc.
2022-0022
12. Ishigami D., Miyawaki S., Imai H., Shimizu M.,
Hongo H., Dofuku S., Ohara K., Teranishi Y.,

13.

14.

15.

16.

17.

Shimada D., Koizumi S., Ono H., Hirano Y.,
Segawa M., Nakatomi H., Saito N. Correction to:
RNF213 p.Arg4810Lys Heterozygosity inMoyamoya Disease Indicates Early Onset and
Bilateral Cerebrovascular Events. Translational
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s12975-021-00971-9
Ishigami D., Miyawaki S., Imai H., Shimizu M.,
Hongo H., Dofuku S., Ohara K., Teranishi Y.,
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Targeting the Primary Tumor Sites Contributes toSurvival in Patients With Skull Base Chordoma.
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with testicular counterparts. Neuro Oncol 24(8):1246-1258, 2022 doi: 10.1093/neuonc/noac021
Takami H., Graffeo C. S., Perry A., Giannini C.,
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Markers in Central Nervous System Germ Cell
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Cases in a Large International Cohort. Cancers
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[Evolving Exploration of the Pathogenesis of CNS
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Medicine]. No Shinkei Geka 50(1):39-50, 2022
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[Hemangioblastoma and von Hippel-Lindau
Disease]. No Shinkei Geka 50(1):101-110, 2022
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PRRX1 induced by BMP signaling decreases
tumorigenesis by epigenetically regulating
glioma-initiating cell properties via DNA
methyltransferase 3A. Molecular oncology 16(1):269-288, 2022 doi: 10.1002/1878-0261.13051
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[Molecularly
Targeted
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Teranishi Y., Hongou H., Miyawaki S., Saito N.
[Solitary fibrous tumor/hemangiopericytoma]. No
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Hongo H., Dofuku S., Okano A., Takayanagi S.,
Ota T., Yoshimura J., Qu W., Mitsui J., MorishitaS., Tsuji S., Saito N. Early prediction of functional
prognosis in neurofibromatosis type 2 patients
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2022 doi: 10.1038/s41598-022-13580-9
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Ishigami D., Hongo H., Dofuku S., Takami H.,
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47. Tsuchiya T., Miyawaki S., Shinya Y., Teranishi Y.,
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48. Tsuchiya T., Takami H., Yoshimoto S., Nambu S.,
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Social Medicine
1. Occupational, Environmental
and Preventive Medicine

121

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

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

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

Homepagehttps://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) 10
students (1 are from outside of the University of Tokyo),
2 technical staffs, 6 technical assistants, 1 project

researcher, 1 visiting researchers, 1 research student, 1
academic support staff, and 1 project specialist. Also,
three collaborative researchers from private companies
have joined our laboratory.

Teaching activities
We give “Preventive Medicine” lecture course tothird-year undergraduate students in the school of
medicine, practical courses to fifth-year undergraduate
students, “Introduction to Preventive Medicine” inmedical science master’s program, and "Surviving
Cancer in Asia," a doctoral program common course in
medicine.
In the “Preventive Medicine” lecture course, specificemphases are on alteration of the disease patternassociated with social change, basic concepts ofoccupational and mental health, and information
science as a key to the understanding of genome andabundant bio/health data, which is a basis of disease
predisposition.
In the practical course for fifth-year undergraduate
students, three staff members are in charge ofenvironmental microbiology measurement, cancer
genome data analysis, and medical image analysis. In
the environmental microbiological measurement,
students collect samples from various environments
and analyze the distribution of microorganisms in thesamples using a long-read sequencer. In cancer genome

122data analysis, students use publicly available singlecell transcriptome data and analyze them from theirown unique perspectives to make sense of the cancer
microenvironment, etc. In medical image analysis,
students classify histopathological images using deeplearning and analyze and discuss the impact of various
techniques to improve its accuracy.

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,
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 Immune Environment 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.
We are also synthesizing antibodies from this immune
repertoire data to develop antibody drugs against
cancer.
2. Cancer Genome Analysis to Explore
Carcinogenic 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.
In addition, we performed trans-ethic genome analysis
of gastric cancer and showed the existence of East
Asian-specific gastric cancer induced by alcohol
drinking and smoking. Currently, we are regarding
cancer tissues as a whole using clinical cancer tissues
and patient-derived xenografts (PDX), by applying
genomics point of view, i.e., single-cell analysis, tocancer cells, immune cells, and vascular stroma cells
that comprise cancer tissue, to elucidate carcinogenic
and progression factors and points of intervention fromhigher dimensions.

123

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
histopathologial 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. Currently,
we’re trying to expand the Luigi database bycollaborating with various hospitals. We also focus on
the development of contents which would seamlessly
connect routine lab tests performed in small clinics andcancer genome medicine given in large core hospitals
by integrated analysis of histopathological informationand cancer genome information.

Publications
1.

2.

3.

Mita, H., Katoh, H., Komura, D., Kakiuchi, M.,
Abe, H., Rokutan, H., Yagi, K., Nomura, S.,
Ushiku, T., Seto, Y., Ishikawa, S., 2022. Aberrant
Cadherin11
Expression
Predicts
Distant
Metastasis of Gastric Cancer. Pathology Research and Practice 154294.
Matsubara, D., Yoshimoto, T., Akolekar, N.,
Totsuka, T., Amano, Y., Kihara, A., Miura, T.,
Isagawa, Y., Sakuma, Y., Ishikawa, S., Ushiku, T.,
Fukayama, M., Niki, T., 2022. Genetic andphenotypic determinants of morphologies in 3‐
dimensional cultures and xenografts of lung tumor
cell lines. Cancer Science cas.15702.
Furuya, G., Katoh, H., Atsumi, S., Hashimoto, I.,
Komura, D., Hatanaka, R., Senga, S., Hayashi, S.,
Akita, S., Matsumura, H., Miura, A., Mita, H.,

Nakakido, M., Nagatoishi, S., Sugiyama, A.,
Suzuki, R., Konishi, H., Yamamoto, A., Abe, H.,
Hiraoka, N., Aoki, K., Kato, Y., Seto, Y.,
Yoshimura, C., Miyadera, K., Tsumoto, K.,
Ushiku, T., Ishikawa, S., 2022. Nucleic acid–triggered tumoral immunity propagates pH ‐selective therapeutic antibodies through tumor‐
driven epitope spreading. Cancer Science cas.
15596.
4. Kaneko, Y., Yamatsugu, K., Yamashita, T.,
Takahashi, K., Tanaka, T., Aki, S., Tatsumi, T.,
Kawamura, T., Miura, M., Ishii, M., Ohkubo, K.,
Osawa, T., Kodama, T., Ishikawa, S., Tsukagoshi,
M., Chansler, M., Sugiyama, A., Kanai, M., Katoh,H., 2022. Pathological complete remission of
relapsed tumor by photo‐activating antibody–
mimetic drug conjugate treatment. Cancer
Science cas.15565.
6. Hongo, H., Miyawaki, S., Teranishi, Y., Mitsui, J.,
Katoh, H., Komura, D., Tsubota, K., Matsukawa,T., Watanabe, M., Kurita, M., Yoshimura, J.,
Dofuku, S., Ohara, K., Ishigami, D., Okano, A.,
Kato, M., Hakuno, F., Takahashi, A., Kunita, A.,
Ishiura, H., Shin, M., Nakatomi, H., Nagao, T.,
Goto, H., Takahashi, S.-I., Ushiku, T., Ishikawa,S., Okazaki, M., Morishita, S., Tsuji, S., Saito, N.,
2022. Somatic GJA4 gain-of-function mutation inorbitalcavernous
venousmalformations.
Angiogenesis 26, 37-52.
7. Tanaka, M., Kunita, A., Yamagishi, M., Katoh, H.,
Ishikawa, S., Yamamoto, H., Abe, J., Arita, J.,
Hasegawa, K., Shibata, T., Ushiku, T., 2022.
KRAS mutation in intrahepatic cholangiocarcinoma: linkage with metastasis‐free survivaland reduced E‐cadherin expression. LiverInternational liv.15366.
8. Liu, B., Katoh, H., Komura, D., Yamamoto, A.,
Ochi, M., Onoyama, T., Abe, H., Ushiku, T., Seto,
Y., Suo, J., Ishikawa, S., 2022. Functional
genomics screening identifies aspartyl‐ tRNA
synthetase as a novel prognostic marker and atherapeutic target for gastric cancers. The Journalof Pathology path.5980.
9. Onoyama, T., Ishikawa, S., Isomoto, H., 2022.
Gastric cancer and genomics: review of literature.
J Gastroenterol. 57, 505-516.
10. Tsubosaka, A., Komura, D., Katoh, H., Kakiuchi,124M., Onoyama, T., Yamamoto, A., Abe, H., Seto,
Y., Ushiku, T., Ishikawa, S., 2022. Single-Cell
Transcriptome Analyses Reveal the Cell Diversity
and Developmental Features of Human Gastricand Metaplastic Mucosa. bioRxiv.
11. Teranishi, Y., Okano, A., Miyawaki, S., Ohara, K.,
Ishigami, D., Hongo, H., Dofuku, S., Takami, H.,
Mitsui, J., Ikemura, M., Komura, D., Katoh, H.,
Ushiku, T., Ishikawa, S., Shin, M., Nakatomi, H.,
Saito, N., 2022. Clinical significance of NF2
alteration in grade I meningiomas revisited;
prognostic impact integrated with extent ofresection, tumour location, and Ki-67 index. acta
neuropathol commun 10, 76.
12. Komura, D., Onoyama, T., Shinbo, K., Odaka, H.,
Hayakawa, M., Ochi, M., Herdiantoputri, R.,
Sakamoto, K., Katoh, H., Ikeda, T., Ushiku, T.,
Ishikawa, S., 2022. Beyond pathologist-levelannotation of large-scale cancer histology forsemantic
segmentation
using
immunofluorescence restaining. bioRxiv.
13. Yamatsugu, K., Katoh, H., Yamashita, T.,
Takahashi, K., Aki, S., Tatsumi, T., Kaneko, Y.,
Kawamura, T., Miura, M., Ishii, M., Ohkubo, K.,
Osawa, T., Kodama, T., Ishikawa, S., Kanai, M.,
Sugiyama, A., 2022. Antibody mimetic drug
conjugate manufactured by high-yield Escherichia
coli expression and non-covalent binding system.
Protein Expression and Purification 192,
106043.
14. Yasuda, T., Lee, H.S., Nam, S.Y., Katoh, H.,
Ishibashi, Y., Yamagata Murayama, S., Matsui, H.,
Masuda, H., Rimbara, E., Sakurazawa, N., Suzuki,
H., Yoshida, H., Seto, Y., Ishikawa, S., Jeon, S.W.,
Nakamura, M., Nomura, S., 2022. NonHelicobacter pylori Helicobacter (NHPH) positive
gastric cancer. Sci Rep 12, 4811.
15. Komura, D., Kawabe, A., Fukuta, K., Sano, K.,
Umezaki, T., Koda, H., Suzuki, R., Tominaga, K.,
Ochi, M., Konishi, H., Masakado, F., Saito, N.,
Sato, Y., Onoyama, T., Nishida, S., Furuya, G.,
Katoh, H., Yamashita, H., Kakimi, K., Seto, Y.,
Ushiku, T., Fukayama, M., Ishikawa, S., 2022.
Universal encoding of pan-cancer histology bydeep texture representations. Cell Reports 38,
110424.
16. Zhang, M., Sugita, I., Komura, D., Katoh, H.,

Shimada, S., Inazawa, J., Tanaka, S., Ishikawa, S.,
2022. Genomic landscape of a mouse model ofdiffuse-type gastric adenocarcinoma. Gastric
Cancer 25, 83–95.
17. Sugita, I., Matsuyama, S., Dobashi, H., Komura,D., Ishikawa, S., 2022. Viola: a structural variant
signature
extractor
withuser-definedclassifications. Bioinformatics 38, 540–542.

125

Department of Public Health/
Department of Health Policy
Professor
Takahiro Higashi, M.D., Ph.D.
(From September 1, 2022)

Associate Professor
Haruhiko Inada, M.D., Ph.D., M.P.H.
(From February 1, 2023)

Research Associate
Atsushi Miyawaki, M.D., Ph.D.
(From September 1, 2022 [Project Research Associate, from April 1 to August 31, 2022])

Homepagehttps://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 in Japan
were introduced after the World War II, following themodel of the U.S. systems for public health andmedical education. The Department of Public Healthwas established in 1947, in Faculty of Medicine, theUniversity of Tokyo. In 1995, the Department becamea part of Division of Social Medicine, Graduate
School of Medicine, as the result of 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, and the Department became apart of School of Public Health (Department of Health
Policy) and remained being a part of Division ofSocial Medicine (Department of Public Health).

The objectives of the Department are both education
and research of public health. The Department trains
graduate and undergraduate students through lectures,
seminars, field practice, and laboratory work in publichealth and occupational medicine, for the degrees ofMedical Doctor (MD), Master of Public Health(MPH), and Doctor of Medical Sciences (equivalent toPhD). The Department has conducted research on awide variety for public health issues, including healthpolicy and economics, occupational medicine, clinicalepidemiology, health services research, and so on. In
addition, the staff members of the Department haveoffered public and occupational health services to thegovernments, industries, and local communities.
In the academic year of 2020, the Department consistsof 3 faculty members above listed, 1 project
researchers (part-time), 2 supporting staff members, 4graduate students (3 in PhD program, 1 in professional
degree course), and 12 part-time lecturers.

Teaching activities
1) Undergraduate Program (Medical School)
Education in public health in the School of Medicine

126

is offered for M2 (4th year), M3 (5th year) and M4(6th year) students. In the Autumn term of the fourthyear in School of Medicine (M2), students areprovided with the following lectures; general publichealth, epidemiology, health and labor administration,
health policy studies, health economics, costeffectiveness, human ecology, lifestyle disease control,
exercise and dietary nutrition, infectious disease andtuberculosis control, disaster medicine, maternal andchild health, cancer control, ICD and statistics,
clinical epidemiology, mental health, global health,and environmental medicine. Similarly, in the sixthyear (M4), an intensive course of public health (e.g.,more advanced public health topics, nutritional
epidemiology, health services research for older
persons, healthcare policy, and cancer control from thepatients' perspective) is provided. All the above
lectures are given by faculty members and outside
visiting lectures including health practitioners.
Field practice and laboratory work in public health isdue in the summer term of the fifth year (M3), which
is jointly provided by Department of Preventive
Medicine and the other departments related to publichealth fields. On average seven to eight students(small group) are assigned to one special topic groupwith a tutor (faculty member or part-time lecturer; we
had 14 groups this year). Each group conducts fieldpractice, review work, or laboratory work, and writes
a report in the style of original or review paper.
In addition to the core curriculum mentioned above,
we accepted students from the School of Medicine
within the Clinical Researcher Development Program.
2) MPH Program
Various courses are given by those departments
affiliated with School of Public Health. Among them,our Department offers three courses; “Health Policy(cancelled due to instructor's schedule)”, “Public
Health Preparedness”, and “Public Health Practice(cancelled due to instructor's schedule)”.
3) PhD Program
The Department offers special lectures, seminars, fieldpractice, and laboratory work on public health andoccupational medicine to graduate students. In thesetraining, special emphasis has been placed on thefollowing points: (1) how to conduct epidemiologicalstudies, (2) how to use epidemiological and statisticalmethods, (3) how to use economic concepts andmethods in the health fields, (4) how to establish thecollaboration with health professionals in the various
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 using
information such as cancer registries and medical
records. These studies have been published in healthpolicy 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 ofdisaster preparedness in local communities andhealthcare facilities, (2) study on risk communicationin public health emergencies, (3) epidemiologicalstudy on those children with cerebral palsy, and (4)various public health issues due to the pandemic of
COVID-19.

References（Original Article）
1.

Yamamoto S, Sakakibara N, Hirano H, Morizane

127

2.

3.

4.

5.

6.

7.

8.

9.

C, Honma Y, Hijioka S, Okusaka T, Higashi T,
Kawai A. The real-world selection of first-line
systemic therapy regimen for metastatic
gastroenteropancreatic neuroendocrine neoplasm
in Japan. Scientific Reports 2022 12, Article
number: 17601.
Ishii T. Watanabe T, Higashi T. Differences in theperformance of adjuvant chemotherapy between
hemodialysis and non-hemodialysis patients.
Cancer Medicine. 2023 Feb;12(4):4033-4041.
doi: 10.1002/cam4.5258. Epub 2022 Sep 21.
Ren N, Nishimura K, Higashi T, Iihara K.
Associations
Between
AdherencetoEvidence-Based, Stroke Quality Indicators andOutcomes of Acute Reperfusion Therapy. Stroke2022 Nov;53(11):3359-3368.
Okuyama A, Watabe M, Makoshi R, Takahashi H,
Tsukada Y, Higashi T. Impact of the COVID-19
pandemic on the diagnosis of cancer in Japan:
analysis of hospital-based cancer registries. Jpn J
Clin Oncol. 2022 Oct 6;52(10):1215-1224. doi:
10.1093/jjco/hyac129.
Ishii T, Watanabe T, Higashi T. Baseline cardiac
function checkup in patients with gastric orbreast cancer receiving trastuzumab oranthracyclines. Cancer Med. 2023 Jan;12(1):122-130. doi: 10.1002/cam4.4929. Epub 2022
Jun 11.
Higashi T. Cancer epidemiology and treatment
patterns for older persons in Japan: a review ofnationwide data and statistics. Jpn J Clin Oncol.
2022 Apr 6;52(4):303-312.
Kanehara R, Goto A, Watanabe T, Inoue K,
Taguri M, Kobayashi S, Imai K, Saito E,
Katanoda K, Iwasaki M, Ohashi K, Noda M,
Higashi T. Association between diabetes andadjuvant chemotherapy implementation inpatients with stage III colorectal cancer. J
Diabetes Investig. 2022 Oct;13(10):1771-1778.
doi: 10.1111/jdi.13837. Epub 2022 Jun 4.
Watanabe T, Sugiyama T, Imai K, Higashi T.
How are new drugs disseminated in Japan?
Analysis using the National Database of Health
Insurance Claims of Japan. Cancer Science, 09
March 2022; DOI: 10.1111/cas.15322
Ishii T, Nakano E, Watanabe T, Higashi T.
Cardiac function checkup during trastuzumab

10.

11.

12.

13.

14.

15.

16.

therapy among patients with breast cancer.
Clinical Breast Cancer, 19 January 2022;
https://doi.org/10.1016/j.clbc.2022.01.005
Kurogi A, Onozuka D, Hagihara A, Nishimura K,
Kada A, Hasegawa M, Higashi T, Kitazono T,
Ohta T, Sakai N, Arai H, Miyamoto S, Sakamoto
T, Iihara K, the J-ASPECT Study Collaborators.
Influence of hospital capabilities and prehospitaltime on outcomes of thrombectomy for stroke inJapan from 2013 to 2016. Scientific Reports 12,
Article number: 3252 (2022), 28 February 2022;
https://doi.org/10.1038/s41598-022-06074-1
Miyawaki, A. Full-time work rates of physicianswith physician spouses vs nonphysician spousesin Japan. JAMA Network Open. 2022 Nov 1;
5(11):e2242143. doi: 10.1001/jamanetworkopen.
2022.42143.
Sano K, Miyawaki A, Abe K, Jin X, Watanabe T,
Tamiya N, Kobayashi Y. Effects of cost sharing
on long-term care service utilization among
home-dwelling older adults in Japan. Health
Policy. 2022 Dec;126(12):1310-1316. doi: 10.
1016/j.healthpol.2022.10.002. Epub 2022 Oct 6.
Miyawaki A, Ikesu R, Tokuda Y, Goto R,
Kobayashi Y, Sano K, Tsugawa Y. Prevalence andchanges of low--value care at acute care
hospitals: a multicentre observational study inJapan.
BMJ Open. 2022; 12(9): e063171.
https://bmjopen.bmj.com/content/12/9/e063171
Taniguchi Y, Miyawaki A, Tsugawa Y, Murayama
H, Tamiya N, Tabuchi T. Family caregiving andchanges in mental health status in Japan during
the COVID-19 pandemic. Archives ofGerontology and Geriatrics. 2022 Jan;98:104531.
https://doi.org/10.1016/j.archger.2021.104531
Taniguchi Y, Kuno T, Komiyama J, Adomi M,
Suzuki T, Abe T, Ishimaru M, Miyawaki A, Saito
M, Ohbe H, Miyamoto Y, Imai S, Kamio T,
Tamiya N, Iwagami M. Comparison of patientcharacteristics and in-hospital mortality between
patients with COVID-19 in 2020 and those with
influenza in 2017–2020: a multicenter,retrospective cohort study in Japan. The Lancet
Regional Health - Western Pacific. 2022 Mar;20:
100365. doi: 10.1016/j.lanwpc.2021.100365
Adomi M, Kuno T, Komiyama J, Taniguchi Y,
Abe T, Miyawaki A, Imai S, Morita K, Saito M,

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Ohbe H, Kamio T, Tamiya N, Iwagami M.
Association
betweenpre‐admission
anticoagulation and in‐hospital death, venous
thromboembolism, and major bleeding amonghospitalized COVID‐19 patients in Japan.
Pharmacoepidemiol Drug Saf. 2022 Apr 7;31(6):680–8. https://doi.org/10.1002/pds.5433
Yanagisawa-Sugita A, Sugiyama T, IhanaSugiyama N, Tanaka H, Imai K, Ueki K, Ohsugi
M, Tamiya N, Kobayashi Y. Incidence ofinterventions for diabetic retinopathy and serious
lower-limb complications and its related factors
in patients with type 2 diabetes using a real-world
large claims database. Diabetology International
13 (3): 548-560, 2022. (doi.org/10.1007/s13340021-00566-7)
Iba A, Tomio J, Abe K, Sugiyama T, Kobayashi Y.
Hospitalizations for ambulatory care sensitive
conditions in a large city of Japan: a descriptive
analysis using claims data. Journal of General
Internal Medicine 37 (15): 3917-3924, 2022.
(doi: 10.1007/s11606-022-07713-z)
Maeda E, Jwa SC, Kumazawa Y, Saito K, Iba A,
Yanagisawa-Sugita A, Kuwahara A, Saito H,
Terada Y, Fukuda T, Ishihara O, Kobayashi Y.
Out‑of‑pocket payment and patients’ treatment
choice for assisted reproductive technology byhousehold income: a conjoint analysis using an
online social research panel in Japan. BMC
Health Services Research 22: 1093, 2022.
doi.org/10.1186/s12913-022-08474-5
Zaitsu M, Takeuchi T, Zaitsu M, Tonooka A,
Uekusa T, Miyake Y, Kobayashi Y, Kobashi G,
Kawachi I. Occupational disparities in tumor
grade and cytosolic HMGB1 expression in renal
cell cancer. Journal of Occupational Health 64:
e12340, 2022. doi:10.1002/1348-9585.12340
力武諒子、渡邊ともね、山元遥子、市瀬雄一、
新野真理子、松木明、太田将仁、坂根純奈、
伊藤ゆり、東 尚弘、若尾文彦：がん診療連携拠点病院等の指定要件に関する調査 厚生の指標2022 年 6 月 号 ( 第 69 巻 第 6 号 )Page15-21
力武 諒子、渡邊 ともね、山元 遥子、市瀬 雄
一、新野 真理子、松木 明、太田 将仁、坂根純奈、伊藤 ゆり、東 尚弘、若尾 文彦：がん診療連携拠点病院等の指定要件関連の詳細に関する実態 病院 81 巻 5 号 （2022 年 5 月）
Page436-441
23. 前田恵理、石原 理、左 勝則、李 廷秀、小林廉毅．韓国における人工授精および生殖補助
医療の公費負担状況―保険適用の背景と影響に関する訪問調査．公衆衛生 86(1): 84-90,
2022.
(Others)
24. 東 尚弘 医療の質を評価して改善することの社会的意義 medicina 59 巻 11 号 Page18181821 （2022.10）
25. 東 尚弘、中山 富雄 がん検診の質の考え方
medicina 59 巻 11 号 Page1966-1969（2022.10）
26. Miyawaki A, Tsugawa Y. Health and publichealth implications of COVID-19 in Asian
countries. Asian Economic Policy Review. 2022;
17(1):18–36. https://doi.org/10.1111/aepr.12358
27. Miyawaki A, Tsugawa Y. Why do homeless
women in New York state experience fewer
hospital revisits after childbirth than housed
women? BMJ Qual Saf. 2022;31(4):243–6. doi:
10.1136/bmjqs-2021-013746
28. Evans, C.E.L., Miyawaki, A., & Mizdrak. A.
Evaluation of interventions, programmes andpolicies in food environments; pp 277-291; in
Textbook of Transforming Food Environments;
CRC Press; Boca Raton, FL, US; 2022; Evans,
C.E.L. ed.; 1st edition. http://dx.doi.org/10.1201/
9781003043720-19
29. 宮脇敦士：アメリカ医療保障制度に関する調査研究報告書【2021 年度版】特集 COVID-19の感染状況と対策 (pp 7-25) 医療経済研究機
構, 2022https://www.ihep.jp/publications/report/
30. 小林廉毅（談）．原因分析でプロセス解明し紛争防止や質向上に貢献（産科医療補償制度の現状と役割）．週刊社会保障 76 (3152): 47-49,2022.
31. 小林廉毅．公衆衛生学の基盤：統計と調査（第80 回日本公衆衛生学会総会学会長講演）．公衆衛生情報 51 (12): 4-5, 2022.
32. 宮脇敦士：医師との結婚で女性医師のフルタ
イム勤務率低下 Medical Tribune 2022 年 12 月
1 号 Vol55 No.23 （2 面「医師のキャリア」）.
33. 東尚弘．地域におけるがん医療の課題と展
望：均てん化は進んだか？ 第 60 回日本癌治
療学会学術集会シンポジウム 2022 年 10 月
20 日

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34. 高山智子、市瀬雄一、渡邊ともね、東尚弘．
がん診療連携拠点病院がん相談支援センターの利用状況と医療の質との関連に関する研究、
一般口頭、第 81 回日本公衆衛生学会総会
2022 年 10 月 7-9 日
35. 市瀬雄一、渡邊ともね、角和珠妃、山元遥子、
新野真理子、東尚弘．経口抗がん薬服用患者を対象とした服薬管理に関する理解度調査、
一般口頭、第 81 回日本公衆衛生学会総会
2022 年 10 月 7-9 日
36. 東 尚弘．インターネット調査の回答の正確性に関する一考察、一般口頭、第 32 回 日本
疫学会学術総会 2022 年 1 月 26-28 日
37. 太田将仁、伊藤ゆり、渡邊ともね、市瀬雄一、
山元遥子、力武諒子、松木明、新野真理子、
坂根純奈、東尚弘、若尾文彦．院内がん登録・DPC・現況報告からみるがん診療連携拠点病院における標準治療実施の現状、一般口頭、
第 32 回 日本疫学会学術総会 2022 年 1 月
26-28 日Social Medicine
2. Forensic Medicine, and Medical
Informatics and Economics

131

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.

Shigeki Tsuneya, 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 150

132

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

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

Research
In cooperation with other universities including
Chiba University, Tokyo Medical and Dental
University, and International University of Health andWelfare, researches in 6 sections (forensic pathology,
clinical forensic medicine, forensic toxicology,
forensic radiology, forensic odontology and forensic
genetics) have proceeded.
1. Forensic Pathology
We conduct research aimed at improving theaccuracy of cause-of-death diagnosis andepidemiological studies related to cause-of-deathinvestigation. For example, we are trying
angiographic 3D-CT and vascular endoscopy in the
search for coronary arteries and cerebral basilar
arteries. We are also conducting research on
diatoms in order to improve the diagnosis ofdrowning. Additionally, we are trying to conduct a
comparative study of the cause-of-death investigation systems in Tokyo and Chiba prefectures.
2. Clinical Forensic Medicine
Clinical forensic medicine is an academic fieldthat collaborates with various clinical departments
to examine a living body that may have been
subjected to some form of invasion to determine
whether or not an invasion has occurred, and todevise measures to prevent accidents based on
information obtained from the accumulation of
cause-of-death information. Currently, in collaboration with pediatricians, we are conducting researchon the accumulation and analysis of pediatric deaths
and their application to prevention. As part of thiseffort, the Chiba Prefecture Child Death Review(CDR) Study Group has been established incooperation with Chiba University. In addition, weare also conducting research on bone strength togain knowledge that will be useful in the evaluationof abuse.
3. Forensic Toxicology
Using LC/MS/MS, LC/QTOF-MS, etc., we areconducting research on detection methods targetinga large number of drugs, including cyanide
compounds and dangerous drugs. Animal studies on
postmortem drug redistribution had also been
conducted. In collaboration with the National
Research Institute of Police Science and others, weare also conducting epidemiological studies on drug
detection in traffic accident fatalities.

133

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

Publications
1.

2.

3.

4.

Chiba F, Inokuchi G, Hoshioka Y, Sakuma A,
Makino Y, Torimitsu S, Yamaguchi R, Saitoh H,
Kono M, Iwase H. Age estimation by evaluationof osteophytes in thoracic and lumbar vertebrae
using postmortem CT images in a modern
Japanese population. Int J Leg Med. 2022;136:
261-267.
Nariai M, Abe H, Hoshioka Y, Makino Y, Iwase
H. Biomarker profiling of postmortem blood fordiabetes mellitus and discussion of possible
applications of metabolomics for forensic
casework. Int J Legal Med. 2022; 136(4): 10751090.
Akutsu T, Saito H, Watanabe K, Toyomane K,
Yamagishi T, Iwase H. Evaluation andsimultaneous determination of rectal mucosa
markers by multiplex reverse transcription-PCR
for biological evidence of sexual assault withanal penetration. Foresic Sci Int Genet. 2022; 59:102712.
Nagasawa S, Mori A, Hirata Y, Motomura A,
Ishii N, Okaba K, Horioka K, Makino Y,
Nakajima M, Torimitsu S, Yamaguchi R,

Inokuchi G, Chiba F, Hoshioka Y, Saito N,
Yoshida M, Yajima D, Akitomi S, Iwase I, Saitoh
H. SmartAmp method can rapidly detect
SARS-CoV-2 in dead bodies. Forensic scienceinternational. 2022; 331: 111168-111168.
5. Kazuta M, Hajime U, Makino Y, Minegishi S,
Iwase H, Sakurada K. A post-mortem computed
tomography imaging method for predicting theanteroposterior and superoinferior positions of
the Japanese adult eyeball in the orbit. Forensic
Imaging. 2022; 29: 200504.
6. Makino Y, Unuma K, Nolte KB, Adolphi NL.
Accuracyofforensic
pathologistsinincorporating post-mortem CT (PMCT) in
forensic death investigation. J Forensic Sci. 2022;
67: 2351-2359.
7. Wen S, Unuma K, Makino Y, Mori H, Uemura K.
Fatal consequence after MiraDry® treatment:
Necrotizing
fasciitis
complicatedwithstreptococcal toxic shock syndrome. Leg Med(Tokyo). 2022; 58:102095.
8. Torimitsu S, Yajima D, Inokuchi G, Makino Y,
Motomura A, Chiba F, Yamaguchi R, Hoshioka Y,
Tsuneya S, Iwase H. Electrolyte analysis of
pleural effusion for discrimination between
seawaterandfreshwaterdrowning
indecomposed bodies. J Forensic Leg Med. 2022;
90: 102389.
9. Torimitsu S, Saka K, Noritake K, Namera A,
Makino Y, Yamaguchi R, Iwase H. Detection oflisdexamfetamine
andits
metabolite
d-amphetamine in urine and gastric contents
collected from a cadaver at forensic autopsy.
Forensic Toxicol. 2022; Online ahead of print.
10. Inokuchi G, Chiba F, Hoshioka Y, Saito N,
Yoshida M, Nagasawa S, Yamagishi Y, Makino Y,
Torimitsu S, Yamaguchi R, Tsuneya S, Inoue H,
MotomuraA,
YajimaD,
Iwase
H.
Methampetamine-related forensic autopsy cases
in a Japanese prefecture over a 7-year period:
characteristics of deaths and blood concentrations.
Legal medicine. 2022; 60: 102181-102181.
11. Saito N, Hashimoto T, Endo M, Inokuchi G,
Shimojo N, Iwase H. Ealy involvement of thechild protection team in a tertiary care hospitalfor detection of child maltreatment. Chiba
Medical J. 2022; 98E: 59-67.

134

12. Yamaguchi R, Makino Y, Torimitsu S, Chiba F,
Kihara
Y,
Iwase
H.
Fatal
bilateralpneumothoraces after electropuncture treatment:
A case report and literature review. J Forensic Sci.
2022; 67(1): 377-383.
13. Yamaguchi R, Makino Y, Inokuchi G, Ishihara K,
Torimitsu S, Chiba F, Hoshioka Y, Urabe S, Oya
Y, Motomura A, Yajima D, Iwase H. Trend andcharacteristics in health care related deaths
investigated through medico-legal autopsies after
system changes in Japan. J Law Med.2022;
29(2): 509-521
14. Yamagishi Y, Nagasawa S, Iwase H, Ogra, Y.
Evaluation of post-mortem interaction between
hemoglobin and oxime-type carbamate pesticides.
Chem. Res. Toxicol. 2022; 35: 1110-1116.
15. Yamagishi Y, Nagasawa S, Iwase H, Ogra, Y.
Post-mortem interaction between methidathionand human serum albumin in blood. J. Toxicol
Sci. 2022; 47: 139-146.
16. Okaba K, Motomura A, Horioka K, Inokuchi G,
Chiba F, Hoshioka Y, Saito N, Makino Y,
Torimitsu S, Yamaguchi R, Tsuneya S, Yajima D,
Iwase H. Prevalence of blood-borne infections inforensic samples: Epidemiology in areas of Chiba,
Japan. Journal of Forensic and Legal Medicine.
2022; 90: 102396.
17. Urabe S, Kurahashi H, Inokuchi G, Chiba F,
Motomura A, Hoshioka Y, Torimitsu S,
Yamaguchi R, Tsuneya S, Iwase H. Carrion flies(Insecta: Diptera) found on human cadavers in
Chiba prefecture, Honshu, Japan, with the firstrecord of Fannia prisca from a human corpse.
Journal of Forensic Sciences. 2022; 67(6): 24692478.
18. Tsuneya S, Nakajima M, Makino Y, Torimitsu S,
Yamaguchi R, Iwase H. The effect of ethanol or
long-time reaction on the diatom test in water
samples using sodium hypochlorite. Leg Med(Tokyo). 2022; 57: 102054.
19. Hirata Y, Inokuchi Go, Tsuneya S, Hoshioka Y,
Chiba F, Yoshida M, Makino Y, Iwase H. A caseof fatal fulminant fat embolism syndrome
following multiple fractures resulting from a fall.
J Forensic Sci. 2022; 67(5): 2115-2121.
20. Saka K, Kudo K, Namera A, Fujii Y, Noritake K,
Torimitsu S, Makino Y, Iwase H. Simple andsimultaneous quantification of cyanide, ethanol,and 1-propanol in blood by headspace GC–MS/
NPD with Deans switch dual detector system. Sci
Justice. 2022; 62: 193-202.

135

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

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

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

Takeshi Imai, Ph.D.

Lecturer
Shinichiro Yokota, PHN,RN,Ph.D., Hidenao Atarashi BMET, Ph.D.

Homepage

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

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

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

Teaching activities
In 2022, the faculty composition, including the
hospital staff, is 1 professor (Ohe), 1 associate
professor (Waki), 2 lecturers (Atarashi, Yokota), 2
assistant professor (specially appointed lecturer(hospital)). (Doi, Ida), 4 assistant professors (Nagae,

136

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

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

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

137

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

5.

6.

7.

References
1.

2.

3.

4.

Kawazoe Y, Shimamoto K, Yamaguchi R,
Nakamura I, Yoneda K, Shinohara E, ShintaniDomoto Y, Ushiku T, Tsukamoto T, Ohe K.
Computational
Pipelinefor
Glomerular
Segmentation and Association of the Quantified
Regions with Prognosis of Kidney Function in IgANephropathy. Diagnostics. 2022;12(12): 2955.
Takeuchi A, Yokota S, Tomotaki A, Fukahori H,
Shimpuku Y, Yoshinaga N. Relationship between
Research Activities and Individual Factors among
Japanese Nursing Researchers during the COVID19 Pandemic. PLOS ONE. 2022;17(8): e0271001.
Hayakawa J, Seki T, KawazoeY, Ohe K. Pathway
Importance by Graph Convolutional Network andShapley Additive Explanations in Gene
Expression Phenotype of Diffuse Large B-cell
Lymphoma. PLOS ONE. 2022;17(6): e0269570.
Masukawa K, Aoyama M, Yokota S, Nakamura J,
Ishida R, Nakayama M, Miyashita M. Machine
Learning Models to Detect Social Distress,
Spiritual Pain, and Severe Physical PsychologicalSymptoms in Terminally Ill Patients with Cancerfrom Unstructured Text Data in Electronic
Medical Records. Palliative Medicine. 2022;36(8):1207-1216.

8.

9.

Tomotaki A, Iwamoto T, Yokota S. ResearchTypes and New Trends on the Omaha System
Published in English and Japanese from 2012 to
2019: A Scoping Review. CIN: Computers,
Informatics, Nursing. 2022;40(8): 531-537.
Kawai Y, Waki K, Yamaguchi S, Shibuta T,
Miyake K, Kimura S, Toyooka T, Nakajima R,
Uneda K, Wakui H, Tamura K, Nangaku M, Ohe
K. The Use of Information and Communication
Technology-Based Self-management System
DialBeticsLite in Treating Abdominal Obesity inJapanese Office Workers: Prospective Single-Arm
Pilot Intervention Study. JMIR Diabetes. 2022;
7(4): e40366.
Kondo M, Okitsu T, Waki K, Yamauchi T,
Nangaku M, Ohe K. Effect of Information andCommunication
Technology-Based
Selfmanagement System DialBeticsLite on Treating
Abdominal Obesity in the Specific Health
Guidance in Japan: Randomized Controlled Trial.
JMIR Formative Research. 2022;6(3): e33852.
Kurasawa H, Waki K, Chiba A, Seki T, Hayashi K,
Fujino A, Haga T, Noguchi A, Ohe K. Treatment
Discontinuation Prediction in Patients With
Diabetes Using a Ranking Model: Machine
Learning Model Development. JMIR Bioinform
Biotech. 2022;3(1): e37951.
Sankoda A, Waki K, Yamaguchi S, Mieno M,
Nangaku M, Yamaguchi T, Ohe K. Effect ofDigital Health Among People With Type 2
Diabetes Mellitus During the COVID-19
Pandemic in Japan. Journal of Diabetes Scienceand Technology. 2022;16(1): 256-258.

Internal Medicine
1. Medicine Ⅰ

139

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

Associate Professor
Hatano Masaru, M.D., Ph.D. (Advanced Medical Center for Heart Failure)

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

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

Eiki Takimoto, M.D., Ph.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, one associate professor, 3 lecturers, 2
hospital lecturers, 16 research assistants, 7 staff
members, and 41 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 2022, a total of 1,777 patients were newly
admitted to our hospital ward of 57 beds. The average
duration of hospitalization was 11.2 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 2022, 18
patients underwent heart transplant (total 189 cases). In
March 2014, our facility was also authorized to perform
lung transplantation. Coronary angiography was
performed in 1,864 patients, of which 417 patients
underwent percutaneous coronary interventions. CT
coronary angiography and cardiovascular MRI were
performed in 636 and 176 patients, respectively. With
regard to arrhythmias, there were 257 cases of catheter
ablation, 99 cases of implantation or replacement ofpacemakers and other specialized pacemaker devices,
including 13 cases of implantation or replacement of
implantable cardioverter-defibrillator and 7 cases of
implantation or replacement of a cardiac resynchronization device.
Out-patient clinics are available as a specialized140

department and as part of the Department of Medicine.
Out-patient clinics are open in the mornings andafternoons from Monday to Friday, and approximately
182.5 patients visited each day. The disease profile
includes ischemic heart disease, heart failure,arrhythmia, hypertension and peripheral artery disease.
There are special outpatient clinics for advanced heart
failure,ischemicheart
disease,pulmonary
hypertension, congenital heart disease, valvular heartdisease, arrhythmia, Marfan syndrome, myocarditis,
cardiac amyloidosis, onco-cardiology, and cardiac
rehabilitation. The department is also focused on acutecases of coronary heart disease and aortic disease, as
emergent catheterization is available on a 24-hour basis.

failure, cardiac transplantation, congenital heartdisease, etc.)
6. New treatments for structural heart disease
7. Diagnosis and treatment of Marfan syndrome andadult congenital heart disease
8. New treatments for pulmonary hypertension
9. New treatments for congenital heart disease
10. Aerobic threshold and cardiac rehabilitation
11. Imaging techniques (echocardiography, MRI, CT,
and SPECT) in cardiovascular diseases
12. Epidemiology and prevention of cardiovasculardisease13. Artificial Intelligence in Cardiology

Publications (2022)
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.

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: multiomics
analyses of pathogenic mechanisms anddevelopment of novel therapies (e.g., gene therapy)
2. Interplay between organs, cells, and molecules inchronic inflammation
3. Genetic analysis of inherited cardiomyopathy
4. Experiments on pathophysiology ofcardiomyopathy using human iPS cells
5. Investigation of disease pathophysiology anddevelopment of novel therapies (severe heart

3.

4.

Adachi Y, Ueda K, Nomura S, Ito K, Katoh M,
Katagiri M, Yamada S, Hashimoto M, Zhai B,
Numata G, Otani A, Hinata M, Hiraike Y, Waki H,
Takeda N, Morita H, Ushiku T, Yamauchi T,
Takimoto E and Komuro I. Beiging ofperivascular adipose tissue regulates its
inflammation and vascular remodeling. Nat
Commun 13:5117, 2022.
Bujo S, Amiya E, Maeda MH, Ishida J, Hatano M,
Ishizuka M, Uehara M, Oshima T, Kojima T,
Nakanishi K, Daimon M, Shimizu J, Toda T and
Komuro I. The effect of immunosuppressive
therapy on cardiac involvements in antimitochondrial antibody-positive myositis. ESC
Heart Fail 9:4112-4119, 2022.
Fukui A, Kaneko H, Okada A, Yano Y, Itoh H,
Matsuoka S, Morita K, Kiriyama H, Kamon T,
Fujiu K, Michihata N, Jo T, Takeda N, Morita H,
Nakamura S, Nishiyama A, Node K, Yokoo T,
Nangaku M, Yasunaga H and Komuro I.
Semiquantitative assessed proteinuria and risk ofheart failure: analysis of a nationwide
epidemiological
database.
Nephrol
Dial
Transplant 37:1691-1699, 2022.
Ieki H, Ito K, Saji M, Kawakami R, Nagatomo Y,
Takada K, Kariyasu T, Machida H, Koyama S,
Yoshida H, Kurosawa R, Matsunaga H, Miyazawa
K, Ozaki K, Onouchi Y, Katsushika S, Matsuoka
R, Shinohara H, Yamaguchi T, Kodera S,
Higashikuni Y, Fujiu K, Akazawa H, Iguchi N,
Isobe M, Yoshikawa T and Komuro I. Deep

141

learning-based age estimation from chest X-rays
indicates cardiovascular prognosis. Commun Med(Lond) 2:159, 2022.
5. Itoh H, Kaneko H, Okada A, Suzuki Y, Fujiu K,
Matsuoka S, Michihata N, Jo T, Nakanishi K,
Takeda N, Morita H, Node K, Di Tullio MR,
Homma S, Yasunaga H and Komuro I. AgeSpecific Relation of Cardiovascular Health
Metrics With Incident Cardiovascular Disease.
Am J Cardiol 177:34-39, 2022.
6. Kamon T, Kaneko H, Itoh H, Okada A, Matsuoka
S, Kiriyama H, Fujiu K, Morita K, Michihata N,
Jo T, Takeda N, Morita H, Nakamura S, Node K,
Yasunaga H and Komuro I. Sex Difference in the
Association between Lipid Profile and Incident
Cardiovascular Disease among Young Adults. J
Atheroscler Thromb 29:1475-1486, 2022.
7. Kaneko H, Yano Y, Lee HH, Lee H, Okada A, Itoh
H, Morita K, Fukui A, Fujiu K, Suzuki Y,
Matsuoka S, Nakamura S, Michihata N, Jo T,
Takeda N, Morita H, Yokoo T, Nishiyama A, NodeK, Viera AJ, Muntner P, Oparil S, Kim HC,
Yasunaga H and Komuro I. Medication-Naive
Blood Pressure and Incident Cancers: Analysis of
2 Nationwide Population-Based Databases. Am J
Hypertens 35:731-739, 2022.
8. Kaneko H, Yano Y, Suzuki Y, Okada A, Itoh H,
Matsuoka S, Fujiu K, Michihata N, Jo T, Takeda
N, Morita H, Node K, Viera AJ, Lima JAC, OparilS, Lam CSP, Carey RM, Yasunaga H and Komuro
I. Reduction in blood pressure for elevated bloodpressure/stage 1 hypertension according to theAmerican College of Cardiology/American Heart
Association guideline and cardiovascularoutcomes. Eur J Prev Cardiol 29:1921-1929, 2022.
9. Ko T, Nomura S, Yamada S, Fujita K, Fujita T,
Satoh M, Oka C, Katoh M, Ito M, Katagiri M,
Sassa T, Zhang B, Hatsuse S, Yamada T, HaradaM, Toko H, Amiya E, Hatano M, Kinoshita O,
Nawata K, Abe H, Ushiku T, Ono M, Ikeuchi M,
Morita H, Aburatani H and Komuro I. Cardiac
fibroblasts regulate the development of heart
failure via Htra3-TGF-beta-IGFBP7 axis. Nat
Commun 13:3275, 2022.
10. Matsuoka S, Kaneko H, Kamon T, Suzuki Y, Yano
Y, Okada A, Itoh H, Morita K, Fukui A, Fujiu K,
Michihata N, Jo T, Takeda N, Morita H, Nakamura

11.

12.

13.

14.

15.

16.

17.

S, Yokoo T, Nishiyama A, Node K, Yasunaga H
and Komuro I. Incorporation of Retinal
Arteriolosclerosis into Risk Stratification of Blood
Pressure Category According to the 2017
ACC/AHA Blood Pressure Guideline. J
Atheroscler Thromb 29:1487-1498, 2022.
Matsuoka S, Kaneko H, Okada A, Morita K, Itoh
H, Michihata N, Jo T, Takeda N, Morita H, Fujiu
K, Nakamura S, Node K, Yasunaga H and Komuro
I. Age Modified Relationship Between Modifiable
Risk Factors and the Risk of Atrial Fibrillation.
Circ Arrhythm Electrophysiol 15:e010409, 2022.
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 and
Komuro I. Blood pressure categorization andsubclinical left ventricular dysfunction in
antihypertensive medication-naive subjects. ESC
Heart Fail 9:1766-1774, 2022.
Nakayama A, Morita H, Sato T, Kawahara T,
Takeda N, Kato S, Itoh H and Komuro I. Small
Dense Low-Density Lipoprotein Cholesterol is a
Potential Marker for Predicting Laser Treatment
for Retinopathy in Diabetic Patients. J Atheroscler
Thromb 29:678-691, 2022.
Numata G, Takimoto E, Kariya T, Adachi Y,
Tokiwa H, Toyoda M, Mafune R, Saito Y,
Nakamura S, Ueda K, Ikeda Y and Komuro I. A
pacing-controlled protocol for frequency-diastolic
relations distinguishes diastolic dysfunction
specific to a mouse HFpEF model. Am J Physiol
Heart Circ Physiol 323:H523-H527, 2022.
Suzuki Y, Kaneko H, Okada A, Matsuoka S, Fujiu
K, Michihata N, Jo T, Takeda N, Morita H, NodeK, Nangaku M, Yasunaga H and Komuro I.
Kidney outcomes in patients with diabetes
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102:1147-1153, 2022.
Suzuki Y, Kaneko H, Yano Y, Okada A, Itoh H,
Ueno K, Matsuoka S, Fujiu K, Michihata N, Jo T,
Takeda N, Morita H, Yokota I, Node K, Yasunaga
H and Komuro I. Dose-dependent relationship ofblood pressure and glycaemic status with risk ofaortic dissection and aneurysm. Eur J Prev Cardiol
29:2338-2346, 2022.
Suzuki Y, Kaneko H, Yano Y, Okada A, Matsuoka

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18.

19.

20.

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S, Fujiu K, Michihata N, Jo T, Takeda N, Morita
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Tsuji M, Kakuda N, Bujo C, Ishida J, Amiya E,
Hatano M, Shimada A, Imai H, Shimada S,
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Sarcopenia and risk of infection in adult hearttransplant recipients in Japan. ESC Heart Fail
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Ueno K, Kamiya K, Kaneko H, Okada A, Itoh H,
Fujiu K, Takeda N, Morita H, Michihata N, Jo T,
Yasunaga H and Komuro I. Acute-Phase Initiationof Cardiac Rehabilitation for Short-Term
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Patients Hospitalized for Acute Heart Failure. J
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Ueno K, Kaneko H, Kamiya K, Itoh H, Okada A,
Suzuki Y, Matsuoka S, Fujiu K, Michihata N, Jo T,
Takeda N, Morita H, Ako J, Yasunaga H and
Komuro I. Clinical utility of simple subjective gait
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Yoshida Y, Nakanishi K, Daimon M, Hirose K,
Ishiwata J, Kaneko H, Nakao T, Mizuno Y, Morita
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Department of Respiratory
Medicine
Professor
Takahide Nagase, M.D.,Ph.D.

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

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

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

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

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

Yu Mikami, M.D., Ph.D.,

Kosuke Makita, M.D.,Ph.D.

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

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

Homepage

http://kokyuki.umin.jp/

Introduction and Organization

Clinical activities

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

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

144

and therapeutic approach to individual patients. Thisconference has been highly appreciated as a prototype
of Cancer Board of the University of Tokyo Hospital,
and, is now held as Respiratory Cancer Board. Thisconference is still one of the most frequently held
Cancer Board at our hospital. Our department
contributes to the pre- and post-surgical evaluation of
respiratory functions, and also provides consultation
on respiratory problems from almost every department
at our hospital.
Together with the Department of Infectious
Disease, we are responsible for taking care of COVID
patients and infection control measures. We supervise
the clinical teams that take care of inpatients withmoderate COVID-19, make decisions on PCR testingand infection prevention practices, and run the feverclinic for patients who visit our hospital on a regularbasis.
At present, primary lung cancer is the leading
cause of cancer death, and is one of the major medical
and social problem to be overcome. Recently, theremarkable effectiveness of molecular-targeted
therapies in primary lung cancer attracted muchattention in both basic science and clinical practice.
Pneumonia is the 3rd leading cause of all deaths whencombined with aspiration pneumonia, and COPD isalso a major cause of death. No effective therapeuticmodalities are currently available for many respiratory
diseases. For example, mortality of acute respiratory
distress syndrome (ARDS) is extremely high despite
intensive care using currently available tools.
Idiopathic pulmonary fibrosis is a progressive andfatal inflammatory and fibrotic disorder of the lungparenchyma, and only a few medications are currently
available to treat the disease. Our focus is to develop anovel and potential therapeutic approach to these
diseases.
Total numbers of in-patients in 2022
1.
2.
3.
4.
5.

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

383
37
40
36
9
18

7. Pneumothorax
8. COPD
9. Others

5826

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

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

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

epithelial cells and fibroblasts in relation to tissue
repair and remodeling, e.g., epithelialmesenchymal transition, and the roles of various
cytokines and chemokines, in asthma and COPD
Detection of small airway disease using impulse
oscillometry and its clinical application
Search for predictive factors for responses tochemotherapy in malignancy including lungcancerEpidemiological study of respiratory diseases,
using
Diagnosis
Procedure
Combination
database.

Takahide Nagase is a GOLD Assembly member.

References
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.

1.

2.

3.

4.








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

5.

Ando T, Kage H, Shinozaki-Ushiku A, Tatsuno K,
Tsutsumi S, Nagayama K, Nakajima J, Kohsaka
S, Miyagawa K, Aburatani H, Mano H, Nagase T.
Composite Clonal Analysis Reveals Transition of
NSCLC Subtypes Through Accumulation ofGene Mutations: A Case Report JTO Clin Res
Rep. 2022 Jan 10;3(2):100277.
Oki R, Hirakawa Y, Oda Y, Nakamura M, Honda
K, Abe H, Domoto Y, Miyashita N, Nagase T,
Nangaku M. Renal-limited ANCA-associatedvasculitis during erlotinib treatment for lungcarcinoma. CEN Case Rep 2022; 11: 67-72.
Murata M, Nakagawa N, Kawasaki T, Yasuo S,
Yoshida T, Ando K, Okamori S, Okada Y.
Adverse events during intrahospital transport ofcritically ill patients: A systematic review andmeta-analysis. Am J Emerg Med. 2022 Feb;52:
13-19.
Mitani A, Hamada K, Yoshikawa N, Morita Y,
Horie T, Inoue Y, Saito M, Ishii T, Sunohara M,
Takahashi R, Emoto N, Nishimoto N, Murano Y,
Okazaki S, Tateishi S, Yao A, Shimura T, Kurano
M, Yatomi Y, Yanagimoto S. Epidemiologicalstudy using igm and igg antibody titers againstsars-cov-2 in the university of  apan,  apan
(ut-cats). J Infect Chemother 2021;27:1342-1349.
Amano Y, Kage H, Tanaka G, Sato Y, Tanaka M,
Nagase T. Multiple Brain Metastases in a Patientwith ROS1 Fusion-Positive Lung Adenocarcinoma as a Disease Flare due to Crizotinib

146

Cessation Caused by Disseminated Aseptic
Inflammation from Crizotinib-Associated Renal
Cysts: A Case Report. Case Rep Oncol 2022;15:
338-344.
6. Kawasaki T, Nakagawa N, Murata M, Yasuo S,
Yoshida T, Ando K, Okamori S, Okada Y.
Diagnostic accuracy of urinary antigen tests forlegionellosis: A systematic review and metaanalysis. Respir Investig. 2022 Mar;60(2):205214.
7. Awano N, Jo T, Izumo T, Inomata M, Morita K,
Matsui H, Fushimi K, Urushiyama H, Nagase T,
Yasunaga H. Recombinant human soluble
thrombomodulin for acute exacerbation of
idiopathic pulmonary fibrosis: a nationwide
observational study. J Intensive Care. 2022 Mar
9;10(1):14.
8. Miyamoto S, Yamazaki T, Shimizu K, Matsubara
T, Kage H, Watanabe K, Kobo H, Matsuyama Y,
Rodin G, Yoshiuchi K. Brief,  anualized andsemistructured
individual
psychotherapy
programme for patients with advanced cancer inJapan: study protocol for Managing Cancer and
Living Meaningfully (CALM) phase 2 trial. BMJ
Open 2022;12:e056136
9. Tian D, Shiiya H, Takahashi M, Terasaki Y,
Urushiyama H, Shinozaki-Ushiku A, Yan HJ,
Sato M, Nakajima J. Noninvasive monitoring of
allograft rejection in a rat lung transplant model:
Applicationofmachinelearning-based
18F-fluorodeoxyglucose
positronemission
tomography radiomics. J Heart Lung Transplant.
2022 Jun;41(6):722-731.
10. Kato T, Radicioni G, Papanikolas MJ, Stoychev
GV, Markovetz MR, Aoki K, Porterfield M,
Okuda K, Barbosa Cardenas SM, Gilmore RC,
Morrison CB, Ehre C, Burns KA, White KK,
Brennan TA, Goodell HP, Thacker H, Loznev HT,
Forsberg LJ, Nagase T, Rubinstein M, Randell
SH, Tiemeyer M, Hill DB, Kesimer M, O’Neal
WK, Ballard ST, Freeman R, Button B, Boucher
RC. Mucus concentration-dependent biophysicalabnormalities unify submucosal gland andsuperficial airway dysfunction in cystic fibrosis.
Sci Adv 2022;8:eabm9718.
11. Abe M, Mitani A, Zong L, Zhang CD, Hoshi K,
Yanagimoto S. High frequency and long duration

12.

13.

14.

15.

16.

17.

18.

of toothbrushing can potentially reduce the riskof common systemic diseases in late adolescence.
Spec Care Dentist 2022 May; 42(3): 317-318.
Roszik J, Lee JJ, Wu YH, Liu X, Kawakami M,
Kurie JM, Belouali A, Boca SM, Gupta S,
Beckman RA, Madhavan S, Dmitrovsky E.
Real-World Studies Link Nonsteroidal Antiinflammatory Drug Use to Improved Overall
Lung Cancer Survival. Cancer Res Commun.
2022 Jul;2(7):590-601.
Tanosaki T, Mikami Y, Shindou H, Suzuki T,
Hashidate-Yoshida T, Hosoki K, Kagawa S,
Miyata J, Kabata H, Masaki K, Hamamoto R,
Kage H, Miyashita N, Makita K, Matsuzaki H,
Suzuki Y, Mitani A, Nagase T, Shimizu T,
Fukunaga K. Lysophosphatidylcholine Acyltransferase 1 Deficiency Promotes Pulmonary
Emphysema via Apoptosis of Alveolar Epithelial
Cells. Inflammation 2022;45:1765-1779
Nakagawa N, Kawakami M. Choosing the
optimal immunotherapeutic strategies for nonsmall cell lung cancer based on clinical factors.
Front Oncol. 2022 Aug 12;12:952393.
Kage H, Kohsaka S, Tatsuno K, Ueno T, Ikegami
M, Zokumasu K, Shinozaki-Ushiku A, Nagai S,
Aburatani H, Mano H, Oda K. Tumor mutationalburden measurement using comprehensive
genomic profiling assay. Jpn J Clin Oncol 2022;
52:925-929.
Urushiyama H, Jo T, Hasegawa W, Yokoyama A,
Ando T, Sakamoto Y, Kumazawa R, Uda K,
Michihata N, Awano N, Hiroki M, Fushimi K,
Yasunaga H, Nagase T. Effect of nintedanib onacute exacerbations of fibrosing interstitial lungdiseases: a national database study in Japan. ERJ
Open Res. 2022 Nov 28;8(4):00209-2022.
Miyakawa K, Miyashita N, Horie M, Terasaki Y,
Tanaka H, Urushiyama H, Fukuda K, Okabe Y,
Ishii T, Kuwahara N, Suzuki HI, Nagase T, Saito
A. ASCL1 regulates super-enhancerassociatedmiRNAs to define molecular subtypes of small
cell lung cancer. Cancer Sci 2022; 113(11): 393246.
Imai M, Nakamura Y, Sunami K, Kage H,
Komine K, Koyama T, Amano T, Ennishi D,
Kanai M, Kenmotsu H, Maeda T, Morita S, Sakai
D, Bando H, Makiyama A, Suzuki T, Hirata M,

147

19.

20.

21.

22.

Kohsaka S, Tsuchihara K, Naito Y, Yoshino T.
Expert panel consensus recommendations on theuse of circulating tumor DNA assays for patientswith advanced solid tumors. Cancer Sci 2022;
113:3646-3656.
Sunami K, Naito Y, Komine K, Amano T, Ennishi
D, Imai M, Kage H, Kanai M, Kenmotsu H,
Koyama T, Maeda T, Morita S, Sakai D, Kohsaka
S, Tsuchihara K, Saigusa Y, Yoshino T.
Chronologicalimprovementin
precision
oncology implementation in Japan. Cancer Sci
2022;113:3995-4000.
Chen Z, Zheng L, Chen Y, Liu X, Kawakami M,
Mustachio LM, Roszik J, Ferry-Galow KV,Parchment RE, Liu X, Andresson T, Duncan G,
Kurie JM, Rodriguez-Canales J, Liu X,
Dmitrovsky E. Loss of ubiquitin-specificpeptidase 18 destabilizes 14-3-3ζ protein andrepresses lung cancer metastasis. Cancer Biol
Ther. 2022 Dec 31;23(1):265-280.
Naito Y, Sunami K, Kage H, Komine K, Amano T,
Imai M, Koyama T, Ennishi D, Kanai M,
Kenmotsu H, Maeda T, Morita S, Sakai D,
Watanabe K, Shirota H, Kinoshita I, Yoshioka M,
Mamesaya N, Ito M, Kohsaka S, Saigusa Y,
Yamamoto K, Hirata M, Tsuchihara K, Yoshino T.
Concordance Between Recommendations From
Multidisciplinary Molecular Tumor Boards andCentral Consensus for Cancer Treatment in Japan.
JAMA Netw Open 2022;5:e2245081.
Tamiya H, Mitani A, Abe T, Nagase Y, Suzuki H,
Jo T, Tanaka G, Nagase T. Association between
Inhalation Instruction Method in Community
Pharmacies and Inhaler Device Handling Error inPatients with Obstructive Lung Disease: An
Evaluation of the Impact of Practical
Demonstration by Pharmacists. Biol Pharm Bull.
2022;45(12):1764

148

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

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

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

Assistant Professor
Yotaro Kudo, M.D., Ph.D.,

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

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

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

Ryota Takahashi, M.D., Ph.D.

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

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

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

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

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

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

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

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

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

Sozabuto Ihara, M.D., Ph.D.,

Ryunosuke Hakuta, M.D., Ph.D.,

Tatsuya Sato, M.D., Ph.D.,

Tomoharu Yamada, M.D., Ph.D.,

Ken Kurokawa, M.D., Ph.D.,

Tatsunori Suzuki, M.D., Ph.D.

Homepage

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

Introduction and Organization

Clinical activities

The Department of Gastroenterology was establishedthrough a reorganization of the Graduate School of
Medicine and that of the Division of Internal Medicineof The University of Tokyo Hospital in 1998. The
department is responsible for clinical services,education, and research activities in the liver,pancreato-biliary, and gastrointestinal tract. It
comprises a professor, two lecturers, 20 assistantprofessors, 11 fellows, 56 graduates, and other visiting
researchers including students from abroad as of March
2023. Some others are under a temporary transfer
inside and outside the country. The North and Southwings on the 11th floor of Ward A have provided core
hospital rooms for the department. Laboratories of thedepartment are scattered on each floor, mainly ofClinical Research Center.

The Department of Gastroenterology owns 81 inpatient
beds in charge. By using these beds, we saw total
26,120 inpatients with 2,607 new inpatients in an
average hospital stay of 9.0 days in the fiscal year of2022. Resident, junior and senior staff members bear
the responsibility for the medical management of each
inpatient in collaboration with subspecialty groups
concerned. We saw total 62,726 outpatients with 1,716
new outpatients (2.7%) in the fiscal year of 2022.
Specialty and subspecialty clinical conferences are heldon Monday evening.
The number of treatments for hepatocellular carcinoma,
represented by percutaneous radiofrequency ablation,nearly 200 cases per year, is showing one of the greatest
achievements in the field. The number of cases
undergoing radiofrequency ablation for metastatic liver

149

tumors is also increasing recent years. In addition, weare making efforts to develop an innovation for dailyclinical activities. For example, fibrosis progression inchronic liver disease is conventionally assessed by liverbiopsy. Recently we can evaluate the stage of liver
fibrosis by FibroScan®, newly developed equipmentthat measures liver stiffness by ultrasound, which isuseful for evaluating increasing non-alcoholicsteatohepatitis patients. In addition, nearly 100% curefor HCV hepatitis can be achieved by using oral
antiviral agents instead of IFN therapy. This will beespecially beneficial for elderly patients and advanced
fibrotic patients.
We perform about 1,000 cases of endoscopic
ultrasonography (EUS) and endoscopic retrograde
cholangiopancreatography (ERCP), the standard
endoscopic procedures for biliary and pancreaticdiseases, annually. We have evaluated over 3,000
pancreatic cystic neoplasms, and also performed
various endoscopic treatments such as endoscopic
extraction of bile duct stones in over 1,500 cases andbiliary drainage with metal stents for malignant biliary
strictures in over 1,200 cases, too. We have contributed
to development and reported clinical studies on
endoscopic papillary balloon dilation (EPBD) andpapillary large balloon dilation (EPLBD) for thetreatment of bile duct stones, and covered metal stents
for malignant as well as benign biliary strictures. Our
expertise includes advanced endoscopic treatment forpatients who are difficult to manage by standard
treatment, such as ERCP using a balloon endoscope
and transluminal drainage, EUS-guided stone
extraction in cases with surgically altered anatomy,
endotherapy for pancreatic stone and stricture. In caseswith pancreatic and biliary tract cancer, we haveinvestigating new chemotherapeutic regimens andrecently introduced preoperative chemotherapy forresectable pancreatic cancer. Comprehensive genome
profiling is performed using tumor specimens collectedby EUS-FNA to facilitate individualized treatment. The
number of cases of intractable diseases such as primarysclerosing cholangitis and IgG4-related diseases, is oneof the highest in Japan.
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 Nonexposed 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 fullthickness resection for submucosal tumor’ has been
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 90 cases in 2022). 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 stentplacements for malignant gastrointestinal obstruction
have been performed at our facility. All thoseinterventions are performed by the members of ourdepartment, 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.
On an outpatient basis, the number of performed
ultrasonography, gastroduodenal endoscopy, andcolonoscopy is 12,500 patients, 10,000 patients, and5,500 patients per year, respectively. In the endoscopy
examinations, we diagnose approximately 380 cases of
esophageal cancer, 550 cases of gastric cancer, and 700
cases of colorectal tumor annually. We perform various
basic studies using these resected tissues to feed the
new finding back to actual clinical activities.

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Teaching activities
The undergraduate medical students regularly take theclinical lectures of the staff in our department. Several
courses of practical teaching are also provided for the
students. Particularly, in the Clinical Clerkshipprogram during the fifth grade, each student joins in the
medical treatment of inward patients as a member ofthe 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.
The residents of internal medicine participate in the
training of our department for 1-4 months in the firstyear. They learn the knowledge of therapeutics anddiagnostics in gastroenterology as well as generalinternal medicine. Our department deals with thetraining curriculum as a medical specialist of internal
medicine. The residents in the course are supported toexperience some diseases in the gastrointestinal field.
The residents who major in gastroenterology as asubspecialty
taketheexperttrainingofgastroenterology in the affiliated hospitals for several
years.
The students of the Department of Gastroenterology in
the Graduate School of Medicine perform a highstandard of medical research in the basic or clinicalfield for four years.

Research activities
Both basic and clinical researchers are equallyencouraged on the condition that the results may
eventually contribute to the cure of gastroenterologicaldisorders. The themes of our recent basic researches
include
the
study
on
carcinogenesis
ingastroenterological neoplasms, mechanism of viral
hepatitis infection, the pathogenesis of metabolic liverdiseases, liver regeneration, liver fibrosis, pathogenesis
of Helicobacter pylori infection, molecularcharacterization of gastrointestinal morphology,
establishing new animal models, tracing celldifferentiation, and stem cell biology for various
diseases in our area. Using new concepts such astransparent organs, genomic and epigenomic profilingof clinical samples, organoids, or liquid biopsy, we
perform various experiments to translate the basic
results into clinics eventually.

Various clinical activities are recorded in database andanalyzed. Studies oriented toward evidence-based
medicine are highly appreciated. Recent studies
include multicenter study to investigate radiofrequency
ablation for liver metastasis of colorectal cancer, theimpact of metabolic factors in hepatocarcinogenesis
and studies using nationwide registry for liverdiseases.We have also designed many clinical trials as
follows; Effects of various drug treatments on
advanced hepatocellular carcinoma, SNPs analyses for
antiviral
treatment
forhepatitisC,
newchemotherapeutic regimens for advanced pancreaticcancer or biliary tract cancer, balloon endoscopeassisted ERCP for surgically altered anatomy, theefficacy of polyglycolic acid sheets for artificial
endoscopic ulcers, development of AI for assisted
endoscopic diagnosis, and personalized salvage
therapy of Helicobacter infection.
Our department always tries to show the newest andhighest-level clinical activities, based on the various
data of many patients, especially those suffering frommalignant diseases. Furthermore, we aim to find the
new aspects of diseases and create a new strategy
against them, which is based on clinical, basic, andepidemiological studies in our area. And incollaboration with Faculty of engineering, we are
actively promoting projects to advance new medical
materials and therapeutic devices through medicalengineering collaboration.

Selected References
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Kawai T, Fujishiro M. OLGIM staging and proton
pump inhibitor use predict the risk of gastric cancer.
Gut. 2022;71(5):1043-1044.
2. Hirose T, Kakushima N, Fujishiro M. Sudden
Chest Pain During Vomiting After Drinking.
Gastroenterology.2022;162(4):e5-e6.
3. Fujishiro M, Matsumoto T. History of endoscopes:
Contribution of the Japan GastroenterologicalEndoscopy Society. Dig Endosc. 2022;34 Suppl
2:13-14.
4. Kogure H, Nakai Y, Fujishiro M. How to not get
lost in the labyrinth during device-assisted
enteroscopy endoscopic retrograde cholangiopancreatography. Dig Endosc. 2022;34(1):85-86.

151

5. Kato H, Tateishi K, Fujiwara H, Nakatsuka T,
Yamamoto K, Kudo Y, Hayakawa Y, Nakagawa H,
Tanaka Y, Ijichi H, Otsuka M, Iwadate D, Oyama
H, Kanai S, Noguchi K, Suzuki T, Sato T, Hakuta
R, Ishigaki K, Saito K, Saito T, Takahara N,
Kishikawa T, Hamada T, Takahashi R,
Miyabayashi K, Mizuno S, Kogure H, Nakai Y,
Hirata Y, Toyoda A, Ichikawa K, Qu W, Morishita
S, Arita J, Tanaka M, Ushiku T, Hasegawa K,
Fujishiro M, Koike K. MNX1-HNF1B Axis Is
Indispensable for Intraductal Papillary Mucinous
Neoplasm Lineages. Gastroenterology. 2022;
162(4):1272-1287.
6. Hisada H, Tamura N, Tsuji Y, Nagao S, Fukagawa
K, Miura Y, Mizutani H, Ohki D, Yakabi S,
Minatsuki C, Takahashi Y, Sakaguchi Y,
Yamamichi N, Fujishiro M. The impact ofsarcopenia on adverse events associated withgastric endoscopic submucosal dissection. Surg
Endosc. 2022;36(9):6387-6395.
7. Arai J, Aoki T, Sato M, Niikura R, Suzuki N,
Ishibashi R, Tsuji Y, Yamada A, Hirata Y, Ushiku T,
Hayakawa Y, Fujishiro M. Machine learning-based
personalized prediction of gastric cancer incidence
using the endoscopic and histologic findings at theinitial endoscopy. Gastrointest Endosc. 2022;
95(5):864-872.
8. Takeuchi C, Sato J, Yamashita S, Sasaki A,
Akahane T, Aoki R, Yamamichi M, Liu YY, Ito M,
Furuta T, Nakajima S, Sakaguchi Y, Takahashi Y,
Tsuji Y, Niimi K, Tomida S, Fujishiro M,
Yamamichi N, Ushijima T. Autoimmune gastritis
induces aberrant DNA methylation reflecting its
carcinogenic potential. J Gastroenterol. 2022;
57(3):144-155.
9. Takahashi Y, Yamamichi N, Kubota D, Shimamoto
T, Nagao S, Sakuma N, Sakaguchi Y, Yakabi S,
Tsuji Y, Wada R, Mitsushima T, Ichinose M,
Fujishiro M.
10. Risk factors for gastric cancer in Japan in the2010s: a large, long-term observational study.
Gastric Cancer. 2022;25(3):481-489. Emura F,
Chandrasekar VT, Hassan C, Armstrong D,
Messmann H, Arantes V, Araya R, Barrera-Leon O,
Bergman JJGHM, Bandhari P, Bourke MJ, Cerisoli
C, Chiu PW, Desai M, Dinis-Ribeiro M, Falk GW,
Fujishiro M, Gaddam S, Goda K, Gross S, Haidry

R, Ho L, Iyer PG, Kashin S, Kothari S, Lee YY,
Matsuda K, Neuhaus H, Oyama T, Ragunath K,
Repici A, Shaheen N, Singh R, Sobrino-Cossio S,
Wang KK, Waxman I, Sharma P. Rio de Janeiro
Global Consensus on Landmarks, Definitions, andClassifications in Barrett's Esophagus: World
Endoscopy
Organization
DelphiStudy.
Gastroenterology. 2022;163(1):84-96
11. Kawamura S, Matsushita Y, Kurosaki S, Tange M,
Fujiwara N, Hayata Y, Hayakawa Y, Suzuki N,
Hata M, Tsuboi M, Kishikawa T, Kinoshita H,
Nakatsuka T, Sato M, Kudo Y, Hoshida Y,
Umemura A, Eguchi A, Ikenoue T, Hirata Y,
Uesugi M, Tateishi R, Tateishi K, Fujishiro M,
Koike K, Nakagawa H. Inhibiting SCAP/SREBP
exacerbates liver injury and carcinogenesis inmurine nonalcoholic steatohepatitis. J Clin Invest.
2022;132(11):e151895.
12. Iida T, Mizutani Y, Esaki N, Ponik SM, Burkel BM,
Weng L, Kuwata K, Masamune A, Ishihara S, Haga
H, Kataoka K, Mii S, Shiraki Y, Ishikawa T, Ohno
E, Kawashima H, Hirooka Y, Fujishiro M,
Takahashi M, Enomoto A. Pharmacologic
conversion of cancer-associated fibroblasts from a
protumor phenotype to an antitumor phenotype
improves the sensitivity of pancreatic cancer tochemotherapeutics. Oncogene. 2022;41(19):27642777.
13. Ohki D, Yamamichi N, Sakaguchi Y, Takahashi Y,
Kageyama-Yahara N, Yamamichi M, Takeuchi C,
Tsuji Y, Sakai Y, Sakurai K, Tomida S, Koike K,
Fujishiro M. Transcriptome of sessile serrated
adenoma/polyps is associated with MSI-highcolorectal cancer and decreased expression of
CDX2. Cancer Med. 2022;11(24):5066-5078.
14. Suzuki T, Masugi Y, Inoue Y, Hamada T, Tanaka M,
Takamatsu M, Arita J, Kato T, Kawaguchi Y,
Kunita A, Nakai Y, Nakano Y, Ono Y, Sasahira N,
Takeda T, Tateishi K, Uemura S, Koike K, Ushiku
T, Takeuchi K, Sakamoto M, Hasegawa K, Kitago
M, Takahashi Y, Fujishiro M; GTK Pancreatic
Cancer Study Group in Japan. KRAS variant allele
frequency, but not mutation positivity, associateswith survival of patients with pancreatic cancer.
Cancer Sci. 2022;113(9):3097-3109.
15. Fukumoto T, Minami T, Moriyama M, Yamada T,
Wake T, Kinoshita MN, Fujiwara N, Nakagomi R,

152

Nakatsuka T, Sato M, Enooku K, Nakagawa H,
Fujishiro M, Shiina S, Koike K, Tateishi R.
Improved prognosis of hepatitis C-related
hepatocellular carcinoma in the era of direct-acting
antivirals. Hepatol Commun. 2022;6(9):2496-2512.
16. Sugano K, Spechler SJ, El-Omar EM, McColl KEL,
Takubo K, Gotoda T, Fujishiro M, Iijima K, Inoue
H, Kawai T, Kinoshita Y, Miwa H, Mukaisho KI,
Murakami K, Seto Y, Tajiri H, Bhatia S, Choi MG,
Fitzgerald RC, Fock KM, Goh KL, Ho KY,
Mahachai V, O'Donovan M, Odze R, Peek R,
Rugge M, Sharma P, Sollano JD, Vieth M, Wu J,
Wu MS, Zou D, Kaminishi M, Malfertheiner P.
Kyoto international consensus report on anatomy,
pathophysiology and clinical significance of thegastro-oesophageal junction. Gut. 2022;71(8):1488-1514.
17. Yamamoto K, Iwadate D, Kato H, Nakai Y, Tateishi
K, Fujishiro M. Targeting autophagy as atherapeutic strategy against pancreatic cancer. J
Gastroenterol. 2022;57(9):603-618.
18. Okushin K, Tateishi R, Takahashi A, Uchino K,
Nakagomi R, Nakatsuka T, Minami T, Sato M,
Fujishiro M, Hasegawa K, Eguchi Y, Kanto T,
Kubo S, Yoshiji H, Miyata H, Izumi N, Kudo M,
Koike K. Current status of primary liver cancer
and decompensated cirrhosis in Japan: launch of anationwide registry for advanced liver diseases(REAL). J Gastroenterol. 2022;57(8):587-597.
19. Kakushima N, Fujishiro M, Chan SM, Cortas GA,
Dinis-Ribeiro M, Gonzalez R, Kodashima S, Lee
SY, Linghu E, Mabe K, Pan W, Parra-Blanco A,
Pioche M, Rollan A, Sumiyama K, Tanimoto M;
World Endoscopy Organization Stomach andDuodenal Diseases Committee.
Proposal ofminimum elements for screening and diagnosis ofgastric cancer by an international Delphi consensus.
DEN Open. 2022;2(1):e97.
20. Yamamoto H, Yano T, Araki A, Esaki M, Ohtsuka
K, Ohmiya N, Oka S, Nakase H, Bamba S, Hirai F,
Hosoe N, Matsuda T, Mitsui K, Watanabe K, Ogata
H, Katsuki S, Matsumoto T, Fujishiro M, Fujimoto
K, Inoue H. Guidelines for endoscopic balloon
dilation in treating Crohn's disease-associatedsmall intestinal strictures (supplement to theClinical Practice Guidelines for Enteroscopy).
Dig Endosc. 2022;34(7):1278-1296.

21. Kubota D, Takahashi Y, Yamamichi N, Matsui M,
Shimamoto T, Minatsuki C, Nakagawa H,
Mizutani S, Tsuji Y, Sakaguchi Y, Tamura N,
Yakabi S, Ohki D, Mizutani H, Niimi K, Wada R,
Fujishiro M. Analysis of Barrett's Esophagus and
Its Risk Factors: A Cross-Sectional Study of
10,122 Subjects at a Japanese Health Examination
Center. Digestion. 2022;103(6):411-420.
22. Hisada H, Tsuji Y, Obata M, Cho R, Nagao S,
Miura Y, Mizutani H, Ohki D, Yakabi S, Takahashi
Y, Sakaguchi Y, Kakushima N, Yamamichi N,
Fujishiro M. The impact of sarcopenia on shortand long-term outcomes of endoscopic submucosal
dissection for early gastric cancer. J Gastroenterol.
2022;57(12):952-961
23. Nakagawa K, Sho M, Fujishiro M, Kakushima N,
Horimatsu T, Okada KI, Iguchi M, Uraoka T, Kato
M, Yamamoto Y, Aoyama T, Akahori T, Eguchi H,
Kanaji S, Kanetaka K, Kuroda S, Nagakawa Y,
Nunobe S, Higuchi R, Fujii T, Yamashita H,
Yamada S, Narita Y, Honma Y, Muro K, Ushiku T,
Ejima Y, Yamaue H, Kodera Y. Clinical practiceguidelines for duodenal cancer 2021.
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Gastroenterol. 2022;57(12):927-941.
24. Shibata C, Otsuka M, Seimiya T, Kishikawa T,
Ishigaki K, Fujishiro M. Lipolysis by pancreaticcancer-derived extracellular vesicles in cancerassociated cachexia via specific integrins. Clin
Transl Med. 2022;12(11):e1089.
25. Seimiya T, Otsuka M, Fujishiro M. Roles ofcircular RNAs in the pathogenesis and treatment ofpancreatic cancer. Front Cell Dev Biol. 2022 Nov
17;10:1023332.
26. Shibata C, Otsuka M, Seimiya T, Ishigaki K,
Miyakawa Y, Kishikawa T, Fujishiro M. Smaller
extracellular vesicles are released from pancreaticcancer cells by the alteration of the lipid
composition under low glucose conditions.
Biochem Biophys Res Commun. 2022;637:314321.

Internal Medicine
2. Medicine Ⅱ154

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

Associate Professor
Noriko Makita, M.D., Ph.D.
Hiroshi Nishi, M.D., Ph.D.

Lecturer

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

Yoshifumi Hamasaki, M.D., Ph.D.

Hospital Lecturer
Nobuaki Ito, M.D., Ph.D.
Imari Mimura, M.D., Ph.D.

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

Yosuke Hirakawa, M.D., Ph.D.,

Junichiro Satoh, M.D., Ph.D.,

Yoichiro Ikeda, M.D., Ph.D.;

Maki Takeuchi, M.D., Ph.D.,

Mai Sugahara, M.D., Ph.D.,

Ryo Matsuura, M.D., Ph.D.,

Shinji Tanaka, M.D., Ph.D.,

Hajime Kato, M.D., Ph.D.,

Official website

http://www.todai-jinnai.com

Introduction and Organization
The Department of Nephrology and Endocrinology
is one of the major divisions in the Department ofInternal Medicine of the University of Tokyo, which
covers nephrology, hypertension, and endocrinology,
and also renal diseases associated with diabetes
mellitus, cardiovascular diseases, collagen diseases
and so on. Usually we have up to 25 inpatients in thehospital. The Professor and each member of the staff
have an active responsibility for all clinical activities.
Each member has an office and a research laboratory.
In our department, almost all members support theclinical works of our residents. We are intimately

working together in all clinical activities under thesupervision of the professor, the associate professors,
and the lecturers.

Clinical activities
The residents are in charge of up to 25 patients ofour department and supervised by associates andfaculty staffs. We have clinical conferences to discuss
the diagnosis and treatment of our patients with all
members of the staff. Particularly difficult cases arefurther discussed with guest specialists from outside.
Nephritis should be morphologically diagnosed byrenal biopsy and the optimal treatment should be155chosen 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
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, epigenetics, 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

156

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
not accept holiday dialysis.
3. Emergency hemodialysis and hemodiafiltration
for ICU patients.
4. Plasma exchange for neurodegenerative diseases,
SLE, TTP, TMA, and pre/post-liver transplantpatients.
5. DFPP for collagenous diseases, MG, HCV, anddermatological disorders.
6. LDL apheresis for nephrotic syndrome and ASO
patients.
7. White blood cell elimination therapy forulcerative colitis and rheumatological arthritis.
8. Cell-free and concentrated ascites reinfusion
therapy (CART) for refractory ascites.
9. 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
syndrome and those functional analyses.
4. Association between factors at the initiation ofrenal replacement therapy and prognosis.
5. Elucidation of basic mechanisms in cardio-renal
syndrome and intervention.
6. Pathophysiology of acute kidney injury and its
applicability for renal regenerative study.
7. AKI biomarkers and their clinical significance in
ICU/CCU.
8. Renal biomarker to determine clinical action
ability in CKD and type-2 DN.

Publications(1) Oki R, Hamasaki Y, Komaru Y, Miyamoto Y,
Matsuura R, Akari S, Nakamura T, Murase T, Doi
K, Nangaku M. Plasma xanthine oxidoreductase
is associated with carotid atherosclerosis in stable
kidneytransplant
recipients.
Nephrology(Carlton). 2022 Apr;27(4):363-370.
(2) Sakashita M, Nangaku M. Multi-omics studies
reveal genes critical for AKI and ferroptosis.
Kidney Int. 2022 Apr;101(4):665-667.
(3) Ishii T, Tanaka T, Nangaku M. Is HIF activation
Janus faced? The therapeutic effects of the
HIF-2α inhibitor. Kidney Int. 2022 May;101(5):866-869.
(4) Inoue R, Nishi H, Osaka M, Yoshida M, Nangaku
M. Neutrophil Protein Kinase R Mediates
Endothelial Adhesion and Migration by the
Promotion of Neutrophil Actin Polymerization. J
Immunol. 2022 May 1;208(9):2173-2183.
(5) Sasaki Y, Higashijima Y, Suehiro JI, Sugasawa T,
Oguri-Nakamura E, Fukuhara S, Nagai N,
Hirakawa Y, Wada Y, Nangaku M, Kanki Y.
Lysine demethylase 2B regulates angiogenesis
via Jumonji C dependent suppression ofangiogenic transcription factors. Biochem
Biophys Res Commun. 2022 May 21;605:16-23.
(6) Kurata Y, Nangaku M. Dapagliflozin for the157

treatment of chronic kidney disease. Expert Rev
Endocrinol Metab. 2022 Jul;17(4):275-291.
(7) Hasegawa S, Nangaku M. Whole-Kidney
Three-Dimensional Staining with CUBIC. J Vis
Exp. 2022 Jul 18;(185).
(8) Hasegawa S, Nangaku M. Anti-aging mechanismof calorie restriction in humans. Kidney Int. 2022
Aug;102(2):223-225.
(9) Hidaka N, Koga M, Kimura S, Hoshino Y, Kato
H, Kinoshita Y, Makita N, Nangaku M,
Horiguchi K, Furukawa Y, Ohnaka K, Inagaki K,
Nakagawa A, Suzuki A, Takeuchi Y, Fukumoto S,
Nakatani F, Ito N. Clinical Challenges in
Diagnosis, Tumor Localization and Treatment ofTumor-Induced Osteomalacia: Outcome of a
Retrospective Surveillance. J Bone Miner Res.
2022 Aug;37(8):1479-1488.
(10) Matsuura R, Honda K, Oki R, Hamasaki Y, Doi K,
Nangaku M. Screening and Management for
Intracranial Aneurysms in Japanese Patients WithADPKD. Kidney Int Rep. 2022 Jun 1;7(8):18931896.
(11) Maruno S, Tanaka T, Nangaku M. Exploring
molecular targets in diabetic kidney disease.
Kidney Res Clin Pract. 2022 Sep;41(Suppl 2):
S33-S45.
(12) Tanemoto F, Nangaku M, Mimura I. Epigenetic
memory contributing to the pathogenesis of
AKI-to-CKD transition. Front Mol Biosci. 2022
Sep 21;9:1003227.
(13) Hirakawa Y, Yoshioka K, Kojima K, Yamashita Y,
Shibahara T, Wada T, Nangaku M, Inagi R.
Potential progression biomarkers of diabetic
kidney disease determined using comprehensive
machine learning analysis of non-targeted
metabolomics. Sci Rep. 2022 Sep 29;12(1):16287.
(14) Hanafusa N, Tu C, McCullough K, Bieber B,
Pisoni RL, Robinson BM, Hasegawa T, Nangaku
M. An investigation into possible sex differencesin Association of Haemoglobin with survival
among Haemodialysis patients in the J-DOPPS
cohort. Nephrology (Carlton). 2022 Oct;27(10):795-803.
(15) Nakamura M, Nangaku M. Snapshots of nascent
RNA can validate different nephron segment
responses in acute kidney injury: a step towardclinically useful biomarkers? Kidney Int. 2022
Oct;102(4):678-680.
(16) Nakamura M, Satoh N, Horita S, Nangaku M.
Insulin-inducedmTOR
signaling
andgluconeogenesis in renal proximal tubules: A
mini-review of current evidence and therapeuticpotential. Front Pharmacol. 2022 Oct 10;13:
1015204.
(17) Oki R, Hamasaki Y, Tsuji S, Suzuki K, Tsuneishi
S, Imafuku M, Komaru Y, Miyamoto Y, Matsuura
R, Doi K, Nangaku M. Clinical frailty assessment
might be associated with mortality in incident
dialysis patients. Sci Rep. 2022 Oct 21;12(1):17651.
(18) Makita N, Sato J, Manaka K, Akahane K, Ito T,
Yamazaki H, Mizoguchi A, Hikima Y, Horikoshi
H, Nangaku M, Iiri T. Successful prednisolone or
calcimimetic treatment of acquired hypocalciuric
hypercalcemia caused by biased allosteric CaSR
autoantibodies. JCI Insight. 2022 Oct 24;7(20):e156742.
(19) Xia Y, Coates PT, Nangaku M. How does
diabetes cause susceptibility to COVID-19 in thekidney: new clues provided by organoids. KidneyInt. 2022 Nov;102(5):951-953.
(20) Sugahara M, Tanaka T, Nangaku M. Future
perspectives of anemia management in chronic
kidney disease using hypoxia-inducible factorprolyl hydroxylase inhibitors. Pharmacol Ther.
2022 Nov;239:108272.
(21) Nakai K, Manaka K, Sato J, Takeuchi M,
Yamazaki Y, Sasano H, Tsurutani Y, Saito J,
Nishikawa T, Iiri T, Nangaku M, Makita N.
Aldosterone-Producing Adenomas of Increased
Size Are Associated With Higher Steroidogenic
Activity. J Clin Endocrinol Metab. 2022 Nov 23;
107(11):3045-3054.
(22) Kato H, Hoshino Y, Hidaka N, Ito N, Makita N,
Nangaku M, Inoue K. Machine Learning-Based
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Department of Diabetes andMetabolic Diseases
Professor
Toshimasa Yamauchi, M.D., Ph.D.

Associate Professor
Masato Iwabu, M.D., Ph.D. (until April 2022)
Nobuhiro Shojima, M.D., Ph.D. (since July 2022)

Lecturer
Nobuhiro Shojima, M.D., Ph.D. (until June 2022)
Masaki Igarashi, M.D., Ph.D. (since Sep 2022)

Project Lecturer
Tomohisa Aoyama, M.D., Ph.D.

Assistant Professor
Satoru Takase, M.D., Ph.D. (until Mar 2023),

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

Masaki Igarashi, M.D., Ph.D. (until Aug 2022),

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

Takayoshi Sasako, M.D. Ph.D. (until Jan 2023),

Gotaro Toda, M.D., Ph.D.,

Masakazu Aihara, M.D., Ph.D.

Yuka Kobayashi, M.D., Ph.D. (until Mar 2023)

URL http://dm.umin.jp/
Introduction and Organization
In 1998 the Department of Internal Medicine at the
University of Tokyo was reorganized to the morefunctional units based on clinical specialties. The
physicians specialized in diabetes and metabolic
diseases from 3 former departments of Internal
Medicine were unified to the Department of Metabolic
Diseases. The Department of Diabetes and Metabolic
Diseases is one of the major divisions in the
Department of Internal Medicine at the University ofTokyo, and covers diabetes mellitus and metabolic
diseases including obesity disease and dyslipidemia.
Under the supervision and direction of the previous
professors Dr. Satoshi Kimura (1998-2003), Dr.
Toshiro Fujita (2003), Takashi Kadowaki (2003-2018)

and current professor Dr. Toshimasa Yamauchi(2018-present), we have been providing a wide-ranged
clinical, teaching and research activities. Currently,
we hold beds mainly on the 12th floor of the North
Wing Ward A of the University of Tokyo Hospital.
Besides the staffs listed above, our division holds
faculties in branches, for example, Department ofClinical Nutrition Therapy (Associate Professor: Dr.
Naoto Kubota), Laboratory for Advanced Research on
Pathophysiology of Metabolic Diseases (Project
Associate Professor: Dr. Miki Okada-Iwabu, ,Department of Healthcare Information Management(Associate Professor: Dr. Kayo Waki, Project
Assistant Professor: Dr. Kana Miyake), Department ofClinical Laboratory (Associate Professor: Dr. Makoto
Kurano), Division for Health Service Promotion, The

160

University of Tokyo (Assistant Professor: Dr. Sachiko
Okazaki) and Center for Epidemiology and Preventive
Medicine (Project Assistant Professor: Dr. Yukari
Masuda). With all these staffs, we actively instruct
and teach the residents and medical school students;
annual evaluation of the teaching skill by the students
always rates our department within the three places of
the top. In addition, there are 14 students of Graduate
School in our division. With all these 59 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 227 new patients
this year (total 33,412 patients per year). On theinpatient ward, we not only take care of around 18
patients in our division as mentioned above, but also
provide a sophisticated management to all patients
suffering from metabolic diseases, especially diabetes
mellitus. Diabetes mellitus, metabolic syndrome, dyslipidemia and obesity disease are becoming moreprevalent in Japan, and lead to complications
including nephropathy, retinopathy, neuropathy andcardiovascular diseases. Thus, in collaboration withother departments, we optimize the treatment of eachpatient.
We provide the educational classes to the patients
every weekday in the inpatient ward, and also givelectures twice a week in the outpatient unit. In
addition, in collaboration with ancillary staffs of our
hospital, we provide patients well-reasoned
instructions regarding nutritional management, excise
therapy and medical therapy.
The weekly official activities of our department
consist of the pre-round case conference and the Ward
Round by the Professor on Monday. We also hold aweekly case conference by the consultation group
staffs.

Teaching activities
As for medical student education, our department

takes a part in systemic lectures for the 4th year
medical students, bed-side learning and clinicalclerkship for the 5th year medical students, andclinical lectures for the 6th year medical students.
In systemic lectures, comprehensive presentation for
the understanding of basic knowledge about theconcept, pathogenesis, diagnosis and treatment ofcommon metabolic diseases is performed.
In clinical lectures, we present clinical cases ofimportant diseases such as diabetes mellitus, and try
to discuss with the students several points forplanning the diagnosis and treatment in collaboration
with the faculties of the Departments of Nephrology,
Cardiology, and Ophthalmology.
During the period of clinical clerkship, the students
have opportunities to experience the daily clinical carewith junior and senior residents as well as with theFaculty members. Each student can learn how to dohistory taking, perform physical examinations andmake the actual plans for the diagnosis and treatment.
In addition, we arrange the program so that thestudents can experience the clinical practice and learn
the disease itself more profoundly. One faculty andone senior-resident always instruct one student.
Especially, Diabetes Clinical Seminar and oral
examination that lead to profound understandings ofthe metabolic diseases are regularly provided by theProfessor.
As for the post-graduate education, attending doctor(staff) and senior resident instruct the junior residents.
We provide advanced teaching through the seminars
and grand conference.

Research activities
There are several laboratories in our departments;
collaborating with each other or with other departments, we focus on the molecular mechanisms of themetabolic diseases and the establishment of the novel
therapeutics.
1) Molecular mechanisms of type 2 diabetes
We have been attempting to elucidate the mechanisms
underlying the development of type 2 diabetes at themolecular and genetic levels. To this end, in
collaboration with RIKEN and several cohorts, we
explored the comprehensive catalog of genomic

161

variations to identify variations conferring susceptibility to type 2 diabetes in the Japanese population.
We are also exploring the signal transduction
pathways and physiological roles of insulin andadipokines in various tissues and the mechanisms ofinsulin secretion under the normal or pathologicalconditions, such as diabetes and obesity disease, using
a number of transgenic and knockout animal models,in parallel with information obtained by wholegenome analysis of human patients. In particular, we
are interested in the physiological and pathophysiological functions of adipokines secreted by adipocytes,
including adiponectin, and the signal transduction
pathway of adiponectin through the receptors,
AdipoR1 and AdipoR2, that we discovered andcharacterized. We have also identified “AdipoRon” asan adiponectin receptor agonist, which will contributeto the development and optimization of AdipoRtargeted therapeutics. In addition, we have beensuccessfully unraveling the molecular mechanisms of
β cell proliferation and inter-tissue communication of
glucose metabolism in obesity disease and type 2
diabetes. Recently, we are investigating brown andwhite adipocyte-specific transcriptional and epigenetic
regulations in obesity. We believe that these findings
and research activities will lead to novel therapeuticstrategies for diabetes and the metabolic syndrome.
2) Pathophysiological roles of lipid storage andatherosclerosis
Our aim is to clarify the significance of metabolic risk
factors in the onset and development of atherosclerosis. We are currently investigating thepathophysiological roles of lipid storage in obesity
disease, fatty liver, diabetes, hyperlipidemia andatherosclerosis using strategies of molecular biology
and genetic engineering techniques. Utilizing theanimal models of lipid disorders and molecularbiological technique, we are analyzing the roles oflipid transporters, nuclear receptors and the antioxidative proteins on the lipid disorders and atherosclerosis. We are currently interested in the cholesterol
and lipid absorption from the intestine and lipid
handling in the cells.
3) Clinical trials and epidemiological studies
We are conducting clinical trials and epidemiologicalstudies including “Japan Diabetes Optimal Integrated
Treatment study for 3 major risk factors ofcardiovascular diseases (J-DOIT3)” follow-up study,"Japan Diabetes compREhensive database projectbased on an Advanced electronic Medical record
System (J-DREAMS)", database project on obesity(J-ORBIT), National Database project, systematic
reviews and meta-analyses with a focus on important
issues such as metabolic syndrome. We investigatedanti-aging effect of Nicotinamide mononucleotide on
muscle function, association between tear and blood
glucose concentrations and investigator initiatedclinical trials targeting for a new class of anti-diabetic
agents.

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Nephrol. 53:240-248, 2022
Suzuki Y, Kaneko H, Okada A, Itoh H, Fujiu K,
Michihata N, Jo T, Takeda N, Morita H,
Yamaguchi S, Kamiya K, Matsunaga A, Ako J,
Node K, Yamauchi T, Nangaku M, Yasunaga H,
Komuro I. Impact of Glucose Tolerance and Its
Change on Incident Proteinuria: Analysis of a
Nationwide Population-Based Dataset. Am J
Nephrol. 9:1-9, 2022
Suzuki Y, Kaneko H, Okada A, Itoh H, Fujiu K,
Michihata N, Jo T, Takeda N,Morita H,
Yamaguchi S, Yano Y, Kamiya K, Matsunaga A,
Ako J, Fukui A, Yokoo T, Nishiyama A, Node K,
Yamauchi T, Nangaku M, Yasunaga H, Komuro I.
Risk for Proteinuria in Newly Defined
Hypertensive People Based on the 2017

165

American College of Cardiology/American Heart
Association Blood Pressure Guideline .Am J
Cardiol.168:83-89, 2022
30. Suzuki Y, Kaneko H, Okada A, Matsuoka S, Itoh
H, Fujiu K, Michihata N, Jo T, Takeda N, Morita
H, Yamaguchi S, Node K, Yamauchi T, Yasunaga
H, Komuro I. Prediabetes in Young Adults and Its
Association With Cardiovascular Health Metrics
in the Progression to Diabetes. J Clin Endocrinol
Metab. 107:1843-1853, 2022
31. Tian J, Chung HK, Moon JS, Nga HT, Lee HY,
Kim JT, Chang JY, Kang SG, Ryu D, Che X,
Choi JY, Tsukasaki M, Sasako T, Lee SH, Shong
M, Yi HS: Skeletal muscle mitoribosomal defects
are linked to low bone mass caused by bonemarrow inflammation in male mice. J Cachexia
Sarcopenia Muscle 13: 1785-1799, 2022
32. Yamaguchi S, Okada A, Sunaga S, Ikeda
Kurakawa K, Yamauchi T, Nangaku M,
Kadowaki T. Impact of COVID-19 pandemic on
healthcare service use for non-COVID-19
patients in Japan: retrospective cohort study.
BMJ Open. 2: e060390, 2022

166

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

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

Ken Morita, M.D., Ph.D

Assistant Professor
Kazuki Taoka, M.D., Ph.D.,

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

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

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

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

Hideaki Mizuno, M.D., Ph.D.

Akira Chiba, 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 ofundergraduate as well as graduate students. We are also
engaged in continuous education of post-graduate
doctors who develop into sophisticated hematologistsof eminent distinction. These activities are performedby the united efforts of all members who belong to thedepartment. Dr. Mineo Kurokawa was assigned as
Professor of the Department of Hematology andOncology in 2005. Other staff of our department
consists of 2 lecturers and 7 assistant professors.

Clinical activities
On the average, 50-70 patients with hematologicaldiseases are treated in the ward. Clinical facilities
include patient rooms with high-efficiency particulate
air filtration and filtrated water supply. Patients who are
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 assistantprofessor) are assigned to a single patient. Since
clinical issues are highly related to hematopoietic stem
cell transplantation especially for patients withhematological diseases, a substantial portion of ourclinical conferences are shared with staff members of
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 70-80 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
tests to detect, characterize, and monitor neoplastic
cells and their results are used in the diagnosis andtreatment.

167

Here we introduce technical aspects on the treatment
strategy:
1. High dose chemotherapy with autologous stem celltransplant:
High-dose
chemotherapy
isadministered for the treatment of hematologicalneoplasms and solid tumors. For the autologous
stem cell support, peripheral blood stem cell isusually selected as a source of stem cells. Recently,
weareactively
performing
autologoustransplantation as a treatment for CNS malignant
lymphoma, which is considered intractable, toimprove the prognosis.
2. Allogeneic hematopoietic stem cell transplant:
Bone marrow cells are harvested from healthy
donors by operation under general anesthesia andimmediately infused to a recipient. Peripheral
blood stem cells (PBSCs) are harvested fromhealthy donors by leukapheresis using an
automated continuous flow blood cell separator.
PBSCs are immediately infused to a recipient orpreserved in liquid nitrogen in cooperation with the
Department of Transfusion Medicine. Allogeneictransplant with non-myeloablative conditioning(also referred to as reduced-intensity stem celltransplant (RIST)) is commonly performed forelderly patients and patients with impaired organfunction. HLA-haploidentical hematopoietic stem
cell transplantation is also ready to be performed topatients if necessary. Allogeneic hematopoietic
stem cell transplant for the elderly is performed
under the admission of Patient Relations andClinical Ethics Center. Cord blood cells are also
used as a source of hematopoietic stem cells.
3. CAR-T Cell Therapy: T cells that are collectedfrom the patients are genetically treated in the lab
to produce special receptors called chimericantigen receptors, or CARs. These CARs allow theT cells to recognize an antigen at the surface oflymphoma cells and activate T cells' ability to killthese tumor cells. By collaborating with the
Department of Cell Therapy and Transplantation
Medicine, the Department of Pediatrics(Hematology/Oncology), and the Cell Processing
Center, we have installed a capacity to perform thismost advanced and promising cancer treatment forpatients with hematologic malignancies, andactively recruiting patients.

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 atacademic 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 pathological mechanismof Erdheim-Chester disease. Translational research todevelop novel methods for diagnosis and treatment
based on basic research is also performed. Every effort
has been made to achieve the highest quality in both

168

clinical and basic medical research. The ultimate aimsof our research are the application of epoch-making
discoveries in research fields to the clinical hematology
and oncology. Representative publications from ourdepartments published in the past year are listed in thereference.

1. Yokomizo T, Ideue T, Morino-Koga S, Tham CY,
Sato T, Takeda N, Kubota Y, Kurokawa M,
Komatsu N, Ogawa M, Araki K, Osato M, Suda T.
Independent origins of fetal liver haematopoietic
stem and progenitor cells. Nature. 2022 Sep;
609(7928):779-784.
2. Oyama T, Taoka K, Chiba A, Matsuda K, Maki H,
Masamoto Y, Kurokawa M. Bing-Neel Syndrome
Successfully Treated with Tirabrutinib. Intern Med.
2022 Dec 1;61(23):3575-3579.
3. Masamoto Y, Shimura A, Kurokawa M. Reduced
bendamustine for elderly patients with follicularlymphoma. Ann Hematol. 2022 Mar;101(3):713715.
4. Nakazaki K, Yoshida M, Masamoto Y, ShinozakiUshiku A, Ikemura M, Hisamoto T, Yasunaga M,
Sato S, Kurokawa M. Discordant lymphomas ofclassic Hodgkin lymphoma and peripheral T-cell
lymphoma following dupilumab treatment for
atopic dermatitis. Int J Hematol. 2022 Sep;116(3):446-452.
5. Miyauchi M, Sasaki K, Kagoya Y, Taoka K,
Masamoto Y, Yamazaki S, Arai S, Mizuno H,
Kurokawa M. CAMK2G is identified as a novel
therapeutic target for myelofibrosis. Blood Adv.
2022 Mar 8;6(5):1585-1597.
6. Takano H, Yasunaga M, Yamazaki I, Nishikawa M,
Masamoto Y, Shinozaki-Ushiku A, Kawakami M,
Y,

dev200082.
8. Masamoto Y, Shimura A, Honda A, Taoka K, Maki
H, Kurokawa M. Obinutuzumab and reduced
bendamustine is effective for elderly patients withfollicular lymphoma. Ann Hematol. 2023 Jan;
102(1):243-244.

References

Yatomidifferentiation. Development. 2022 Feb 15;149(4):Kurokawa

M.

Degenerated

mitochondria in leukemic blast appeared as
granules on May-Grunwald-Giemsa staining. Ann
Hematol. 2022 May;101(5):1135-1136.
7. Shull LC, Lencer ES, Kim HM, Goyama S,
Kurokawa M, Costello JC, Jones K, Artinger KB.
PRDM paralogs antagonistically balance Wnt/βcatenin activity during craniofacial chondrocyte

9. Shiroshita K, Kobayashi H, Watanuki S, Karigane
D, Sorimachi Y, Fujita S, Tamaki S, Haraguchi M,
Itokawa N, Aoyoama K, Koide S, Masamoto Y,
Kobayashi K, Nakamura-Ishizu A, Kurokawa M,
Iwama A, Okamoto S, Kataoka K, Takubo K. A
culture platform to study quiescent hematopoietic
stem cells following genome editing. Cell Rep
Methods. 2022 Dec 5;2(12):100354.
10. Higo T, Suzuki Y, Sato M, Koya J, Mizuno H,
Miyauchi M, Masamoto Y, Kataoka K, Sumitomo
Y, Tsuruta-Kishino T, Sato T, Kurokawa M.
Heterozygous Dnmt3a R878C induces expansionof quiescent hematopoietic stem cell pool. Exp
Hematol. 2022 May;109:45-54.
11. Murakami D, Maki H, Matsuda K, Masamoto Y,
Suzuki F, Amemiya S, Osawa K, Hinata M,
Ikemura M, Ushiku T, Kurokawa M. Cerebral
toxoplasmosis complicating lymphoplasmacytic
lymphoma in partial remission. J Infect Chemother.
2022 Feb;28(2):279-282.
12. Ogawa E, Edamitsu T, Ohmori H, Kohu K,
Kurokawa M, Kiyonari H, Satake M, Okuyama R.
Transcription Factors Runx1 and Runx3 Suppress
Keratin

ExpressioninUndifferentiatedKeratinocytes. Int J Mol Sci. 2022 Sep 2;23(17):10039.
13. Kurihara Y, Mizuno H, Honda A, Shimura A,
Fujioka Y, Maki H, Kurokawa M. CCDC88C-FLT3
gene fusion in CD34-positive haematopoietic stem
and multilineage cells in myeloid/lymphoidneoplasm with eosinophilia. J Cell Mol Med. 2022
Feb;26(3):950-952.
14. Hayashida H, Honda A, Hino T, Mizuno H,
Toyama K, Kurokawa M. A case of thymoma
showing significant tumor reduction after antithymocyte globulin. Gen Thorac Cardiovasc Surg.

1692022 Jan;70(1):96-99.

adrenoleukodystrophy: A nationwide retrospective

15. Oyama T, Matsuda K, Honda A, Maki H,
Masamoto Y, Murakami D, Toya T, Sakurai M,

analysis in Japan. Pediatr Transplant. 2022 Feb;
26(1):e14125.

Kataoka K, Doki N, Kurokawa M. Clinical

23. Mizuta S, Ugai T, Kato H, Doki N, Ota S, Kawakita

characteristics of steroid-responsive but dependent

T, Katayama Y, Kurokawa M, Nakamae H, Yano S,

chronic graft-versus-host disease: a multicenter

Nawa Y, Kanda Y, Fukuda T, Atsuta Y, Kako S.

retrospective analysis. Int J Hematol. 2023 Feb;

Propensity score matching/reweighting analysis

117(2):260-268.

comparing autologous and allogeneic stem cell

16. Murakami D, Matsuda K, Honda A, Masamoto Y,
Kurokawa

M.

Severeinfections

andtransplantation for B-lineage acute lymphoblastic

renalleukemia. Int J Hematol. 2022 Sep;116(3):393-400.

dysfunction during immunosuppressive therapy

24. Matsuda K, Jo T, Shimura A, Honda A, Taoka K,

with cyclosporine A for aplastic anemia. Int J

Masamoto Y, Matsui H, Fushimi K, Yasunaga H,

Hematol. 2022 Oct;116(4):482-488.

Kurokawa M. Risk of febrile neutropenia in very

17. Fukui Y, Honda A, Takano H, Obo T, Mizuno H,

elderly patients aged ≥80 years receiving their first

Masamoto Y, Kurokawa M. Severe autoimmune

cycle of R-CHOP regimen: a nationwide real-

pancytopenia after autologous hematopoietic stem

world study in Japan. Br J Haematol. 2022 May;

cell transplantation for Hodgkin lymphoma. J Clin

197(3):e37-e41.

Exp Hematop. 2022 Dec 28;62(4):217-221.

25. Yoshida M, Matsuda K, Endo K, Honda A, Maki H,

18. Masamoto Y, Taoka K, Maki H, Kurokawa M.

Taoka K, Masamoto Y, Wakimoto Y, Jubishi D,

Bone marrow involvement is a risk factor for

Moriya K, Kurokawa M. Toxic shock likeinfusion-related reactions in patients with follicularsyndrome caused by Streptococcus agalactiae

lymphoma treated by obinutuzumab. Ann Hematol.

bacteremia during treatment for multiple myeloma.

2022 Dec;101(12):2795-2797.

J Infect Chemother. 2023 Apr;29(4):407-409.

19. Ebisawa K, Masamoto Y, Yagi K, Kurokawa M. A
case

of

JAK2

thrombocythemia

V617F

positive

successfully

essential

controlled

26. Oyama T, Matsuda K, Honda A, Yasunaga M,
Nakazaki K, Maki H, Masamoto Y, Kurokawa M.

byLong-term follow-up of central nervous system

imatinib mesylate. Ann Hematol. 2022 Nov;

relapse in patients with acute promyelocytic

101(11):2551-2552.

leukemia treated with all-trans retinoic acid and20. Hino T, Honda A, Shimura A, Masamoto Y,
Kurokawa M. R-GCD regimen in elderly patientschemotherapy. Leuk Lymphoma. 2022 Dec;63(14):3497-3500.

with relapsed or refractory aggressive non-

27. Sato M, Yasunaga M, Ohzu M, Toyama K,

Hodgkin's B-cell lymphoma: a retrospective

Nakazaki K, Nakahara F, Kubo T, Okura N, Abe O,

single-center analysis. Int J Hematol. 2022 Feb;

Kurokawa M. Successful diagnosis of veno-

115(2):296-297.

occlusive

diseasecausedbyinotuzumab

21. Ebisawa K, Honda A, Chiba A, Masamoto Y,

ozogamicin through minimal-invasive angiography:

Okazaki H, Kurokawa M. High D-index duringa case report. Ann Hematol. 2022 May;101(5):mobilization predicts poor mobilization of CD34+

1153-1155.

cells after anti-lymphoma salvage chemotherapy. J
Clin Apher. 2022 Feb;37(1):4-12.

28. Ito Y, Honda A, Kurokawa M. Impact of vitamin Dlevel at diagnosis and transplantation on the

22. Kato K, Yabe H, Shimozawa N, Adachi S,

prognosis of hematological malignancy: a meta-

Kurokawa M, Hashii Y, Sato A, Yoshida N, Kaga

analysis. Blood Adv. 2022 Mar 8;6(5):1499-1511.

M, Onodera O, Kato S, Atsuta Y, Morio T. Stem

29. Matsuda K, Oyama T, Maki H, Nakazaki K,

cell transplantation for pediatric patients with

Yasunaga M, Honda A, Masamoto Y, Kurokawa M.

170

Prompt Initiation of Conventional Chemotherapy
to Avoid Early Death in Patients with Newly
Diagnosed Acute Promyelocytic Leukemia. Intern
Med. 2023 Aug 1;62(15):2181-2185.
30. Oyama T, Taoka K, Chiba A, Masamoto Y, Ikemura
M, Honda A, Maki H, Kurokawa M. Daratumumab
plus lenalidomide and dexamethasone for relapsed
POEMS syndrome with bone plasmacytoma
harboring 17p deletion. Int J Hematol. 2023 Mar;
117(3):463-467.
31. Ito Y, Honda A, Kurokawa M. COVID-19 mRNA
Vaccine in Patients With Lymphoid Malignancy or
Anti-CD20 Antibody Therapy: A Systematic
Review and Meta-Analysis. Clin Lymphoma
Myeloma Leuk. 2022 Aug;22(8):e691-e707.
32. Miyashita H, Taoka K, Kume A, Ushiku A, Ushiku
T, Toyama K, Kurokawa M. Clinical usefulness ofa novel classification of T cell distribution patterns
in the tumor microenvironment of follicularlymphoma to detect transformation. Ann Hematol.
2022 Nov;101(11):2477-2483.
33. Murayama R, Oyama H, Abe-Doi M, Masamoto Y,
Kashiwabara K, Tobe H, Komiyama C, Sanada H,
Kurokawa M. Safety verification of a new
peripheral intravenous catheter placed in the upperarm vein for administration of drugs with highirritant potential. Drug Discov Ther. 2022 Jul 20;
16(3):128-134.
34. Yoshida M, Morita K, Fukushima H, Jona M,
Nishikawa M, Yatomi Y, Kishino Y, Iwasaki A,
Ushiku T, Imadome KI, Honda A, Maki H,
Kurokawa M. Development of Epstein-Barr virusassociatedlymphoproliferative

disorderandhemophagocytic lymphohistiocytosis during longterm lenalidomide maintenance therapy in multiple
myeloma. Int J Hematol. 2023 May;117(5):769773.
35. Sato M, Honda A, Maki H, Toyama K, Yamaguchi
R, Ikeda M, Moriya K, Kurokawa M. Successfultreatment of pneumonia caused by multidrugresistant Pseudomonas aeruginosa after allogeneic
hematopoietic stem cell transplantation withcolistin and amikacin inhalation therapy. J InfectChemother. 2022 Jan;28(1):91-94.

171

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

Associate Professor
Hirofumi Shoda, M.D., Ph.D. (Rheumatology)

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

Hospital Lecturer
Haruka Tsuchiya, M.D., Ph.D. (Rheumatology)
Yumi Tsuchida，M.D., Ph.D. (Rheumatology)

Research Associate
Toshihiko Komai, M.D., Ph.D. (Rheumatology)
Toshiaki Shimizu, M.D., Ph.D. (Rheumatology)
Bunki Natsumoto, M.D., Ph.D. (Rheumatology)
Masanori Kono, M.D., Ph.D. (Rheumatology)

Project Associate professor
Tomohisa Okamura, M.D., Ph.D. (Rheumatology)

Project Research Associate
Yasuo Nagafuchi，M.D., Ph.D. (Rheumatology)
Mineto Ohta, M.D., Ph.D. (Rheumatology)

Homepage

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

Introduction and Organization
The Department of Allergy and Rheumatology
presently consists of 15 staffs mentioned above, who
preside over 3 medical staff, 18 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, Molecular Life Innovation Ward, andthe 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172

cover clinical immunology, connective tissue diseases
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.

5. Analysis o mice models of immune-relateddiseases.
6. Analysis of autoimmune disease-specific iPS cells
7. 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.

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,
such as systemic lupus erythematosus, and its
clinical application to precision medicine.
2. Analysis of newly identified autoimmuneassociated T cell subset and its roles in
autoimmune diseases.
3. Analysis of T cell and B cell repertoires in
autoimmune diseases.
4. Analysis of synovial tissues in rheumatoid
arthritis.

3.

Distinct transcriptome architectures underlying
lupus establishment and exacerbation. Nakano M,
Ota M, Takeshima Y, Iwasaki Y, Hatano H,
Nagafuchi Y, Itamiya T, Maeda J, Yoshida R,
Yamada S, Nishiwaki A, Takahashi H, Takahashi
H, Akutsu Y, Kusuda T, Suetsugu H, Liu L, Kim
K, Yin X, Bang SY, Cui Y, Lee HS, Shoda H,
Zhang X, Bae SC, Terao C, Yamamoto K,
Okamura T, Ishigaki K, Fujio K. Cell. 2022 Sep
1;185(18):3375-3389.e21.
Multi-ancestry genome-wide association analyses
identify novel genetic mechanisms in rheumatoid
arthritis. Ishigaki K, Sakaue S, Terao C, Luo Y,
Sonehara K, Yamaguchi K, Amariuta T, Too CL,
Laufer VA, Scott IC, Viatte S, Takahashi M,
Ohmura K, Murasawa A, Hashimoto M, Ito H,
Hammoudeh M, Emadi SA, Masri BK, Halabi H,
Badsha H, Uthman IW, Wu X, Lin L, Li T, Plant
D, Barton A, Orozco G, Verstappen SMM,
Bowes J, MacGregor AJ, Honda S, Koido M,
Tomizuka K, Kamatani Y, Tanaka H, Tanaka E,
Suzuki A, Maeda Y, Yamamoto K, Miyawaki S,
Xie G, Zhang J, Amos CI, Keystone E, Wolbink
G, van der Horst-Bruinsma I, Cui J, Liao KP,
Carroll RJ, Lee HS, Bang SY, Siminovitch KA,
de Vries N, Alfredsson L, Rantapää-Dahlqvist S,
Karlson EW, Bae SC, Kimberly RP, Edberg JC,
Mariette X, Huizinga T, Dieudé P, Schneider M,
Kerick M, Denny JC; BioBank Japan Project;
Matsuda K, Matsuo K, Mimori T, Matsuda F,
Fujio K, Tanaka Y, Kumanogoh A, Traylor M,
Lewis CM, Eyre S, Xu H, Saxena R, Arayssi T,
Kochi Y, Ikari K, Harigai M, Gregersen PK,
Yamamoto K, Louis Bridges S Jr, Padyukov L,
Martin J, Klareskog L, Okada Y, Raychaudhuri S.
Nat Genet. 2022 Nov;54(11):1640-1651.
Immune cell multiomics analysis reveals
contribution of oxidative phosphorylation to
B-cell functions and organ damage of lupus.

173

Takeshima Y, Iwasaki Y, Nakano M, Narushima
Y, Ota M, Nagafuchi Y, Sumitomo S, Okamura T,
Elkon K, Ishigaki K, Suzuki A, Kochi Y,
Yamamoto K, Fujio K. Ann Rheum Dis. 2022
Jun;81(6):845-853.
4. Entering the era of precision medicine throughmultiomics approach. Fujio K. Inflamm Regen.
2022 Sep 9;42(1):42.
5. Jaccoud's Arthropathy in Systemic Lupus
Erythematosus. Izuka S, Natsumoto B, Shoda H,
Fujio K. Intern Med. 2023 Mar 1;62(5):809-810.
6. Significance of the multiomics approach toelucidate disease mechanisms in humans. Fujio K.
Inflamm Regen. 2022 Nov 4;42(1):41.
7. Emerging role of leptin in joint inflammation anddestruction. Tsuchiya H, Fujio K. Immunol Med.
2022 Mar;45(1):27-34.
8. ANCA-associated vasculitis with protein-losing
enteropathyischaracterizedbyhypocomplementemia. Goto M, Tsuchida Y, Terada K,
Takahashi H, Sugimori Y, Komai T, Iwasaki Y,
Shoda H, Fujio K. Rheumatol Int. 2022 Oct;42(10):1863-1872.
9. The Pathophysiological Roles of Regulatory T
Cells in the Early Phase of Systemic Sclerosis.
Kobayashi S, Nagafuchi Y, Shoda H, Fujio K.
Front Immunol. 2022 May 24;13:900638.
10. Self-limited
Polymyalgia
Rheumatica-like
Syndrome Following mRNA-1273 SARS-CoV-2
Vaccination. Izuka S, Komai T, Natsumoto B,
Shoda H, Fujio K. Intern Med. 2022 Mar 15;
61(6):903-906.
11. Indications for fertility preservation not includedin the 2017 Japan Society of Clinical Oncology
Guideline for Fertility Preservation in Pediatric,
Adolescent, and Young Adult Patients treatedwith gonadal toxicity, including benign diseases.
Ono M, Matsumoto K, Boku N, Fujii N,
Tsuchida Y, Furui T, Harada M, Kanda Y, Kawai
A, Miyachi M, Murashima A, Nakayama R,
Nishiyama H, Shimizu C, Sugiyama K, Takai Y,
Fujio K, Morishige KI, Osuga Y, Suzuki N. Int J
Clin Oncol. 2022 Feb;27(2):301-309.
12. Efficacy of canakinumab on AA amyloidosis inlate-onset NLRP3-associated autoinflammatory
disease with an I574F somatic mosaic mutation.
Itamiya T, Komai T, Kanda H, Nagafuchi Y,

13.

14.

15.

16.

17.

18.

19.

Chang H, Shibata S, Ishiura H, Shoda H, Toda T,
Fujio K. Clin Rheumatol. 2022 Jul;41(7):22332237.
The differential diagnosis of IgG4-related disease
based on machine learning. Yamamoto M,
Nojima M, Kamekura R, Kuribara-Souta A,
Uehara M, Yamazaki H, Yoshikawa N, Aochi S,
Mizushima I, Watanabe T, Nishiwaki A, Komai
T, Shoda H, Kitagori K, Yoshifuji H, Hamano H,
Kawano M, Takano KI, Fujio K, Tanaka H.
Arthritis Res Ther. 2022 Mar 19;24(1):71.
Anti-Ku antibody-positive myositis presenting asa wide range of axial myopathies andmyocarditis: A case report and review of theliterature. Kono M, Komai T, Yuki H, Hanata N,
Kakumoto T, Kubota A, Hashimoto Maeda M,
Toda T, Shoda H, Fujio K. Mod Rheumatol
Case Rep. 2022 Jan 7;6(1):64-68.
The transcription factor Sox4 is required forthymic tuft cell development. Mino N, Muro R,
Ota A, Nitta S, Lefebvre V, Nitta T, Fujio K,
Takayanagi H. Int Immunol. 2022 Jan 1;34(1):45-52.
Long-term risks of malignancy in myositisspecific antibody-positive idiopathic inflammatory myopathy. Izuka S, Komai T, Shoda H,
Fujio K. Rheumatol Int. 2023 Feb;43(2):335-343. doi: 10.1007/s00296-022-05214-0.
Splicing QTL analysis focusing on coding
sequences reveals mechanisms for diseasesusceptibility loci. Yamaguchi K, Ishigaki K,
Suzuki A, Tsuchida Y, Tsuchiya H, Sumitomo S,
Nagafuchi Y, Miya F, Tsunoda T, Shoda H, Fujio
K, Yamamoto K, Kochi Y. Nat Commun. 2022
Aug 24;13(1):4659.
AFF3, a susceptibility factor for autoimmune
diseases, is a molecular facilitator of
immunoglobulin class switch recombination.
Tsukumo SI, Subramani PG, Seija N, Tabata M,
Maekawa Y, Mori Y, Ishifune C, Itoh Y, Ota M,
Fujio K, Di Noia JM, Yasutomo K. Sci Adv.
2022 Aug 26;8(34):eabq0008.
A diagnostic score for eosinophilic granulomatosis with polyangiitis among eosinophilic
disorders. Takahashi H, Komai T, Setoguchi K,
Shoda H, Fujio K. Allergol Int. 2023 Apr;72(2):316-323.

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20. Control of naive and effector CD4 T cell receptor
repertoires by rheumatoid-arthritis-risk HLA
alleles. Nagafuchi Y, Ota M, Hatano H, Inoue M,
Kobayashi S, Okubo M, Sugimori Y, Nakano M,
Yamada S, Yoshida R, Tsuchida Y, Iwasaki Y,
Shoda H, Okada Y, Yamamoto K, Ishigaki K,
Okamura T, Fujio K. J Autoimmun. 2022 Dec;
133:102907.
21. A nationwide questionnaire survey on theprevalence of ankylosing spondylitis andnon-radiographic axial spondyloarthritis in Japan.
Matsubara Y, Nakamura Y, Tamura N, Kameda
H, Otomo K, Kishimoto M, Kadono Y, Tsuji S,
Atsumi T, Matsuno H, Takagi M, Kobayashi S,
Fujio K, Nishimoto N, Okamoto N, Nakajima A,
Matsui K, Yamamura M, Nakashima Y,
Kawakami A, Mori M, Tomita T. Mod
Rheumatol. 2022 Aug 20;32(5):960-967.
22. Serum extracellular traps associate with theactivation of myeloid cells in SLE patients withthe low level of anti-DNA antibodies. Hanata N,
Ota M, Tsuchida Y, Nagafuchi Y, Okamura T,
Shoda H, Fujio K. Sci Rep. 2022 Nov 1;12(1):18397.
23. Dysregulation of the gene signature of effector
regulatory T cells in the early phase of systemicsclerosis. Kobayashi S, Nagafuchi Y, Okubo M,
Sugimori Y, Hatano H, Yamada S, Nakano M,
Yoshida R, Takeshima Y, Ota M, Tsuchida Y,
Iwasaki Y, Setoguchi K, Kubo K, Okamura T,
Yamamoto K, Shoda H, Fujio K. Rheumatology(Oxford). 2022 Oct 6;61(10):4163-4174.
24. The possible effects of the Japan Society ofClinical Oncology Clinical Practice Guidelines
2017 on the practice of fertility preservation infemale cancer patients in Japan. Kunitomi C,
Harada M, Sanada Y, Kusamoto A, Takai Y,
Furui T, Kitagawa Y, Yamada M, Watanabe C,
Tsugawa K, Nishiyama H, Hosoi H, Miyachi M,
Sugiyama K, Maeda Y, Kawai A, Hamatani T,
Fujio K, Suzuki N, Osuga Y. Reprod Med Biol.
2022 Mar 21;21(1):e12453.
25. Selection of treatment regimens based on shareddecision-making in patients with rheumatoid
arthritis on remission in the FREE-J study.
Tanaka Y, Yamaguchi A, Miyamoto T, Tanimura
K, Iwai H, Kaneko Y, Takeuchi T, Amano K,

26.

27.

28.

29.

Iwamoto N, Kawakami A, Murakami M,
Nishimoto N, Atsumi T, Sumida T, Ohmura K,
Mimori T, Yamanaka H, Fujio K, Fujino Y, Saito
K, Nakano K, Hirata S, Nakayamada S.
Rheumatology (Oxford). 2022 Nov 2;61(11):4273-4285.
Autotaxin is a potential link between genetic risk
factors and immunological disturbances ofplasmacytoid dendritic cells in systematic lupus
erythematosus. Tsuchida Y, Shoda H, Nakano M,
Ota M, Okamura T, Yamamoto K, Kurano M,
Yatomi Y, Fujio K, Sawada T. Lupus. 2022 Nov;
31(13):1578-1585.
Transcriptome analysis of immune cells from
Behçet's syndrome patients: the importance of
IL-17-producing cells and antigen-presenting
cells in the pathogenesis of Behçet's syndrome.
Okubo M, Sumitomo S, Tsuchida Y, Nagafuchi
Y, Takeshima Y, Yanaoka H, Shirai H,
Kobayashi S, Sugimori Y, Maeda J, Hatano H,
Iwasaki Y, Shoda H, Okamura T, Yamamoto K,
Ota M, Fujio K. Arthritis Res Ther. 2022 Aug
8;24(1):186.
Predominant mesangial IgM, C3, and λ lightchain depositions and interstitial nephritis in apatient with overlap syndrome and positivity for
anti-mitochondrial M2 antibody: a case report.
Yamada S, Kanda H, Abe H, Domoto YS,
Yoshida R, Harada H, Kubo K, Ushiku T, Fujio
K. Mod Rheumatol Case Rep. 2022 Jan 7;6(1):124-127.
Rheumatoid arthritis in a patient with compound
heterozygous variants in the COL11A2 gene andprogressive hearing loss: A case report. Tsuchida
Y, Nagafuchi Y, Uehara T, Suzuki H, Yamada M,
Kono M, Hatano H, Shoda H, Fujio K, Kosaki K.
Medicine (Baltimore). 2022 Feb 18;101(7):e28828.

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Department of Infectious
Diseases (Internal Medicine)
Professor
Takeya Tsutsumi, M.D., Ph.D.

Associate Professor
Shu Okugawa, M.D., Ph.D.

Assistant Professor
Koh Okamoto, M.D., Ph.D.

Daisuke Jubishi, M.D., Ph.D.

Hideki Hashimoto, M.D.,

Ph.D.

Homepagehttps://plaza.umin.ac.jp/utid/index.html

Introduction and Organization
The Department of Infectious Diseases has been
one of the leading academic organizations specialized
for internal medicine, in particular, infectious disease
medicine in Japan since 1998, when the Departmentsof Internal Medicine, established in 1890, wererearranged into new ones according to subspecialty ofinternal medicine. Our department has been chiefly
engaged in clinical, educational and research activities
for infectious diseases including bacterial, fungal andviral infections of all organs including HIV infection,
tuberculosis and viral hepatitis. Our department islocated on 13th floor of the University of Tokyo
Hospital Building and has well-furnished researchlaboratories including P-2 class laboratory, andcomputer rooms as own properties. In clinical andresearch activities, we are collaborating with the
Department of Infection Control and Prevention. One
professor, one associate professor, three assistantprofessors, some residents and full-time staff members
are all performing their own duties in clinical,
educational and research activities.

Clinical activities
We have hospital beds on the 13th floor of the Ward
A of University of Tokyo Hospital. Diseases include

HIV infection, viral hepatitis, pneumonia, drugresistant bacteria infections or tuberculosis, EBV
infection, CMV infection, parasite infection, sexualtransmitted infection, etc. Every effort is made to givepatients the best care and best quality of life. Assistantassociates and residents take care of inpatients. The
case presentation by residents is held every day.
Weekly clinical conference is held to discuss all cases,in particular, those with clinical problems difficult tobe solved. Consultations are very frequent from otherdepartments on the management of infectious diseases.
The general diagnostic, therapeutic plans anddecisions for each patient are given at the Professor’s
round.
Our department offers out-patient care everyday on
infectious diseases and general medicine. We are also
engaged in infection control and prevention of
emerging infectious diseases with the department of
infection control and prevention.

Teaching activities
Our department takes a part in clinical lectures andbed-side learning (clinical clerkship) of the internal
medicine for undergraduate medical students
according to the educational programs of the
University of Tokyo. For the fourth year medical

176

students, six lectures of infectious diseases are given.
In addition, principles of medical diagnosis are taught
at the bedside. During the clinical clerkship for fifthand sixth year students, our associates teach them on
man-to man basis the basic way of thinking for correct
diagnosis and therapy, the techniques of interrogationand physical examination, the way for interpretationsof laboratory tests and other medical examinations,and the basic medical procedures on each case. The
education of junior residents and fellows is performed
as described in “Clinical Activities”.

7) 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.
8) Clinical research on COVID-19.

Publications
1.

Research activities
Both clinical and basic research are necessary to
improve the diagnosis and treatment to infectious
diseases. The members of our department are doing
best to obtain new findings using highly sophisticatedmethodologies. A intramural research conference isheld, in which some members present their annual
research progresses to be discussed by all the
department staff. In addition, each laboratory holds its
own conference and/or journal club on a weekly or
bi-weekly basis.
The research field covers wide areas of infectious
diseases including HIV infection, viral hepatitis andhepatocarcinogenesis, and bacterial infection. Also,
various emerging and re-emerging infectious diseases
are covered. Following themes are currently being
investigated in the department.
1) Establishment of effective therapy for HCV and
HBV infection: we have made a great contribution
in the establishment of the guideline for treatmentof hepatitis viral infection in Japan.
2) 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.
3) Epidemiological study of infectious diseases by
various pathogens.
4) 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.
5) Pathogenesis of Escherichia coli infection.
6) Pathogenesis of Clostridioides difficile infection

2.

3.

4.

5.

Takashita E, Yamayoshi S, Halfmann P, Wilson N,
Ries H, Richardson A, Bobholz M, Vuyk W,
Maddox R, Baker DA, Friedrich TC, O'Connor
DH, Uraki R, Ito M, Sakai-Tagawa Y, Adachi E,
Saito M, Koga M, Tsutsumi T, IwatsukiHorimoto K, Kiso M, Yotsuyanagi H, Watanabe S,
Hasegawa H, Imai M, Kawaoka Y. In Vitro
Efficacy of Antiviral Agents against Omicron
Subvariant BA.4.6. N Engl J Med. 2022;387:
2094.
Adachi E, Saito M, Koga M, Tsutsumi T,
Yotsuyanagi H. Favorable Outcome Following
Sotrovimab Monoclonal Antibody in a Patientwith Prolonged SARS-CoV-2 Omicron Infection
with HIV/AIDS. Intern Med. 2022;61:3459
Yamaoka Y, Sasai M, Suehiro Y, Hashimoto S,
Goto A, Yamamoto N, Suzuki N, Higaki S, Fujii I,
Suzuki C, Matsumoto T, Hoshida T, Koga M,
Tsutsumi T, Lim LA, Matsubara Y, Tomochika S,
Yoshida S, Hazama S, Yotsuyanagi H, Nagano H,
Sakaida I, Takami T, Yamasaki T. Comparison of
two primer-probe sets of Fusobacterium
nucleatum using droplet digital polymerase chain
reaction for the detection of colorectal neoplasia
from faecal samples. Ann Clin Biochem. 2022;
59:396.
Nagai H, Saito M, Adachi E, Sakai-Tagawa Y,
Yamayoshi S, Kiso M, Kawamata T, Koga M,
Kawaoka Y, Tsutsumi T, Yotsuyanagi H.
Casirivimab/Imdevimab for Active COVID-19
Pneumonia Which Persisted for Nine Months in a
Patient with Follicular Lymphoma during
Anti-CD20 Therapy. Jpn J Infect Dis. 2022;75:
608.
Mizutani T, Ishizaka A, Koga M, Tsutsumi T,
Yotsuyanagi H. Role of Microbiota in Viral
Infections and Pathological Progression. Viruses.
2022;14:950.

177

6.

Halfmann PJ, Kuroda M, Armbrust T, Theiler J,
Balaram A, Moreno GK, Accola MA,
Iwatsuki-Horimoto K, Valdez R, Stoneman E,
Braun K, Yamayoshi S, Somsen E, Baczenas JJ,
Mitamura K, Hagihara M, Adachi E, Koga M,
McLaughlin M, Rehrauer W, Imai M, Yamamoto
S, Tsutsumi T, Saito M, Friedrich TC, O'Connor
SL, O'Connor DH, Gordon A, Korber B,
Kawaoka Y. Characterization of the SARS-CoV-2
B.1.621 (Mu) variant. Sci Transl Med. 2022;14:
eabm4908.
7. Uraki R, Kiso M, Iida S, Imai M, Takashita E,
Kuroda M, Halfmann PJ, Loeber S, Maemura T,
Yamayoshi S, Fujisaki S, Wang Z, Ito M, Ujie M,
Iwatsuki-Horimoto K, Furusawa Y, Wright R,
Chong Z, Ozono S, Yasuhara A, Ueki H,
Sakai-Tagawa Y, Li R, Liu Y, Larson D, Koga M,
Tsutsumi T, Adachi E, Saito M, Yamamoto S,
Hagihara M, Mitamura K, Sato T, Hojo M,
Hattori SI, Maeda K, Valdez R; IASO study
team; Okuda M, Murakami J, Duong C, Godbole
S, Douek DC, Maeda K, Watanabe S, Gordon A,
Ohmagari N, Yotsuyanagi H, Diamond MS,
Hasegawa H, Mitsuya H, Suzuki T, Kawaoka Y.
Characterization and antiviral susceptibility of
SARS-CoV-2 Omicron BA.2. Nature. 2022;607:
119.
8. Adachi E, Nagai E, Saito M, Isobe M, Konuma T,
Koga M, Tsutsumi T, Nannya Y, Yotsuyanagi H.
Anti-spike protein antibody titer at the time ofbreakthrough infection of SARS-CoV-2 omicron.
J Infect Chemother. 2022;28:1015.
9. Mizutani T, Ishizaka A, Koga M, Ikeuchi K, Saito
M, Adachi E, Yamayoshi S, Iwatsuki-Horimoto K,
Yasuhara A, Kiyono H, Matano T, Suzuki Y,
Tsutsumi T, Kawaoka Y, Yotsuyanagi H.
Correlation Analysis between Gut Microbiota
Alterations and the Cytokine Response inPatients with Coronavirus Disease during
Hospitalization. Microbiol Spectr. 2022;10:e0168921.
10. Adachi E, Saito M, Nagai H, Ikeuchi K, Koga M,
Tsutsumi T, Yotsuyanagi H. Transient depletionof T cells during COVID-19 and seasonal
influenza in people living with HIV. J Med Virol.
2022;94:1789

11. Koga M, Senkoji T, Kubota M, Ishizaka A,
Mizutani T, Sedohara A, Ikeuchi K, Kikuchi T,
Adachi E, Saito M, Koibuchi T, Hosomichi K,
Ohashi J, Kawana- Tachikawa A, Matano T,
Tsutsumi T (corresponding author), Yotsuyanagi
H. Predictors associated with a better response to
the Japanese aluminum-free hepatitis A vaccine,
Aimmugen®, for people living with HIV.
Hepatol Res. 2022;52:227
12. Ikeuchi K, Okushin K, Saito M, Adachi E,
Tsutsumi T, Takura T, Yotsuyanagi H. Prevalenceof HIV infection among non-elderly individuals
with hepatitis C in Japan: a population-based
cohort study using a health insurance claim data.
BMC Infect Dis. 2022;22:167.
13. Sekiba K, Otsuka M, Funato K, Miyakawa Y,
Tanaka E, Seimiya T, Yamagami M, Tsutsumi T,
Okushin K, Miyakawa K, Ryo A, Koike K.
HBx-induced degradation of Smc5/6 complex
impairs homologous recombination-mediatedrepair of damaged DNA. J Hepatol. 2022;76:53.
14. Kurano M, Okamoto K, Jubishi D, Hashimoto H,
Sakai E, Saigusa D, Kano K, Aoki J, Harada S,
Okugawa S, Doi K, Moriya K, Yatomi Y.
Dynamic modulations of sphingolipids andglycerophospholipids in COVID-19. Clin Transl
Med. 2022;12:e1069.
15. Kurano M, Jubishi D, Okamoto K, Hashimoto H,
Sakai E, Morita Y, Saigusa D, Kano K, Aoki J,
Harada S, Okugawa S, Doi K, Moriya K, Yatomi
Y. Dynamic modulations of urinary sphingolipid
and glycerophospholipid levels in COVID-19 andcorrelations with COVID-19-associated kidney
injuries. J Biomed Sci. 2022;29:94.
16. Yamaguchi R, Yamamoto T, Okamoto K,
Tatsuno K, Ikeda M, Tanaka T, Wakabayashi Y,
Sato T, Okugawa S, Moriya K, Suzuki H.
Prospective audit and feedback implementation
by a multidisciplinary antimicrobial stewardshipteam shortens the time to de-escalation ofanti-MRSA agents. PLoS One. 2022;17:e0271812.
17. Yamamoto S, Ikeda M, Ohama Y, Sunouchi T,
Hoshino Y, Ito H, Yamashita M, Kanno Y,
Okamoto K, Yamagoe S, Miyazaki Y, Okugawa
S, Fujishiro J, Moriya K. Aureobasidium
melanigenum
catheter-related
bloodstream

178

infection: a case report. BMC Infect Dis. 2022;
22:335.
18. Ito H, Okamoto K, Ariyoshi T, Yamamoto S,
Yamashita M, Kanno Y, Ikeda M, Okugawa S,
Moriya K. Neisseria meningitidis serogroup
W135 in a traveler visiting Japan from Argentina,
2019. J Infect Chemother. 2022;28:1180.
19. Jubishi D, Okamoto K, Hamada K, Ishii T,
Hashimoto H, Shinohara T, Yamashita M,
Wakimoto Y, Otani A, Hisasue N, Ikeda M,
Harada S, Okugawa S, Moriya K, Yanagimoto S.
The association between adverse reactions andimmune response against SARS-CoV-2 spike
protein after vaccination with BNT162b2 among
healthcare workers in a single healthcare system:a prospective observational cohort study. Hum
Vaccin Immunother. 2022;18:2048559.
20. Kitaura S, Okamoto K, Wakabayashi Y, Okada Y,
Okazaki A, Ikeda M, Okugawa S, Fujimoto F,
Bujo C, Minatsuki S, Tsushima K, Chikamatsu K,
Mitarai S, Moriya K. A Cold-Blooded Tiptoer:
Nonresolving Cellulitis in an Immunocompromised Patient. Open Forum Infect Dis.
2022;9:ofac074.
21. Jin C, Wakimoto Y, Ikeda M, Ohama Y, Ri M,
Yamashita H, Ohtani A, Yamashita M, Shinohara
T, Jubishi D, Kanno Y, Okamoto K, Higurashi Y,
Harada S, Okugawa S, Seto Y, Moriya K. Humanabdominal abscess caused by Necropsobacterrosorum and tips for its identification: A casereport. J Infect Chemother. 2022;28:833.
22. Morita Y, Kurano M, Jubishi D, Ikeda M,
Okamoto K, Tanaka M, Harada S, Okugawa S,
Moriya K, Yatomi Y. Urine sediment findings
were milder in patients with COVID-19associated renal injuries than in those with
non-COVID-19-associated renal injuries. Int J
Infect Dis. 2022;117:302.
23. Yamashita M, Ikeda M, Kato I, Ohama Y, Ando
M, Ikemura M, Jubishi D, Kanno Y, Okamoto K,
Umeyama T, Nakamura S, Miyazaki Y, Okugawa
S, Moriya K. Protothecosis in the mucosa of thepharynx mimicking pharyngeal cancer in an
immunocompetent individual: a case report. Ann
Clin Microbiol Antimicrob. 2022;21:5.
24. Yamaguchi R, Okamoto K, Yamamoto T, Harada
S, Tanaka T, Suzuki H, Moriya K. Impact oftargeted intervention using a collaborative
approach for oral thirdgeneration
cephalosporins: An interrupted time-series
analysis. Antimicrob
Steward Healthc
Epidemiol. 2022;2:e115.
25. Shimura T, Kurano M, Okamoto K, Jubishi D,
Hashimoto H, Kano K, Igarashi K, Shimamoto
S, Aoki J, Moriya K, Yatomi Y. Decrease inserum levels of autotaxin in COVID-19 patients.
Ann Med. 2022;54:3189.
26. Kitaura S, Jindai K, Okamoto K. Japan
perspective on antimicrobial stewardship andsolid organ transplantation. Transpl Infect Dis.
2022;24:e13939.
27. Kanematsu A, Okamoto K, Nakagawa N, Sonoda
H, Moriya K. Identification of Odoribacter
splanchnicus bacteremia using MALDI-TOF
mass spectrometry and 16S rRNA sequencing:A case report. Anaerobe. 2022;78:102663.
28. Ohama Y, Nomura Y, Mizoguchi M, Higurashi Y,
Okamoto K, Harada S. Accurate Identificationof Klebsiella variicola by MALDI-TOF Mass
Spectrometry inClinical Microbiology
Laboratories. Microbiol Spectr. 2022;10:e0284422.
29. Kurano M, Ohmiya H, Kishi Y, Okada J, Nakano
Y, Yokoyama R, Qian C, Xia F, He F, Zheng L,
Yu Y, Jubishi D, Okamoto K, Moriya K, Kodama
T, Yatomi Y. Measurement of SARS-CoV-2
Antibody Titers Improves the Prediction
Accuracy of COVID-19 Maximum Severity by
Machine Learning in Non-Vaccinated Patients.
Front Immunol. 2022;13:811952.
30. Beppu H, Fukuda T, Kawanishi T, Yasui F, Toda
M, Kimura H, Nakamura Y, Nakamura Y,
Kojima K, Ogawa H, Ishiwatari A, Kamei Y,
Ogawa T, Abe Y, Endo M,
Hanawa T,
Mizobuchi R, Sugita C, Okamoto K, Hatakeyama
S, Yamada T, Kohara M,
Wakai S.
Hemodialysis patients with coronavirus disease
2019: reduced antibody response. Clin Exp
Nephrol. 2022;26:170.
31. Kato S, Nakano Y, Nakano Y, Okamoto K,
Takasugi N, Hidaka M, Sekiguchi M, HiwatariM, Kurano M, Kato M. COVID-19 in anadolescent with aplastic anemia undergoing
immunosuppressive therapy: A case report and179details of antibody testing for SARS-CoV-2.
Pediatr Blood Cancer. 2022 ;69:e29332.
32. Okamoto K, Yamada N, Suzuki T, Muramatsu T,
Uemura H, Gatanaga H, Kato T, Hatakeyama S.
Emergence of Hepatitis C Virus Genotype 2c
Infection Among Human Immunodeficiency
Virus-Infected Men Who Have Sex With Men inTokyo, Japan. Sex Transm Dis. 2022;49:e29.
33. Nakamura K, Kawakami T, Naraba H, Motoki M,
Ikechi D, Nakano H, Mochizuki M, Takahashi
Y, Hashimoto H. Impact of oligomeric enteralnutrition with low-molecular-weight whey
peptides on diarrhea in critical care nutrition. J
Clin Biochem Nutr. 2022;71:255.
34. Yamakawa K, Yamamoto R, Terayama T,
Hashimoto H, Ishihara T, Ishimaru G, Imura H,
Okano H, Narita C, Mayumi T, Yasuda H,
Yamada K, Yamada H, Kawasaki T, Shime N,
Doi K, Egi M, Ogura H, Aihara M, Kushimoto S,
Nishida O; Special Committee of the Japanese
Clinical Practice Guidelines for the Managementof Sepsis and Septic Shock 2020 (J‐SSCG
2020), the COVID‐19 Task Force. Japanese
rapid/living
recommendationson
drugmanagement for COVID-19: updated guidelines(July 2022). Acute Med Surg. 2022;9:e789.
35. Yoshida H, Motohashi T, De Bus L, De Waele J,
Takaba A, Kuriyama A, Kobayashi A, Tanaka
C, Hashi H, Hashimoto H, Nashiki H, Shibata M,
Kanamoto M, Inoue M,
Hashimoto S,
Katayama S, Fujiwara S, Kameda S, Shindo S,
Suzuki T, Komuro T, Kawagishi T, Kawano Y,
Fujita Y, Kida Y, Hara Y, Fujitani S; DIANA
Study Japanese group. Use of broad-spectrum
antimicrobials for more than 72 h and thedetection of multidrug-resistant bacteria inJapanese intensive care units: a multicenter
retrospective cohort study. Antimicrob Resist
Infect Control. 2022;11:119.
36. Nakano H, Hashimoto H, Mochizuki M, Naraba
H, Takahashi Y, Sonoo T, Nakamura
K.
Evaluation of Intravascular Volume Using theInternal Jugular Vein Cardiac Collapse Index in
the Emergency Department: A Preliminary
Prospective Observational Study. Ultrasound
Med Biol. 2022;48:1169.

37. Kanda N, Nakano H, Naraba H, Kawasaki A,
Ohno N, Yoshikawa Y, Sakuramoto H,
Takahashi Y, Sonoo T, Hashimoto H, Nakamura
K. The efficacy and safety of nurse- initiatedsedation management in an intensive care unit: A
two-phase prospective study in Japan. Jpn J
Nurs Sci. 2022;19:e12486.
38. Ikechi D, Hashimoto H, Nakano H, Nakamura K.
A Case of Suspected COVID-19 Vaccinerelated Thrombophlebitis. Intern Med. 2022;61:
1631.
39. Naraba H, Goto T, Tokuda M, Sonoo T, Nakano
H, Takahashi Y, Hashimoto H, Nakamura K.
Accuracy and Stability of a Subcutaneous Flash
Glucose Monitoring System in Critically Ill
Patients. J Diabetes Sci Technol. 2022;16:1128.
40. Yoshida M, Matsuda K, Endo K, Honda A, Maki
H, Taoka K, Masamoto Y, WakimotoY,
Jubishi D, Moriya K, Kurokawa M. Toxic shock
like syndrome caused by
Streptococcus
agalactiae bacteremia during treatment for
multiple myeloma. J Infect Chemother. 2023;
29:407.
41. Okuda M, Sakai-Tagawa Y, Koga M, Koibuchi T,
Kikuchi T, Adachi E, Ahyoung Lim
L,
Yamamoto S, Yotsuyanagi H, Negishi K, Jubishi
D, Yamayoshi S, Kawaoka Y. Immunological
Correlates of Prevention of the Onset of Seasonal
H3N2 Influenza. J Infect Dis. 2022;226:1800.
42. Kurano M, Morita Y, Nakano Y, Yokoyama R,
Shimura T, Qian C, Xia F, He F, Zheng L,
Ohmiya H, Kishi Y, Okada J, Yoshikawa N,
Nakajima K, Nagura Y, Okazaki H, Jubishi D,
Moriya K, Seto Y, Yasui F, Kohara M, Wakui M,
Kawamura T, Kodama T, Yatomi Y. Response
kinetics of different classes of antibodies to
SARS-CoV2
infection in the Japanese
population: The IgA and IgG titers increased
earlier
than
the
IgM
titers.
Int
Immunopharmacol. 2022;103:108491.
43. Yoshimura J, Yamakawa K, Ohta Y, Nakamura K,
Hashimoto H, Kawada M, Takahashi H,
Yamagiwa T, Kodate A, Miyamoto K, Fujimi S,
Morimoto T. Effect of Gram Stain-Guided Initial
Antibiotic Therapy on Clinical Response inPatients With Ventilator-Associated Pneumonia:

180

The GRACE-VAP Randomized Clinical Trial.
JAMA Netw Open. 2022;5:e226136.
44. Kanda N, Hashimoto H, Suzuki T, Nakamura K.
Performance of the new FilmArray Blood Culture
Identification 2 panel and its potential impact on
clinical use in patients with Gram-negative
bacteremia. J Infect Chemother. 2022;28:1037.

181

Department of Stress Science andPsychosomatic Medicine
Associate Professor
Kazuhiro Yoshiuchi, M.D., Ph.D.

Associate
Makoto Otani, M.D., Ph.D.

Research Associate
Tadahiro Yamazaki, M.D.

Homepagehttps://plaza.umin.ac.jp/~psmut/

Introduction and Organization
The Department of Stress Science andPsychosomatic Medicine is one of 11 divisions of the
Department of Internal Medicine, the University ofTokyo. It covers eating disorder, panic disorder, andvarious psychosomatic diseases such as chronicheadache, irritable bowel syndrome, functional
dyspepsia, hypertension, diabetes mellitus, andhyperthyroidism. Our teaching staff consists of one
associate professor, one associate, one research
associate, and 5 adjunct professors, and othermembers are 2 senior residents, 13 graduate students,and 5 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 2022 April to 2023 March, overall 2,464
patients (89 individuals) were admitted to the ward,
most of whom were eating disorder patients.
Outpatient clinic is attended on every morning andafternoon in three consultation rooms by approximate-ly fifteen physicians. During 2022 April to 2023
March, the numbers of the new outpatients and of theoverall outpatients in our department were 149 and
4,807, 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 one-on-one
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

182

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.

2.

3.

4.

5.

6.
Thirteen graduate students and 5 researchers
actively conducted their researches along with our
teaching staff. We have been also collaborating withmany scientists belonging to other departments either
in Japan or abroad. Research conferences are held
once a month, where one of the graduate students
presents his/her research for open discussion by all themembers of our department.

7.

References
1.

Takeuchi H, Suwa K, Kishi A, Nakamura T,
Yoshiuchi K, Yamamoto Y. The effects ofobjective push-type sleep feedback on habitual
sleep behavior and momentary symptoms in daily
life: mobile health intervention trial using ahealthcare IoT system. JMIR mHealth and8.

uHealth 2022;10(10):e39150
Yokomichi N, Maeda I, Morita T, Yoshiuchi K,
Ogawa S, Hisanaga T, Sakashita A, Nakahara R,
Kaneishi K, Iwase S. Association of
antipsychotic dose with survival of advanced
cancer patients with delirium Journal of Pain and
Symptom Management. J Pain Symptom Manage2022;64(1):28–36
Matsumoto Y, Umemura S, Okizaki A, Fujisawa
D, Kobayashi N, Tanaka Y, Sasaki C, Shimizu K,
Ogawa A, Kinoshita H, Uchitomi Y, Yoshiuchi K,
Matsuyama Y, Motira T, Goto K, Ohe Y. Early
specialized palliative care for patients withmetastatic lung cancer receiving chemotherapy: A
feasibility study of a nurse-led screeningtriggered program. Jap J Clin Oncol 2022;52:
375-382
Yoshikawa E, Fujisawa D, Hisamura K,
Murakami Y, Okuyama T, Yoshiuchi K. The
potential role of peer support interventions intreating depressive symptoms in cancer patients.
J Nippon Med Sch 2022;89:16-23
Inoue S, Maeda I, Ogawa A, Yoshiuchi K, Terada
S, Yamada N. Safety and effectiveness of
perospirone in comparison to risperidone fortreatment of delirium in patients with advanced
cancer: A multicenter prospective observational
study in real-world psycho-oncology settings.
Acta Medica Okayama 2022;76(2):195-202
Kurisu K, Fujimori M, Harashima S, Akechi T,
Matsuda T, Saika K, Yoshiuchi K, Miyashiro I,
Uchitomi Y. Suicide, other externally caused
injuries, and cardiovascular disease within two
years after cancer diagnosis: a nationwide
population-based study in Japan (J-SUPPORT1902). Cancer Med. 2023;12(3):3442-3451
Kurisu K, Hashimoto M, Ishizawa T, Shibayama
O, Inada S, Fujisawa D, Inoguchi H, Shimoda H,
Inoue S, Ogawa A, Akechi T, Shimizu K,
Uchitomi Y, Matsuyama Y, Yoshiuchi K.
Development of computer adaptive testing formeasuring depression in patients with cancer. Sci
Rep. 2022;12(1):8247
Miyamoto S, Yamazaki T, Shimizu K, Matsubara
T, Kage H, Watanabe K, Kobo H, Matsuyama Y,
Rodin G, Yoshiuchi K. Brief, manualised andsemistructured
individual
psychotherapy

183

programme for patients with advanced cancer inJapan: study protocol for Managing Cancer and
Living Meaningfully (CALM) phase 2 trial. BMJ
Open. 2022;12(3):e056136
9. Kurisu K, Matsuoka M, Sato K, Hattori A,
Yamanaka Y, Nohara N, Otani M, Yoshiuchi K.
Increased prevalence of eating disorders in Japan
since the start of the COVID-19 pandemic.
Eating and Weight Disorders 2022;27:2251–2255
10. Sakamoto R, Ohtake Y, Kataoka Y, Matsuda Y,
Hata T, Otonari J,Yamane A, Matsuoka H,
Yoshiuchi K. The efficacy of acceptance &commitment therapy for type 2 diabetes: asystematic review and meta-analysis. J Diabetes
Investig 2022;13(2):262–270
11. Kurisu K, Inada S, Maeda I, Ogawa A, Iwase S,
Akechi T, Motita T, Oyamada S, Yamaguchi T,
Imai K, Nakahara R, Kaneishi K, Nakajima N,
Sumitani M, Yoshiuchi K*. A decision tree
prediction model for a short-term outcome ofdelirium in patients with advanced cancer
receiving pharmacological interventions: asecondary analysis of a multicenter andprospective observational study (Phase-R).
Palliat Support Care 2022;20(2):153-158

Internal Medicine
3. Clinical Laboratory Medicine
and Pathology

185

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

Lecturer
Toshiyuki Ikeda, M.D., Ph.D.

Research Associate
Toshiya Hino, M.D., Ph.D., Takahiro Hongo, M.D., Ph.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

186

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
1) 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 immunology, 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.

187

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.

References
1.

Summary" by Cardigan, Rebecca; New, Helen;
Estcourt, Lise; Zhiburt, Eugene; Dubey, Rounak;
Bengtsson, Jesper; Jöud, Magnus; Castillo,
Carlos; Cid, Joan; Lozano, Miquel; Gounder,
Dhana; Flanagan, Peter; Morley, Sarah; Clarke,
Gwen; Devine, Dana; Hindawi, Salwa; Al Otaibi,
Aqeel; Bub, Carolina; Kutner, Jose; Ikeda,
Toshiyuki; Goto, Naoko; Okazaki, Hitoshi;
Fontaine , Magali; Pasion, Jeremiah; Song,
Linda; Latham, Tom; Kerkhoffs, Jean-Louis; De
Haas, Masja; Zwaginga, Jaap Jan; Gathof, Birgit;
Ommer, Katharina; Pirenne, France; Raba,
Michel; François, Anne; Daly, James; Powley,
Tanya ; Dunbar, Nancy, International Forum on
Policies and Practice for Transfusion of ABO andRhD Non-identical Platelets: Vox Sang 2022
Jan;117(1):136-144.
2. Kazutoshi Ebisawa, Akira Honda, Arika Chiba,
Yosuke Masamoto, Hitoshi Okazaki. and Mineo
Kurokawa
High D-index during mobilization predicted
lower collection of CD34+ cells afteranti-lymphoma salvage chemotherapy J Clin
Apher 2022 Feb;37(1):4-12.
3. Makoto Kurano , Yoshifumi Morita, Yuki Nakano,
Rin Yokoyama, Takuya Shimura , Chungen Qian ,Fuzhen Xia , Fan He, Liang Zheng , Hiroko
Ohmiya, Yoshiro Kishi, Jun Okada, Naoyuki
Yoshikawa, Kazuki Nakajima, Yutaka Nagura,
Hitoshi Okazaki, Daisuke Jubishi, Kyoji Moriya,
Yasuyuki Seto, Fumihiko Yasui, Michinori
Kohara, Masatoshi Wakui, Takeshi Kawamura,
Tatsuhiko Kodama, Yutaka Yatomi
Response kinetics of different classes of antibodies to
SARS-CoV2 infection in the Japanese
population: The IgA and IgG titers increased
earlier than the IgM titers Int Immunopharmacol
2022 Feb;103:108491.

4.

Ikeda T, Terada R, Nagura Y, Okazaki H
High-dose intravenous iron supplementation after
preoperative autologous blood donation is usefulto prevent post-donation/preoperative anemia
Transfus Apher Sci. 2022 Jun;61(3):103348.

Reproductive, Developmental andAging Sciences
1. Obstetrics and Gynecology

189

Department of
Reproductive Endocrinology
Professors
Yutaka Osuga

Homepage http://www.h.u-tokyo.ac.jp/patient/depts/a_joseika02/index.html#reproduction
https://www.gynecology-htu.jp/
Organization
The Department of Reproductive Endocrinology isorganized by Assistant Professors Takeshi Nagamatsu.
All the staff members are taking part in both clinicaland research activities. For the clinical aspect, we areengaged with in-patient and out-patient care including
the activities in the delivery units.

Activities
In clinical section, we have an out-patient clinic for
infertility, gynecological endocrine diseases, genetic
counseling and assisted reproductive technologies(ART).
We have a highly organized infertility clinic, where
every patient is systemically examined and after diagnosis of underlying infertility factor (s) appropriate
treatment is performed following our protocol. Once itturns out that higher level of treatment is necessary,
ART is applied to such cases. We have been engaged
in in vitro fertilization and embryo transfer (IVF-ET)
as a main axis of ART for twenty years. Conventional
IVF-ET is mainly indicated to cases with tubal factor,
mild male factor, immunological factor or of
unexplained infertility factor. In case of severe male
factor or other fertilization disorder intracytoplasmic
sperm injection (ICSI) is performed. Now we haveabout 220 OPU cycles of IVF-ET every year, whichconventional IVF-ET and ICSI share almost equally.
The clinical pregnancy rate of conventional IVF-ET isaround 30% per embryo transfer cycle, which iscomparable with that of ICSI. Other ART techniquessuch as embryo cryopreservation and assisted hatching
are also performed.
In basic research section, a couple of projects asfollows are under way, some of which have alreadyyielded interesting findings; 1) the mechanism offolliculogenesis and follicular apoptosis in the ovary,2) the functions of gynecologic hormones such as
gonadotropins and ovarian steroids, 3) the analysis /etiology of endometriosis, adenomyosis and fibroma
and so on.

References published in 2022
1.

2.

3.

Hosoya S, Piedvache A, Nakamura A, Nasu R,
Hine M, Itoi S, Yokomizo R, Umezawa A,
Hiraike O, Koga K, Osuga Y, Narumi S,
Morisaki N. Prolongation of the Menstrual Cycle
After Receipt of the Primary Series and Booster
Doses of mRNA Coronavirus Disease 2019
(COVID-19) Vaccination. Obstet Gynecol. 2023
Dec 14.
Hiratsuka D, Omura E, Ishizawa C, Iida R, Fukui
Y, Hiraoka T, Akaeda S, Matsuo M, Harada M,
Wada-Hiraike O, Osuga Y, Hirota Y. Pregnancy
is associated with reduced progression ofsymptomatic adenomyosis: a retrospective pilot
study. BMC Pregnancy Childbirth. 2023 Sep
4;23(1):634.
Hiraike O, Koga K, Taniguchi F, Harada T,
Takeshita T, Shiota M, Osuga Y. A nationwide
survey of the use of the laparoscopic power

190

morcellator.; Laparoscopic power morcellator
Research Committee in Japan Society of
Gynecologic and Obstetric Endoscopy and
Minimally Invasive Therapy (JSGOE). J Obstet
Gynaecol Res. 2023 Feb;49(2):682-690
4. Uehara M, Hiraike O, Hirano M, Harada M,
Koga K, Yoshimura N, Tanaka S, Osuga Y.
Evaluation of atherosclerosis-related biomarkers
during perimenopause: A prospective cohort
study in women with endometriosis. J Obstet
Gynaecol Res. 2022 Dec;48(12):3160-3170
5. Harada T, Taniguchi F, Kitajima M, Kitawaki J,
Koga K, Momoeda M, Mori T, Murakami T,
Narahara H, Osuga Y, Yamaguchi K. Clinicalpractice guidelines for endometriosis in Japan(The 3rd edition). J Obstet Gynaecol Res. 2022
Dec;48(12):2993-3044.
6. Maeda E, Hiraike O, Sugimori H, Kinoshita A,
Hirao M, Nomura K, Osuga Y. Working
conditions contribute to fertility-related quality oflife: a cross-sectional study in Japan. Reprod
Biomed Online. 2022 Dec;45(6):1285-1295.
7. Ishizawa C, Hirota Y, Iida R, Kaku T, Hirata T,
Fukui Y, Omura E, Akaeda S, Hiraoka T, Matsuo
M,
Osuga
Y.
Levonorgestrel-Releasing
Intrauterine System Improves MenorrhagiaRelated Quality of Life in Patients with
Symptomatic Adenomyosis.Reprod Sci. 2023
Mar;30(3):966-973. doi: 10.1007/s43032-02201077-9. Epub 2022 Sep 7.PMID: 36071343
8. Uehara M, Wada-Hiraike O, Koga K, Yamamoto
N, Hirano M, Harada M, Hirota Y, Osuga Y.
Prediction of the final menstrual period in womentaking Dienogest using estradiol and folliclestimulating hormone values: a case-control study.
Endocr J. 2022 Dec 28;69(12):1437-1445.
9. Iwata M, Oikawa Y, Shimizu Y, Sakashita N,
Shoji A, Igarashi A, Osuga Y. Efficacy of
Low-Dose Estrogen-Progestins and Progestins inJapanese Women with Dysmenorrhea: A
Systematic Review and Network Meta-analysis.
Adv Ther. 2022 Nov;39(11):4892-4909.
10. Yamada M, Ishikawa T, Iwasa T, Oishi H, Osuka
S, Oka K, Ono S, Ono M, Orisaka M, Kanasaki H,
Kawano Y, Kawamura K, Kishi H, Kimura F,
Kuroda S, Kuwahara A, Kobayashi H, Komiya A,
Saito H, Sato K, Sato S, Shiraishi K, Shirasawa H,

11.

12.

13.

14.

15.

16.

Suzuki T, Takai Y, Takae S, Takahashi T,
Takiuchi T, Tachibana M, Tamura I, Tamura H,
Jwa SC, Baba T, Harada M, Hirata T, Fukui A,
Fukuda Y, Fukuhara S, Maruyama T, Yumura Y,
Yoshino O, Hirota Y, Tsujimura A, Kuji N,
Osuga Y. Guidelines for Reproductive Medicine
in Japan. Reprod Med Biol. 2022 Aug 24;21(1)Nagashima N, Hirata T, Arakawa T, Neriishi K,
Sun H, Harada M, Hirota Y, Koga K, WadaHiraike O, Osuga Y. Long-term conservative
managementofsymptomatic
bladder
endometriosis: A case series of 17 patients.
Taiwan J Obstet Gynecol. 2022 Jul;61(4):606611.
Takahashi H, Tanaka H, Osuga Y, Miura K, Saito
S, Sato S, Sugawara J, Ide S, Koh I, Yamauchi K,
Okuyama A, Okuno K, Kuwata T, Fujieda S,
Ikeda T. Retained products of conception(RPOC) following delivery without placenta
previa: Which patients with RPOC show
postpartum hemorrhage? Placenta. 2022 Jun 24;
124:12-17.
Uehara M, Wada-Hiraike O, Hirano M, Koga K,
Yoshimura N, Tanaka S, Osuga Y. Relationshipbetween bone mineral density and ovarianfunction and thyroid function in perimenopausal
women with endometriosis: a prospective study.
BMC Womens Health. 2022 Apr 27;22(1):134.
Wada-Hiraike O, Yamada S, Osuga Y. An
extremely rare case of pituitary functioning
gonadotroph microadenoma accompanied by
ovarian hyperstimulation syndrome in a womanof reproductive age. F S Rep. 2022 Feb 3;3(1):79-83.
Katagiri Y, Jwa SC, Kuwahara A, Iwasa T, Ono
M, Kato K, Kishi H, Kuwabara Y, Harada M,
Hamatani T, Osuga Y. Assisted reproductive
technology in Japan: A summary report for 2019by the Ethics Committee of the Japan Society of
Obstetrics and Gynecology. Reprod Med Biol.
2021 Dec 14;21(1)Kunitomi C, Harada M, Sanada Y, Kusamoto A,
Takai Y, Furui T, Kitagawa Y, Yamada M,
Watanabe C, Tsugawa K, Nishiyama H, Hosoi H,
Miyachi M, Sugiyama K, Maeda Y, Kawai A,
Hamatani T, Fujio K, Suzuki N, Osuga Y. The
possible effects of the Japan Society of Clinical191

Oncology Clinical Practice Guidelines 2017 on
the practice of fertility preservation in female
cancer patients in Japan. Reprod Med Biol. 2022
Mar 21;21(1):e12453.
17. Ono M, Matsumoto K, Boku N, Fujii N,
Tsuchida Y, Furui T, Harada M, Kanda Y, Kawai
A, Miyachi M, Murashima A, Nakayama R,
Nishiyama H, Shimizu C, Sugiyama K, Takai Y,
Fujio K, Morishige KI, Osuga Y, Suzuki N.
Correction
to:Indications
forfertility
preservation not included in the 2017 Japan
Society of Clinical Oncology Guideline for
Fertility Preservation in Pediatric, Adolescent,and Young Adult Patients treated with gonadal
toxicity, including benign diseases. Int J Clin
Oncol. 2022 Apr;27(4):825-826.
18. Tozawa A, Kimura F, Takai Y, Nakajima T,
Ushijima K, Kobayashi H, Satoh T, Harada M,
Sugimoto K, Saji S, Shimizu C, Akiyama K,
Bando H, Kuwahara A, Furui T, Okada H, Kawai
K, Shinohara N, Nagao K, Kitajima M, Suenobu
S, Soejima T, Miyachi M, Miyoshi Y, Yoneda A,
Horie A, Ishida Y, Usui N, Kanda Y, Fujii N,
Endo M, Nakayama R, Hoshi M, Yonemoto T,
Kiyotani C, Okita N, Baba E, Muto M, Kikuchi I,
Morishige KI, Tsugawa K, Nishiyama H, Hosoi
H, Tanimoto M, Kawai A, Sugiyama K, Boku N,
Yonemura M, Hayashi N, Aoki D, Suzuki N,
Osuga Y. Correction to: Japan Society of ClinicalOncology Clinical Practice Guidelines 2017 forfertility preservation in childhood, adolescent,and young adult cancer patients: part 2. Int J Clin
Oncol. 2022 Mar;27(3):635-637.
19. Tozawa A, Kimura F, Takai Y, Nakajima T,
Ushijima K, Kobayashi H, Satoh T, Harada M,
Sugimoto K, Saji S, Shimizu C, Akiyama K,
Bando H, Kuwahara A, Furui T, Okada H, Kawai
K, Shinohara N, Nagao K, Kitajima M, Suenobu
S, Soejima T, Miyachi M, Miyoshi Y, Yoneda A,
Horie A, Ishida Y, Usui N, Kanda Y, Fujii N,
Endo M, Nakayama R, Hoshi M, Yonemoto T,
Kiyotani C, Okita N, Baba E, Muto M, Kikuchi I,
Morishige KI, Tsugawa K, Nishiyama H, Hosoi
H, Tanimoto M, Kawai A, Sugiyama K, Boku N,
Yonemura M, Hayashi N, Aoki D, Suzuki N,
Osuga Y. Japan Society of Clinical Oncology
Clinical Practice Guidelines 2017 for fertility

20.

21.

22.

23.

preservation in childhood, adolescent, and young
adult cancer patients: part 2. Int J Clin Oncol.
2022 Feb;27(2):281-300.
Harada M, Kimura F, Takai Y, Nakajima T,
Ushijima K, Kobayashi H, Satoh T, Tozawa A,
Sugimoto K, Saji S, Shimizu C, Akiyama K,
Bando H, Kuwahara A, Furui T, Okada H, Kawai
K, Shinohara N, Nagao K, Kitajima M, Suenobu
S, Soejima T, Miyachi M, Miyoshi Y, Yoneda A,
Horie A, Ishida Y, Usui N, Kanda Y, Fujii N,
Endo M, Nakayama R, Hoshi M, Yonemoto T,
Kiyotani C, Okita N, Baba E, Muto M, Kikuchi I,
Morishige KI, Tsugawa K, Nishiyama H, Hosoi
H, Tanimoto M, Kawai A, Sugiyama K, Boku N,
Yonemura M, Hayashi N, Aoki D, Osuga Y,
Suzuki N. Japan Society of Clinical Oncology
Clinical Practice Guidelines 2017 for fertility
preservation in childhood, adolescent, and young
adult cancer patients: part 1. Int J Clin Oncol.
2022 Feb;27(2):265-280.
Kuji S, Harada M, Yoshioka N, Kajiyama H,
Satoh T, Mikami M, Shozu M, Enomoto T,
Osuga Y, Suzuki N. Survival and reproductive
outcomes
after
fertility-sparing
surgery
performed for borderline epithelial ovarian tumor
in Japanese adolescents and young adults:
Results of a retrospective nationwide study. J
Obstet Gynaecol Res. 2022 Mar;48(3):806-816.
Harada T, Osuga Y, Suzuki Y, Fujisawa M,
Fukui M, Kitawaki J. Relugolix, an oral
gonadotropin-releasing
hormonereceptor
antagonist, reduces endometriosis-associated pain
compared with leuprorelin in Japanese women: aphase 3, randomized, double-blind, noninferiority
study. Fertil Steril. 2022 Mar;117(3):583-592.
Ono M, Matsumoto K, Boku N, Fujii N,
Tsuchida Y, Furui T, Harada M, Kanda Y, Kawai
A, Miyachi M, Murashima A, Nakayama R,
Nishiyama H, Shimizu C, Sugiyama K, Takai Y,
Fujio K, Morishige KI, Osuga Y, Suzuki N.
Indications for fertility preservation not includedin the 2017 Japan Society of Clinical Oncology
Guideline for Fertility Preservation in Pediatric,
Adolescent, and Young Adult Patients treatedwith gonadal toxicity, including benign diseases.
Int J Clin Oncol. 2022 Feb;27(2):301-309.

192

Department of
Gynecologic Oncology
Associate Professor
Yutaka Osuga, Yasushi Hirota

Homepagehttps://www.gynecology-htu.jp/

Organization
The Department of Gynecologic Oncology isorganized by one professor and one associate
professors, being directed practically by Professor
Yutaka Osuga, the Department of Obstetrics andGynecology. The staff members are taking part inclinical and research activities as well as teachingactivities.

Activities
In the clinical activities, more than 150 patientswith gynecological cancer and more than one
thousand patients with benign gynecological diseases
are treated in our department every year. Appropriate
combinations of surgical treatment, chemotherapy andradiotherapy have been chosen according to thepatients’ conditions, and favorable clinical outcomes
have been achieved. Minimally-invasive surgery isfrequently employed in the treatment of benign andgynecological tumors and genital organ malformation.
We take charge of more than 400 cases of endoscopic
gynecological surgery including robotically-assisted
laparoscopic surgery annually. We also employ theclinical trials of JCOG (Japan Clinical Oncology
Group) and JGOG (Japanese Gynecologic Oncology
Group) as well as the single-institution clinical trials.
Advanced treatment performed in our department is asfollows:(1) Cancer genomic medicine (Genetic tests of thehereditary gynecologic cancers)(2) Radical trachelectomy for women of childbearing
age with early cervical cancer(3) Laparoscopic sacralcolpopexy for pelvic organ
prolapse(4) Adenomyomectomy
Based on our knowledge and experience in thisfield, we also perform clinical, translational and basic
research energetically. Our department focuses on thepathogenesis and the pathophysiology of malignant
gynecological diseases such as cervical, endometrial
and ovarian cancers, and benign diseases such as
endometriosis and adenomyosis. Our ongoing projects
are as follows:(1) Establishment of new therapeutic approachtargeting histone modification enzymes ingynecological malignancies(2) Search for epigenomic biomarkers using deeplearning in gynecological malignancies(3) Development of an automated hysteroscopic
diagnosis system for gynecological diseases using
deep learning(4) Control mechanism of genome stability ingynecological malignancies(5) Search for novel biomarkers using germline andsomatic variants in gynecological cancers(6) Genomic approach to elucidate the pathogenesis
and pathophysiology of endometriosis andadenomyosis(7) Immunological aspects in the pathophysiology ofendometriosis

References published in 2022
1.

Indications for fertility preservation not includedin the 2017 Japan Society of Clinical Oncology

193

2.

3.

4.

5.

6.

Guideline for Fertility Preservation in Pediatric,
Adolescent, and Young Adult Patients treatedwith gonadal toxicity, including benign diseases.
Ono M, Matsumoto K, Boku N, Fujii N,
Tsuchida Y, Furui T, Harada M, Kanda Y, Kawai
A, Miyachi M, Murashima A, Nakayama R,
Nishiyama H, Shimizu C, Sugiyama K, Takai Y,
Fujio K, Morishige KI, Osuga Y, Suzuki N.Int J
Clin Oncol. 2022 Feb;27(2):301-309.
Histone arginine methyltransferase CARM1
selective inhibitor TP-064 induces apoptosis inendometrial cancer. Inoue F, Sone K, Toyohara Y,
Tanimoto S, Takahashi Y, Kusakabe M, Kukita
A, Honjoh H, Nishijima A, Taguchi A,
Miyamoto Y, Tanikawa M, Iriyama T, Uchino
MM, Tsuruga T, Wada-Hiraike O, Oda K, Osuga
Y.Biochem Biophys Res Commun. 2022 Apr 23;
601:123-128.
MED1, a novel binding partner of BRCA1,
regulates homologous recombination and R-loop
processing. Honjoh H, Tanikawa M, WadaHiraike O, Oda K, Inaba H, Kukita A, Kawata Y,
Kusakabe M, Tsuchimochi S, Taguchi A,
Miyamoto Y, Sone K, Tsuruga T, Mori-UchinoM, Matsumoto Y, Osuga Y.Sci Rep. 2022 Oct
13;12(1):17140.
The metabolic stress-activated checkpoint
LKB1-MARK3 axis acts as a tumor suppressor inhigh-grade serous ovarian carcinoma. Machino H,
Kaneko S, Komatsu M, Ikawa N, Asada K,
Nakato R, Shozu K, Dozen A, Sone K, Yoshida
H, Kato T, Oda K, Osuga Y, Fujii T, von Keudell
G, Saloura V, Hamamoto R.Commun Biol. 2022
Jan 11;5(1):39.
Development of a deep learning method for
improving diagnostic accuracy for uterine
sarcoma cases. Toyohara Y, Sone K, Noda K,
Yoshida K, Kurokawa R, Tanishima T, Kato S,
Inui S, Nakai Y, Ishida M, Gonoi W, Tanimoto S,
Takahashi Y, Inoue F, Kukita A, Kawata Y,
Taguchi A, Furusawa A, Miyamoto Y, Tsukazaki
T, Tanikawa M, Iriyama T, Mori-Uchino M,
Tsuruga T, Oda K, Yasugi T, Takechi K, Abe O,
Osuga Y.Sci Rep. 2022 Nov 16;12(1):19612.
Effect of primary prophylaxis with pegfilgrastim
in endometrial cancer patients treated withdoxorubicin and cisplatin. Tojima Y, Taguchi A,

Mori M, Nara K, Miyamoto Y, Tanikawa M,
Sone K, Tsuruga T, Yamamoto T, Oda K, Suzuki
H, Osuga Y.Taiwan J Obstet Gynecol. 2022
Mar;61(2):265-269.
7. Suspicious Positive Peritoneal Cytology (Class
III) in Endometrial Cancer Does Not AffectPrognosis. Sone K, Suzuki E, Taguchi A, Honjoh
H, Nishijima A, Eguchi S, Miyamoto Y, Iriyama
T, Mori M, Osuga Y.J Clin Med. 2022 Nov
3;11(21):6527.
8. Manual vacuum aspiration (women's MVA) for
endometrial biopsy for patients with suspected
endometrial malignancies. Saito E, Matsumoto Y,
Nitta S, Fujino S, Tsuruga T, Mori-Uchino M,
Iwase H, Kasamatsu T, Kugu K, Osuga Y.J
Obstet Gynaecol Res. 2022 Nov;48(11):28962902.
9. Cells with stem-like properties are associatedwith the development of HPV18-positive cervicalcancer. Kusakabe M, Taguchi A, Tanikawa M,
Wagatsuma R, Yamazaki M, Tsuchimochi S,
Toyohara Y, Kawata A, Baba S, Ueno T, Sone K,
Mori-Uchino M, Ikemura M, Matsunaga H,
Nagamatsu T, Wada-Hiraike O, Kawazu M,
Ushiku T, Takeyama H, Oda K, Kawana K,
Mano H, Osuga Y.Cancer Sci. 2023 Mar;114(3):885-895.
10. Genetic diagnosis of pseudomyxoma peritonei
originating from mucinous borderline tumor
inside an ovarian teratoma. Taguchi A, Rokutan
H, Oda K, Tanikawa M, Tanimoto S, Sone K,
Mori M, Tsuruga T, Kohsaka S, Tatsuno K,
Shinozaki-Ushiku A, Miyagawa K, Mano H,
Aburatani H, Ushiku T, Osuga Y.BMC Med
Genomics. 2022 Mar 7;15(1):51.
11. Prognosis of high-risk human papillomavirusrelated cervical lesions: A hidden Markov model
analysis of a single-center cohort in Japan. Ikesu
R, Taguchi A, Hara K, Kawana K, Tsuruga T,
Tomio J, Osuga Y.Cancer Med. 2022 Feb;11(3):664-675.
12. Endometrial
cancerwithconcomitantendometriosis is highly associated with ovarian
endometrioid carcinoma: a retrospective cohort
study. Ishizaka A, Taguchi A, Tsuruga T,
Maruyama M, Kawata A, Miyamoto Y,
Tanikawa M, Ikemura M, Sone K, Mori M, Koga

194

13.

14.

15.

16.

K, Ushiku T, Oda K, Osuga Y.BMC Womens
Health. 2022 Aug 5;22(1):332.
Recurrent malignant melanoma of the uterine
cervix treated with anti-PD-1 antibodies andanti-CTLA-4 antibodies: A case report. Sone K,
Kukita A, Masui Y, Yamada D, ShinozakiUshiku A, Kawata A, Taguchi A, Miyamoto Y,
Tanikawa M, Iriyama T, Mori-Uchino M,
Tsuruga T, Osuga Y.Mol Clin Oncol. 2022 Mar;
16(3):63.
Transiently elevated D-dimer levels postconcentrated ascites reinfusion therapy cannot be
used to predict deep vein thrombosis-pulmonary
embolism.Sone K, Taguchi A, Kawata A, Eguchi
S, Miyamoto Y, Tanikawa M, Uchino-Mori M,
Iriyama T, Tsuruga T, Osuga Y.J Obstet
Gynaecol Res. 2022 Mar;48(3):817-823.
The Histone Methyltransferase SETD8 Regulates
the Expression of Tumor Suppressor Genes via
H4K20 Methylation and the p53 Signaling
Pathway in Endometrial Cancer Cells. Kukita A,
Sone K, Kaneko S, Kawakami E, Oki S, Kojima
M, Wada M, Toyohara Y, Takahashi Y, Inoue F,
Tanimoto S, Taguchi A, Fukuda T, Miyamoto Y,
Tanikawa M, Mori-Uchino M, Tsuruga T,
Iriyama T, Matsumoto Y, Nagasaka K, WadaHiraike O, Oda K, Hamamoto R, Osuga Y.
Cancers (Basel). 2022 Oct 31;14(21):5367.
Recurrent cervical cancer with PD-L1
amplification treated with nivolumab: A caseenrolled in the BELIEVE trial. Yoshimoto D,
Taguchi A, Tanikawa M, Sone K, Shimoi T,
Tsuruga T, Oda K, Osuga Y.J Obstet Gynaecol
Res. 2022 Jul;48(7):2010-2014.

195

Department of Perinatal Medicine
Professor
Osuga Yutaka

Homepage https://www.obstetrics-htu.jp/english/
Organization
The Department of Perinatal Medicine is organized
by one professor and one associate professor, being
directed practically by Professor Tomoyuki Fujii, thechairman of the Department of Obstetrics andGynecology. All the staff members take part in bothclinical and research activities, as well as teachingactivities, with about 20 associates of the Universityof Tokyo Hospital. From the clinical aspect, they are
engaged with in-patient and out-patient care including
the activities in the delivery units.

Activities
Clinical service for perinatology in the Universityof Tokyo Hospital consists of out-patient clinic andthe delivery unit. [See Delivery Unit of the Universityof Tokyo Hospital]
With the advance of the techniques for prenatal
diagnosis of pathological pregnancies and congenital
malformations, the area of fetal medicine is spreading.
Intensive scrutiny using ultrasonography makes it
possible to clarify background causes of fetal growth
restriction. New techniques for genetic analysis havebeen introduced into prenatal diagnosis. The
perinatologists and medical engineering team in our
department are working on clinical research to clarify
the pathoetiology of preterm birth and preeclampsia.
Perineal ultrasound is a new approach for assessing
labor progress. Using this technique, our challenge isto establish novel clinical approach for precise andobjective evaluation of labor progression which cancontribute to safer labor management. Pregnancy
complicated with adenomyosis is associated withvariety of adverse perinatal events, such as second
trimester miscarriage, preeclampsia, and placental

malposition. Our mission is to establish optimal
clinical management which improves perinatal
outcomes for both the mother and the neonate.
Recurrent pregnancy loss (RPL) is a condition inwhich a woman has two or more clinical pregnancy
losses. Our department has been providing a “special
clinic for RPL”. About 150 new couples with RPLvisit us every year. Underlying causes of RPL are
identifiedbyscreening
tests.
Anatomical,
chromosomal, hormonal, biological, and autoimmune
factors can trigger RPL. For RPL women with
autoimmune factors, especially with antiphospholipid
antibodies, anti-coagulation therapy using heparin andlow dose aspirin is performed. For low risk group, lowdose aspirin is administered. Causative factor is notdetectable in half of the women with RPL. Supportive
care rather than pharmacological intervention isimportant for those women. In our clinic, mental
stress in RPL women is evaluated using K6 scale. We
are investigating the relationship between their mental
status and the outcome in the subsequent pregnancy.
After a renewal of the inpatient’s wards forobstetrics and NICU/GCU/PICU in 2019, the newperinatal medical center restarted as one of the largest
facility in Japan and is accommodated with full
capacity to treat with all maternal and fetal diseases.
We are proud to provide advanced medical care forevery patient.

References published in 2022
1. Iriyama T, Sayama S, Osuga Y. Role of adenosine
signaling in preeclampsia. J Obstet Gynaecol Res.
2022 Jan;48(1):49-57.

196

2.

3.

4.

5.

6.

7.

8.

Nakanishi M, Iriyama T, Sayama S, Hanaoka S,
Toshimitsu M, Seyama T, Sone K, Kumasawa K,
Nagamatsu T, Osuga Y. Pregnancy-induced
hemorrhagic degeneration of adenomyosis. J
Obstet Gynaecol Res. 2022 May;48(5):12651270.
Mimura N, Nagamatsu T, Morita K, Taguchi A,
Toya T, Kumasawa K, Iriyama T, Kawana K,
Inoue N, Fujii T, Osuga Y. Suppression of humantrophoblast
syncytializationbyhuman
cytomegalovirus infection. Placenta. 2022 Jan;
117:200-208.
Kasuya M, Akiba N, Iriyama T, Sayama S,
Kubota K, Toshimitsu M, Seyama T, Sone K,
Kumasawa K, Nagamatsu T, Fujii T, Osuga Y.
The impact of fetal growth restriction indiagnosing preeclampsia on the severity ofmaternal features. J Obstet Gynaecol Res. 2022
Apr;48(4):912-919.
Kato K, Nagamatsu T, Yamaguchi S, Ichinose M,
Sayama S, Toshimitsu M, Seyama T, Kumasawa
K, Iriyama T, Osuga Y. Changes in fetal
presentation in the preterm period and theprediction of non-cephalic delivery. J Matern
Fetal Neonatal Med. 2023 Dec;36(1):2141564.
Sayama S, Iriyama T, Nakayama T, Seyama T,
Sone K, Kumasawa K, Nagamatsu T, Suzuki K,
Fujii T, Osuga Y. Prenatal diagnosis of pyriform
sinus fistula using ultrasonography by detecting
the communication to the pharynx. Taiwan J
Obstet Gynecol. 2022 Mar;61(2):385-387.
Katoh Y, Iriyama T, Yano E, Sayama S, Seyama T,
Kotajima-Murakami H, Sato A, Sakuma H,
Iguchi Y, Yoshikawa M, Inaoka N, Ichinose M,
Toshimitsu M, Sone K, Kumasawa K, Nagamatsu
T, Ikeda K, Osuga Y. Increased production of
inflammatory cytokines and activation of
microglia in the fetal brain of preeclamptic miceinduced by angiotensin II. J Reprod Immunol.
2022 Dec;154:103752.
Yoshikawa M, Seyama T, Iriyama T, Sayama S,
Fujii T, Toshimitsu M, Nakaya M, Kurokawa R,
Shibata E, Watadani T, Kumasawa K, Nagamatsu
T, Koga K, Osuga Y. A Case of Preeclampsia
with Uterine Necrosis after Uterine Artery
Embolization for Postpartum Hemorrhage. Case
Rep Obstet Gynecol. 2022 May 17;2022:

2859766.
9. Yano E, Iriyama T, Hanaoka S, Sayama S,
Ichinose M, Toshimitsu M, Seyama T, Sone K,
Kumasawa K, Nagamatsu T, Kobayashi K, Fujii
T, Osuga Y. Anatomical identification of ischialspines applicable to intrapartum transperineal
ultrasound based on magnetic resonance imaging
of pregnant women. J Matern Fetal Neonatal Med.
2022 Dec;35(25):9736-9741.
10. Ichinose M, Iriyama T, Sayama S, Toshimitsu M,
Seyama T, Sone K, Kumasawa K, Nagamatsu T,
Hanaoka S, Osuga Y. Postpartum degeneration of
adenomyosis with diffuse cyst-like changes andlocalized hemorrhage detected by sequential
magnetic resonance imaging. J Obstet Gynaecol
Res. 2022 Nov;48(11):2973-2978.
11. Yano E, Iriyama T, Sayama S, Ariyosi Y, Akiba N,
Ichinose M, Toshimitsu M, Seyama T, Sone K,
Kumasawa K, Nagamatsu T, Nakayama T,
Kobayashi K, Osuga Y. The head direction to theangle of progression ratio: a quantitative
parameter for intrapartum evaluation of cephalicmalposition. Am J Obstet Gynecol MFM. 2023
Jan;5(1):100755.
12. Sayama S, Iriyama T, Takeda N, Yamauchi H,
Toshimitsu M, Seyama T, Sone K, Kumasawa K,
Nagamatsu T, Fujii T, Osuga Y. Proposed
Management Policy for Pregnant Women with
Loeys-Dietz Syndrome Following Prophylactic
Aortic Root Replacement Based on Experiencefrom a Tertiary Care Center. Int Heart J. 2022;
63(1):176-179.

197

Department of Molecular andCellular Reproductive Medicine
Professor
Yutaka Osuga

Associate Professor
Osamu Hiraike

Homepage https://www.gynecology-htu.jp/
Organization
The Department of Molecular and Cellular
Reproductive Medicine is organized by one professor
and one associate professor.

Activities
Our department mainly aims to investigate thereproductive endocrinology, and molecular biologicalmethods are utilized to accomplish this purpose. Basic
researches are currently performed and we reportmany interesting findings annualy. We specificallyfocus on the role of inflammation and transcription
machinery in these issues. Senescence and aging
process are also extensively investigated.
1) The mechanism of folliculogenesis, follicularatresia and intrafollicular microenvironment in theovary.
2) The physiological functions of sex steroid
hormones and gonadotoropins.
3) The molecular mechanisms of endometriosis.
4) The molecular mechanisms of uterine fibroid andadenomyosis.
5) The effects of aging and cellular senescence on the
reproductive system.
In clinical section, we have an out-patient clinic for
infertility, gynecological endocrine disorders andgenetic counseling. We also perform minimallyinvasive surgery for benign gynecological diseases
including endometriosis, uterine fibroid, adenomyosis,

infertility, and pelvic organ prolapse. More than 90%of surgery cases for benign gynecological disorders
are operated using endoscope, and we deal with morethan 400 cases annually.
In accordance with the notion of life stage specificapproches, we also manage patients complaining
primary/secondary amenorrhea, infertility, dysmenorrhea, heavy menstrual bleeding, and climactirium.
Osteoporosis in their 10’s to 20’s and perimenopausal
age could be a heavy burden for patinets and we havealready established the primary care system for these
women. Numerous number of female athletes refer toour clinic as well.

References published in 2022
1.

2.

Elsherbini M, Koga K, Maki E, Kumasawa K,
Satake E, Taguchi A, Makabe T, Takeuchi A,
Izumi G, Takamura M, Harada M, Hirata T,
Hirota Y, Wada-Hiraike O, Osuga Y. Impact ofChronic Exposure to Endometriosis on Perinatal
Outcomes: Establishment of a Mouse Model.
Biomedicines. 2022 Oct 19;10(10):2627.
Elsherbini M, Koga K, Hiraoka T, Kumasawa K,
Maki E, Satake E, Taguchi A, Makabe T,
Takeuchi A, Izumi G, Takamura M, Harada M,
Hirata T, Hirota Y, Wada-Hiraike O, Osuga Y.
Establishment of a novel mouse model ofadenomyosis suitable for longitudinal andquantitative analysis and perinatal outcome
studies. Sci Rep. 2022 Oct 20;12(1)

198

3.

4.

5.

6.

7.

8.

9.

Koike H, Harada M, Kusamoto A, Kunitomi C,
Xu Z, Tanaka T, Urata Y, Nose E, Takahashi N,
Wada-Hiraike O, Hirota Y, Koga K, Osuga Y.
Notch Signaling Induced by Endoplasmic
Reticulum Stress Regulates Cumulus-Oocyte
Complex Expansion in Polycystic Ovary
Syndrome. Biomolecules. 2022 Jul 27;12(8):1037.
Sun H, Hirata T, Koga K, Arakawa T, Nagashima
N, Neriishi K, Elsherbini M, Maki E, Izumi G,
Harada M, Hirota Y, Wada-Hiraike O, Osuga Y.
Elevated phosphorylation of estrogen receptor α
at serine-118 in ovarian endometrioma. F S Sci.
2022 Nov;3(4):401-409.
Hiratsuka D, Aikawa S, Hirota Y, Fukui Y,
Akaeda S, Hiraoka T, Matsuo M, Osuga Y. DNA
Methylation and Histone Modification Are thePossible
RegulatorsofPreimplantation
Blastocyst Activation in Mice. Reprod Sci. 2023
Feb;30(2):494-525.
Hirakawa T, Yotsumoto F, Shirasu N, Kiyoshima
C, Urushiyama D, Yoshikawa K, Miyata K,
Kurakazu M, Koga KA, Aoki M, Nabeshima K,
Koga KS, Osuga Y, Komatsu H, Taniguchi F,
Harada T, Yasunaga S, Miyamoto S. Trophic andimmunomodulatory effects of adipose tissue
derived stem cells in a preclinical murine modelof endometriosis. Sci Rep. 2022 May 16;12(1):8031.
Aikawa S, Hirota Y, Fukui Y, Ishizawa C, IIda R,
Kaku T, Hirata T, Akaeda S, Hiraoka T, Matsuo
M, Osuga Y. A gene network of uterine luminal
epitheliumorganizes
mouse
blastocyst
implantation. Reprod Med Biol. 2022 Jan 5;21(1):
Hiraoka T, Hirota Y, Aikawa S, Iida R, Ishizawa
C, Kaku T, Hirata T, Fukui Y, Akaeda S, Matsuo
M, Shimizu-Hirota R, Takeda N, Osuga Y.
Constant Activation of STAT3 Contributes to theDevelopment of Adenomyosis in Females.
Endocrinology. 2022 May 1;163(5)Fukui Y, Hirota Y, Aikawa S, Ishizawa C, Iida R,
Kaku T, Hirata T, Akaeda S, Hiraoka T, Matsuo
M, Osuga Y. Uterine Receptivity is Reflected by
LIF Expression in the Cervix. Reprod Sci. 2022
May;29(5):1457-1462.

Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

200

Department of Pediatrics,
Department of Developmental
Pediatrics
Professor
Motohiro Kato, M.D., Ph.D.
Naoto Takahashi, M.D., Ph.D. (Department of Pediatric and Neonatal Intensive Care Unit)

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

Lecturer
Ryo Inuzuka, M.D., PhD., Shoichiro Kanda, M.D.,Ph.D., Kohei Kashima, M.D.,Ph.D.
(Department of Maternal, Fetal and Neonatal Medicine)

Project Lecturer
Atsushi Sato, M.D.,Ph.D., Yuko Kajiho, M.D.,Ph.D., Akiko Kinumaki, M.D.,Ph.D.

Research Associate
Mami Kobayashi, M.D., Takako Matsuoka, M.D.,Ph.D., Shunpei Uchino, M.D.,Ph.D.,
Hiroshi Terashima, M.D., Takanobu Inoue, M.D.,Ph.D., Hitomi Masuda, M.D.,
Yoshihiko Shitara, M.D., Takeo Mukai, M.D.,Ph.D., Atsushi Ito, M.D.,Ph.D.,
Kentaro Watanabe, M.D.,Ph.D., Yu Tanaka, M.D.,Ph.D., Takuya Oshima, M.D.,
Hiroshi Muto, M.D., Mieko Maezawa, M.D., Kazuhiro Shiraga, M.D.,
Kenichiro Hayashi, M.D., Masahiro Sekiguchi, M.D., Ph.D., Hiroyuki Tanaka, M.D., Ph.D.,
Yu Kakimoto, M.D., Hidetoshi Ohta, M.D., Moe Hidaka, M.D., Kaname Uchida, M.D.,
Koji Hirohata, M.D., Yosuke Ogawa, M.D., Hisataka Nozawa, M.D., Yuriko Katayama,
M.D., Koichi Takamizawa, M.D., Kaname Sato, M.D., Kyosuke Ibi, M.D., Natsuho Adachi,
M.D., Hiroki Kitaoka M.D., Ayumi Kunikata, M.D., Shutaro Inoue, M.D., Yui Ozawa, M.D.,
Marina Tanaka, M.D., Kumiko Uryu, M.D., Rumi Taniguchi, M.D., Yukiko Kuroda, M.D.,
Akiko Shibata, M.D., Miyuki Ota M.D., Etsushi Toyofuku, M.D., Satoko Kobayashi, M.D.,
Ayami Sato, M.D., Keiko Watanabe, M.D.
(As of March 31, 2023)

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

201

Introduction and Organization
The Department of Pediatrics and the Departmentof Developmental Pediatrics are sub-divisions of the
Reproductive, Developmental and Aging Medicines,
at the Graduate School of Medicine at The Universityof Tokyo. Our staff consists of 2 professors, 2
associate professors, 3 lecturers, 3 project lecturers,
34 research associates on March 31, 2023.
Our outpatient services are housed on the second
floor of the outpatient clinic building, while inpatientcare is offered at the Pediatric Medical Center locatedin the inpatient building. Our administrative offices
are located at the second floor of the East Research
Building. Additionally, our laboratories are situatedon the seventh floor of the Clinical Research Centerand on the second and third floors of the East
Research Building.
Our departments are dedicated to providing highquality clinical care, teaching, and research inpediatrics and developmental pediatrics. We
continually strive to improve our services andofferings to meet the evolving needs of our patients,
their families, and the broader community. Our
ultimate aim is to become a leading center for
pediatric and developmental medical care, not only inTokyo but also on a global scale.

Clinical activities
Our outpatient pediatric clinics provide care acrossa broad spectrum of pediatric disorders, including but
not limited to hematology/oncology, cardiology,
neurology,
nephrology,
endocrinology,
andneonatology. Moreover, patients with conditions
related to genetics, pulmonology, and allergology/
immunology are attended to by part-time physicians
specializing in each field. Additionally, we maintaincontinuity of care post-discharge through our
outpatient clinics, coordinating care that aligns withthe specific needs of patients and their families
through partnerships with local medical institutions.
We operate specialized clinics covering all fields ofpediatric disorders. Pediatric and neonatal patients areadmitted to the Pediatric Medical Center where theyreceive targeted treatments. Since June 2019, we haveintensified our focus on critical care, culminating in
the establishment of the section for Pediatric andPerinatal Intensive Care. This includes a Neonatal
Intensive Care Unit (NICU) with 21 beds and a
Pediatric Intensive Care Unit (PICU) with 12 beds,
serving as one of the tertiary centers for pediatricemergencies in the eastern part of Tokyo. Our PICU
delivers state-of-the-art monitoring and comprehensive care for children suffering from critical
illnesses or injuries, and those with complex medical
conditions.
In our NICU and Growing Care Unit (GCU), whichhas 36 beds, we care for high-risk infants, includingpremature babies weighing under 500 grams andnewborns requiring invasive interventions forcongenital disorders. We offer high-quality,
specialized medical care as a leading perinatal centerin Tokyo, involving multi-disciplinary collaboration
with obstetricians, pediatric cardiologists, cardiac
surgeons, pediatric surgeons, ophthalmologists,neurosurgeons, among others. Our approach also
incorporates family-centered care through coordination with co-medical staff.
In the general ward of the Pediatric Medical Center,
we provide comprehensive care for children sufferingfrom a wide range of conditions including
hematological/oncologicaldisorders,cardiacconditions, neuromuscular issues, immunologicaldiseases, renal and urinary tract diseases,
endocrinological conditions, metabolic disorders, andpsychosomatic diseases. This is done in collaboration
with related departments. Additionally, our hospitalhas received accreditation as a provider of chimericantigen receptor T-cell therapy.
We offer a comprehensive package of support
services. These include subsidized housing through
McDonald House, an on-site school to help young
patients continue their education, and a variety ofadditional services such as psychosocial support forfamilies, translation services, and volunteer groups.

Teaching activities
M2 students are given pediatric systematic lectures
covering each specialty area. M3 students undergo a2-week participatory ward training (M3 ClinicalClerkship). During the training period, students are
assigned to each clinical team and are in charge of202

inpatients, taking their medical history, examining
them, recording their admission records, andobserving various specialized examinations. During
the internship in the pediatric ward, the students will
do cruzes in pediatric neurology, nephrology,transfusion,
endocrinology,
neonatology,
hematology/oncology,
cardiology,
emergency
resuscitation, and others. On Tuesdays, the students
will be exposed to and discuss pediatric cases as awhole through online rounds of chart rounds. During
the second week of the internship, each student will
present their assigned cases to foster experience inpresentation skills and question and answer sessions.
The M4 clinical clerkship is a one-month program thatprovides highly specialized training that cannot be
experienced in the two-week ward training. pediatrics
with a focus on the typical development of healthy
children. The professor or associate professor
conducts an examination on the last day. In addition,
students are provided with online learning content
through the pediatrics educational website.

Research activities
Our research divisions focus on nephrology,
hematology/oncology,
neurology,
cardiology,
endocrinology/metabolism, immunology/allergy, andneonatology. We also operate interdisciplinary
research groups that focus on areas like cell biology,
genetic molecular biology, and epidemiology. The
highlights of our research activities over the past year
are as follows:
Hematology/Oncology group:
Our division has performed whole-genome
sequencing (WGS), whole-exome sequencing (WES),
and RNA-sequencing to characterize the genetic
landscapes of several pediatric cancers, including
leukemia, brain tumors, and soft tissue sarcomas.
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 andcongenital anomalies of the kidney and urinary tract.
We are also developing a novel urinary test using
urinary extracellular vesicles.
Endocrinology and Metabolism group:

We are analyzing genes and mechanisms involved in
endocrinology and metabolic diseases. We analyze
the molecular biological mechanisms using model
animals and iPS cells. We are also studying pathways
in growth plate cartilage in relation to pediatricgrowth and development, including single-cell RNA
analysis using mouse and human specimens.
Cardiology group:
To reveal the molecular mechanism of cardiomyopathy, we performed genome-wide association
studies and generated an animal model for
cardiomyopathy.
Additionally,
we
perform
hemodynamic analysis for patients with congenital
heart disease using clinical imaging modalities.
Neurology Group:
After a clinical trial of valganciclovir for congenital
cytomegalovirus infection has shown therapeutic
efficacy for recovering hearing difficulty, we continue
to follow up on hearing and psychomotor
development.
Neonatology group:
Epigenetic changes in cord blood and postnatal
peripheral blood of preterm and SGA infants areinvestigated using epigenome-wide methylation
analysis. The influence of gut microbiome on neonatal
immune function and nutritional status is also
investigated. Cytokine profiles have been investigatedin order to elucidate pathophysiology of several
diseases in perinatal period. Molecular mechanism of
neonatal immune tolerance is also an importantresearch topic in the group.
PICU group:
The Pediatric Intensive Care Unit (PICU) Group
promotes research originating from clinical practice.
The group conducts research directly related tounderstanding, evaluating, and treating pathologicalconditions in clinical practice, including biologicalresponse research using bedside physiological data,such as heart rate variability analysis, quantificationof nerve reflexes, evaluation of cerebral blood flow
regulation, and pulse wave analysis; medical safety
research using DWH; development of new diagnostic
equipment and evaluation systems using AI; anddevelopment of novel bedside digital fundoscope. We
are conducting research directly related to theunderstanding, evaluation, and treatment ofpathological conditions in clinical practice.

203

Selected References
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7.

Takizawa K, Ueda K, Sekiguchi M, Nakano E,
Nishimura T, Kajiho Y, Kanda S, Miura K,
Hattori M, Hashimoto J, Hamasaki Y, Hisano M,
Omori T, Okamoto T, Kitayama H, Fujita N,
Kuramochi H, Ichiki T, Oka A, Harita Y.
Urinary extracellular vesicles signature fordiagnosis of kidney disease. iScience. 25(11):105416, 2022
Nakamura M, Kanda S, Kajiho Y, Hinata M,
Tomonaga K, Fujishiro J, Harita Y. A case ofright hypodysplastic kidney and ectopic ureter
associated with bicornuate uterus in a prepubertal
girl. CEN Case Rep. 12(1):122-129, 2023
Miura K, Kaneko N, Hashimoto T, Ishizuka K,
Shirai Y, Hisano M, Chikamoto H, Akioka Y,
Kanda S, Harita Y, Yamamoto T, Hattori M.
Precise clinicopathologic findings for applicationof genetic testing in pediatric kidney transplant
recipients
with
focal
segmental
glomerulosclerosis/steroid-resistantnephrotic
syndrome. Pediatr Nephrol. 38(2):417-429, 2023
Critical brainstem encephalitis/encephalopathy
in a child with COVID-19. Kunikata A, Hayashi
K, Kinumaki A, Akatsuka Y, Shimoda K, Kato
M, Matsui H. Pediatr Int. 64：e15353, 2022
Circulating
nephrinautoantibodies
andposttransplant recurrence of primary focal
segmental glomerulosclerosis. Hattori M, Shirai
Y, Kanda S, Ishizuka K, Kaneko N, Ando T,
Eguchi M, Miura K. Am J Transplant. 2022 Oct;22(10):2478-2480. doi: 10.1111/ajt.17077.
Urinary extracellular vesicles signature fordiagnosis of kidney disease. Takizawa K, Ueda
K, Sekiguchi M, Nakano E, Nishimura T, Kajiho
Y, Kanda S, Miura K, Hattori M, Hashimoto J,
Hamasaki Y, Hisano M, Omori T, Okamoto T,
Kitayama H, Fujita N, Kuramochi H, Ichiki T,
Oka A, Harita Y. iScience. 2022 Nov 8;25(11):105416. doi: 10.1016/j.isci.2022.105416.
Ibi K, Takahashi N. Assisted reproductive
technology and neonatal intensive care unit: A
retrospective observational study from a single
center. J Obstet Gynaecol Res. 2023 Jan;49(1):273-279. doi: 10.1111/jog.15478. Epub 2022 Oct
25.

8.

9.

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13.

14.

15.

16.

Takahashi N, Shoji H, Arai H, Tanaka K,
Kakiuchi S, Yoda H, Shimizu T. Effect of biotin
supplementation in infant formula: A multicenter study in Japan. Pediatr Int. 2023 Jan;65(1):e15359. doi: 10.1111/ped.15359.
Morioka I, Kakei Y, Omori T, Nozu K, Fujioka
K, Takahashi N, Yoshikawa T, Moriuchi H, Ito
Y, Oka A; Japanese Congenital
Cytomegalovirus
StudyGroup.
Oral
Valganciclovir Therapy in Infants Aged ≤2Months with Congenital Cytomegalovirus
Disease: A Multicenter, Single-Arm, Open-Label
Clinical Trial in Japan. J Clin Med. 2022 Jun 21;
11(13):3582. doi: 10.3390/jcm11133582.
Inuzuka R, Nii M, Inai K, Shimada E, Shinohara
T, Kogiso T, Ono H, Otsuki SI,
Kurita Y, Takeda A, Hirono K, Takei K,
Yasukohchi S, Yoshikawa T, Furutani Y,
Shinozaki T, Matsuyama Y, Senzaki H,
Tokushige K, Nakanishi T. Predictors of livercirrhosis and hepatocellular carcinoma among
perioperative survivors of the Fontan operation.
Heart. 2023 Jan 27;109(4):276-282.
Dimopoulos K, Constantine A, Clift P, Condliffe
R, Moledina S, Jansen K, Inuzuka R, Veldtman
GR, Cua CL, Tay ELW, Opotowsky AR,
Giannakoulas G, Alonso-Gonzalez R, Cordina R,
Capone G, Namuyonga J, Scott CH, D'Alto M,
Gamero FJ, Chicoine B, Gu H, Limsuwan A,
Majekodunmi T, Budts W, Coghlan G, Broberg
CS; for Down Syndrome International (DSi).
CardiovascularComplicationsof
Down
Syndrome: Scoping Review and Expert
Consensus. Circulation. 2023 Jan 31;147(5):425441.
Omori A, Inuzuka R, Matsui H, Hirata Y. Aortic
and bronchial perforation caused by a vascular
clip 3 years after its placement. Eur J
Cardiothorac Surg. 2022 Sep 2;62(4):ezac457.
Watanabe K, Kimura S, Seki M, Isobe T, Kubota
Y, Sekiguchi M et al. Identification of theultrahigh-risk subgroup in neuroblastoma cases
through DNA methylation analysis and its
treatment exploiting cancer metabolism.
Oncogene. 2022;41:4994-5007.
Isobe T, Takagi M, Sato-Otsubo A, Nishimura A,
Nagae G, Yamagishi C et al. Multi-omics

204

analysis defines highly refractory RAS burdened
immature subgroup of infant acute lymphoblastic
leukemia. Nature communications. 2022;13:4501.
17. Hiwatari M, Seki M, Matsuno R, Yoshida K,
Nagasawa T, Sato-Otsubo A et al. Novel
TENM3-ALK fusion is an alternate mechanism
for ALK activation in neuroblastoma. Oncogene.
2022;41:2789-97.

205

Department of Pediatric Surgery
Professor
Jun Fujishiro, M.D., Ph.D.

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

Shinya Takazawa, M.D., Ph.D.

Research Associate
Kenichiro Konishi, M.D, Ph.D

Toshiko Takezoe, M.D., Ph.D.

Ph.D.

Akinori Ichinose, M.D.

Homepage

Tomohiro Sunouchi, M.D

Keisuke Suzuki, M.D.,

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

206

Clinical activities
Staff members higher than the level of research
associate take charge of the outpatient clinic from
Monday through Friday. The pediatric surgicaloutpatient clinic takes place in the same location as
the pediatric outpatient clinic, and we closelycooperate with pediatricians to diagnose and treat
patients. We also have specialized outpatient clinics,
liver and biliary tract clinics, a tumor clinic, and aspina bifida clinic. Recently, a second-opinion clinic
opened to provide careful detailed explanations, andthis has received a favorable reception.
Our ward was transferred to the hospital's second floorof B wing from the second floor of south of the A
wing on January 2018. Other pediatric surgicalpatients also are admitted to this ward. We have sevenbeds in the ward, and about 300 patients a year are
hospitalized within it. Most operation cases are
inguinal hernia, but we manage other cases such as
respiratory surgery disease, neonatal digestive organ
obstructions, infant malignant tumors such as Wilms'
tumor and neuroblastoma, biliary tract diseases suchas biliary tract dilatation and biliary atresia,
respiratory anomalies such as tracheal stenosis andlung cysts, gastrointestinal anomalies, and urologicaldisorders including hydronephrosis and vesicoureteral
reflux.
We work with other pediatric surgery teams at otherinstitutions who perform endoscopic surgery (laparoscopic surgery/thoracoscopic surgery). We havedeveloped an endoscopic surgery technique forpediatric diseases not covered by insurance, for cases
requiring advanced medical care. Furthermore, we
surgically manage seriously ill, mentally andphysically handicapped infants, as well as patientswith intractable nervous system diseases, to improvetheir quality of life, and we cooperate withpediatricians (neonatologists) to treat patients withprenatal diagnoses.

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.

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

References
1)

Yamaguchi K, Horie C, Takane K, Ikenoue T,
Nakagawa S, Isobe Y, Ota Y, Ushiku T, Tanaka
M, Fujishiro J, Hoshino N, Arisue A, Nishizuka
S, Aikou S, Shida D, Furukawa Y.

207

2)

3)

4)

5)

6)

7)

Identificationofodontogenic
ameloblast
associated as a novel target gene of the Wnt/βcatenin signaling pathway.
Cancer Sci. 2022; 00: 1- 13. doi:10.1111/cas.
15657
Sukezaki A, Kato S, Makise N, Watadani T,
Fujishiro J.
Pseudotumoral cystitis mimicking malignancy ina child.
Pediatr Int. 2022; 64(1):e15160. doi:10.1111/ped.
15160. PMID: 35616154
Sakaguchi H, Konishi K, Yasuda R, Sasaki H,
Yoshimaru K, Tainaka T, Fukahori S, Sanada Y,
Iwama I, Shoji H, Kinoshita M, Matsuura T,
Fujishiro J, Uchida H, Nio M, Yamashita Y,
Mizuochi T.
Serum matrix metalloproteinase-7 in biliaryatresia: a Japanese multicenter study
Hepatol Res. 2022; ;52(5):479-487. doi: 10.1111/
hepr.13753. PMID: 35106887
Kawano T, Souzaki R, Sumida W, Ishimaru T,
Fujishiro J, Hishiki T, Kinoshita Y, Kawashima
H, Uchida H, Tajiri T, Yoneda A, Oue T, Kuroda
T, Koshinaga T, Hiyama E, Nio M, Inomata Y,
Taguchi T, Ieiri S.
Laparoscopic
approachforabdominal
neuroblastoma in Japan: results from nationwide
multicenter survey.
Surg Endosc. 2022; 36(5): 3028-3038. doi:
10.1007/s00464-021-08599-4. PMID: 34143289
Yamamoto S, Ikeda M, Ohama Y, Sunouchi T,
Hoshino Y, Ito H, Yamashita M, Kanno Y,
Okamoto K, Yamagoe S, Miyazaki Y, Okugawa
S, Fujishiro J, Moriya K.
Aureobasidium melanigenum catheter-related
bloodstream infection: a case report.
BMC Infect Dis. 2022; 22(1):335. doi:
10.1186/s12879-022-07310-9. PMID: 35382751
Omata K, Yoshida M, Suzuki K, Kawashima H,
Fujishiro J.
Ectopic gallbladder with congenital biliary
dilatation: a pediatric case report.
Surg Case Rep. 2022; 8(1):51. doi: 10.1186/
s40792-022-01401-0. PMID: 35347468
Li Y, Watanabe E, Kawashima Y, Plichta DR,
Wang Z, Ujike M, Ang QY, Wu R, Furuichi M,
Takeshita K, Yoshida K, Nishiyama K, Kearney

SM, Suda W, Hattori M, Sasajima S, Matsunaga
T, Zhang X, Watanabe K, Fujishiro J, Norman
JM, Olle B, Matsuyama S, Namkoong H,
Uwamino Y, Ishii M, Fukunaga K, Hasegawa N,
Ohara O, Xavier RJ, Atarashi K, Honda K.
Identification of trypsin-degrading commensals
in the large intestine.
Nature. 2022 Sep; 609(7927): 582-589. doi:
10.1038/s41586-022-05181-3. Epub 2022 Sep 7.
PMID: 36071157
8) Watanabe E, Ota H, Takasugi N, Hiwatari M,
Fujishiro J
A school-aged case of intratumor bleeding of an
adrenal neuroblastoma rescued by transcatheter
atrial embolization.
Pediatr Int. 2022 Jan;64(1):e14987. doi: 10.1111/
ped.14987. PMID: 35312221
9) Fujiogi M, Konishi T, Michihata N, Hashimoto Y,
Matsui H, Ishimaru T, Fushimi K, Yasunaga H,
Fujishiro J.
Perioperative outcomes of thyroid cancer surgery
in children and adults: a nationwide inpatient
database study in Japan.
Ann Clin Epidemiol 2022, https://doi.org/10.
37737/ace.23004
10) Misako Nakamura , Shoichiro Kanda , Yuko
Kajiho , Munetoshi Hinata , Kotaro Tomonaga ,Jun Fujishiro , Yutaka Harita
A case of right hypodysplastic kidney and ectopic
ureter associated with bicornuate uterus in a
prepubertal girl
CEN Case Rep,. 2023 Feb;12(1):122-129. doi:
10.1007/s13730-022-00730-1.
11) Ishimaru T, Fujiogi M, Michihata N, Konishi T,
Morita K, Matsui H, Uda K, Fushimi K,
Kawashima H, Fujishiro J, Yasunaga H
Perioperative outcomes of laparoscopicallyassisted anorectoplasty versus conventional
procedures for anorectal malformation: aretrospective nationwide database study.
Pediatr Surg Int. 2022;38(12):1785-1791. doi:
10.1007/s00383-022-05234-8. PMID: 36102983
12) Asai A, Wu JF, Wang KS, Yamataka A, Nio M,
Su DJ, Short C, Tsuboi K, Ochi T, Sasaki H,
Okubo R, Yodoshi T, Konishi K, Rogers ME,
Tiao GMThe Outcome of Patients With Cystic Biliary208

Atresia With Intact Proximal Hepatic Ducts
Following Hepatic-Cyst-Jejunostomy.
J Pediatr Gastroenterol Nutr. 2022 Aug 1;75(2):131-137.
13) Konishi KI, Suzuki K, Komura M, Kudo H,
Ishimaru T, Sugiyama M, Komuro H, Iwanaka T,
Fujishiro J.
Endoscopic nasobiliary drainage tube insertion
for treatment of afferent loop obstruction in apregnant woman after Kasai portoenterostomy.
J Pediatr Surg Case Rep. Volume 78, March
2022, 102194.
14) Sakaguchi H, Konishi KI, Yasuda R, Sasaki H,
Yoshimaru K, Tainaka T, Fukahori S, Sanada Y,
Iwama I, Shoji H, Kinoshita M, Matsuura T,
Fujishiro J, Uchida H, Nio M, Yamashita Y,
Mizuochi T.
Serum matrix metalloproteinase-7 in biliaryatresia: A Japanese multicenter study.
Hepatol Res. 2022 Feb 1.
15) Morita K, Fujiogi M, Michihata N, Matsui H,
Fushimi K, Yasunaga H, Fujishiro J.
Oral Antibiotics and Organ Space Infection after
Appendectomy and Intravenous Antibiotics
Therapy for Complicated Appendicitis inChildren.
Eur J Pediatr Surg. 2022 Dec 28. doi: 10.1055/a1958-7915. PMID: 36220134
16) Marques Marinho M, Oikawa R, Hayashi K,
Takazawa S, Harada K, Mitsuishi M.
Design and validation of looping assistancemethods in robotic-assisted neonatal surgicalsuturing in a chest model
Int J Med Robot. 2022 Oct 27;e2476. doi:
10.1002/rcs.2476.
17) Hayashi K, Mori M, Sanmoto Y, Oiki H,
Ishimaru T, Arakawa Y, Koh K, Kawashima H.
Relationship between the timing of chemotherapy
and surgical complications following surgicalbiopsy in children with malignant solid tumors
Pediatr Blood Cancer. 2023 Jan;70(1):e30030.
doi: 10.1002/pbc.30030.
18) Naohiro Takamoto, Shinya Takazawa, Yuki
Yoshida, Tamotus Sasaki, Akira Nishi
Examination of the effectiveness of bedsidenasojejunal tube placement using a portable
imaging device with a flat panel detector

Nagoya J Med. Sci. 84. 772-781, 2022

Reproductive, Developmental andAging Sciences
3. Aging Sciences

210

Department of Geriatric Medicine
Department of Aging Research
Professor
Masahiro Akishita, MD, PhD.

Associate Professor
Sumito Ogawa, MD, PhD.

Lecturer
Taro Kojima, MD, PhD.

Masaki Ishii, MD, PhD.

Kotaro Azuma, MD, PhD.

Research Associate
Mitsutaka Yakabe, MD, PhD.

Michiko Nanao, MD, PhD.

Yoko Yamada, MD, PhD.

Tatsuya Hosoi, MD, PhD.

Homepagehttps://www.h.u-tokyo.ac.jp/english/centers-services/clinicaldivisions/geriatric-medicine/index.html (English)
http://geriatrics.umin.jp/ (Japanese)

Introduction and Organization
The Department of Geriatric Medicine wasestablished in 1962, as the first geriatric department
in Japan.
Since older adult patients tend to have multiple
organ disorders, these patients should be taken cared
as a whole from multiple points of view. In addition,
symptoms, signs and responses to the treatment in theolder adult patients could be quite different from theyounger counterparts. Specific knowledge on thephysiological and metabolic changes with aging isnecessary when these older adult patients are treated.
Quality of life of the patients is another point of viewwhich should be emphasized. The department belongs
to the division of Internal Medicine. The staff includes
one professor, one associate professor, three lecturers,
and four assistant professors.
Our sub-specialty includes pneumology, cardiology,
neurology, hematology, endocrinology, and bonemetabolism, besides geriatrics. The main objective ofour research is to elucidate the pathophysiology of
aging process and to understand older adult patientsfrom viewpoints of basic aging science using
molecular biology technique and clinical aspects
using the recent advancement of technology andgeriatric assessment.

Clinical activities
The Department of Geriatric Medicine specialized
in the diagnosis and treatment of dementia, frailty,
geriatric syndrome and polypharmacy in older adults.
We provide Comprehensive Geriatric Assessment(CGA) and manages multiple diseases in older
patients who have physical and/or mental disabilities.
The Department of Geriatric Medicine belongs toInternal Medicine. In the outpatient setting, we accept
patients every day in the three outpatient wards (#207,#208, and #209). We also provide specialized outpatient treatment on dementia, frailty and sarcopenia,
osteoporosis, chronic obstructive pulmonary disease

211(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 fortreatment of gender sensitive conditions. In theinpatient setting, we have our proper wards in the 13th
floor of our hospital, and generally accept
approximately 10 patients who are treated by junior,senior, and chief residents of our staff. Older patients
often suffer from a variety of diseases and clinicalproblems. To deal with them, our department forms
multi-disciplinary teams composed of geriatricians
and related specialists such as psychologists andpharmacists to provide comprehensive medical care.

Education
Clinical education is provided for fifth- and sixthyear medical students on a man-to-man basis with afaculty staff member. During the period, the student
studies one or two cases, through which the student
learns the techniques of interrogation and physicalexamination, interpretation of laboratory tests, andactual medical procedures. Interpretation of theresults of geriatric assessment is studied throughlectures in a case-oriented manner with an emphasis
placed on the multidisciplinary basis of geriatricpatients.

Research
The purpose of our study is to fulfill the society
where older adult people enjoy healthy independent
life. We are engaged in studies on various topics
including epidemiological studies, clinical studies,and basic molecular studies to contribute to our
research aim. Our main research themes are as follows.
1) Research on the molecular mechanism ofvascular calcification
2) Regulation of vascular function by sex hormone
3) Molecular biology for the control of aging:
Association of vascular and neuronal senescence and the role of Sirt1
4) Molecular biology and treatment of sarcopenia5) Multicenter-investigation of the optimal treatment strategy for hypertension or lipid disorderin the older adult patients
6) Clinical study on metabolic syndrome in theolder adult patients
7) Research on the appearance of patients withcognitive impairment; Development of AI model
which detects cognitive impairment from thefacial expression8) Research on appropriate healthcare for the older
adult patients including pharmacotherapy9) Expression and regulation of nuclear receptors
in osteoblast and osteoclast10) Molecular mechanism under the treatment of
osteoporosis11) Genetic analysis of osteoporosis and osteoarthritis
12) Identification and functional analysis of thetarget gene networks associated with hormone
responsiveness in prostate and breast cancers13) Roles of nuclear receptors in age-relateddiseases and cancers14) Molecular mechanism of vitamin K function
and its roles in aging
15) Novel roles of antimicrobial peptide, defensin16) Adrenomedullin and airway hyperresponsiveness17) Klotho protein and vitamin D in lung18) Clinical investigation of sleep-related breathing
disorder19) Observational study on medical treatment/careprovided in the end-of-life stage of life20) Observational study on the outcome of frail
patients
21) Clinical study on the relationship between22) metabolic diseases and pulmonary aging

Publications (Original Articles)
1.

2.

Akashi S, Oguri M, Ikeno E, Manita M, Taura
J, Watanabe S, Hayashi T, Akao M, Okumura
K, Akishita M, Yamashita T. Outcomes andSafety of Very-Low-Dose Edoxaban in FrailPatients With Atrial Fibrillation in the
ELDERCARE-AF Randomized Clinical Trial.
JAMA Netw Open. 2022;5:e2228500.
Akishita M, Suzuki S, Inoue H, Akao M,
Atarashi H, Ikeda T, Koretsune Y, Okumura K,
Shimizu W, Tsutsui H, Toyoda K, Hirayama A,
Yasaka M, Yamaguchi T, Teramukai S, Kimura
T, Morishima Y, Takita A, Yamashita T. Frailty

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and outcomes in older adults with non-valvularatrial fibrillation from the ANAFIE registry. Arch
Gerontol Geriatr. 2022;101:104661.
3. Azuma K, Osuka Y, Kojima N, Sasai H, Kim H,
Inoue S. Association of Vitamin K Insufficiency as
Evaluatedby
Serum
Undercarboxylated
Osteocalcin With Frailty in Community-Dwelling
Older Adults. Front Aging. 2022;3:865178. doi:
10.3389/fragi.2022.865178.
4. Chen LK, Iijima K, Shimada H, Arai H.
Community re-designs for healthy longevity: Japanand Taiwan examples. Arch Gerontol Geriatr.
2022 23;104875, doi: 10.1016/j.archger.2022.
104875.
5. Fujikawa H, Son D, Aoki T, Kondo K,
Takemura Y, Saito M, Den N, Eto M. Translating
and validating a Japanese version of the instrument
for patient assessment of medical professionalism(J-IPAMP): a cross-sectional survey. BMC Med
Edu. 2022;22:641. doi: 10.1186/s12909-02203699-8.
6. Fujikawa H, Son D, Aoki T, Eto M. Association
between patient care ownership and personal orenvironmental factors among medical trainees: amulticenter cross-sectional study. BMC Med Edu.
2022;22:666. doi: 10.1186/s12909-022-03730-y.
7. Fujikawa H, Eto M. What Is the Optimal Amountof Supervision to Induce Residents to Develop
Patient Care Ownership? Acad Med. 2022;97:1578.
doi: 10.1097/ACM.0000000000004927.
8. Fujikawa H, Mitsuyama T, Son D, Izumiya M,
Eto M. Development and Validation of a
Performance Assessment Checklist Scale for
Vaccine Administration. Int Med. 2022. doi:
10.2169/internalmedicine.9268-21.
9. Hattori Y, Hamada S, Yamanaka T, Kidana K,
Iwagami M, Sakata N, Tamiya N, Kojima T,
Ogawa S, Akishita M. Drug prescribing changes
in the last year of life among homebound older
adults: national retrospective cohort study. BMJ
Support Palliat Care. 2022. Jul 13: bmjspcare2022-003639. doi: 10.1136/spcare-2022-003639.
Epub ahead of print. PMID: 35831182.
10. Hattori Y, Hamada S, Ishizaki T, Sakata N,
Iwagami M, Tamiya N, Akishita M, Yamanaka
T. National trends in gastrostomy in older adults
between 2014 and 2019 in Japan. Geriatr Gerontol

11.

12.

13.

14.

15.

16.

Int. 2022;22(8):648-652.
Hidaka R, Masuda Y, Ogawa K, Tanaka T,
Kanazawa M, Suzuki K, Stading M, Iijima K,
Matsuo K. Impact of oral frailty prevention
program with textured lunch gatherings on attitudeand behavior towards eating habits and improving
oral frailty: The Comprehensive Awareness
Modification of Mouth, Chewing And Meal
(CAMCAM) program. Preprint from Research
Square, 02 Mar 2023, doi: 10.21203/rs.3.rs2604863/v1 PPR: PPR624235
Hosoi T, Yakabe M, Sasakawa H, Sasako T,
Ueki K, Kato S, Tokuoka SM, Oda Y, Abe M,
Matsumoto T, Akishita M, Ogawa S. Sarcopenia
phenotype and impaired muscle function in malemice with fast-twitch muscle-specific knockout of
the androgen receptor. Proc Natl Acad Sci USA.
2023;120(4):e2218032120.
Hosoi T, Yamana H, Tamiya H, Matsui H,
Fushimi K, Akishita M, Yasunaga H, Ogawa S.
Association between comprehensive geriatricassessment and polypharmacy at discharge inpatients with ischaemic stroke: a nationwide
retrospective cohort study. EClinicalMedicine 50:
101528,2022
Ide H, Akehi Y, Fukuhara S, Ohira S, Ogawa S,
Kataoka T, Kumagai H, Kobayashi K, Komiya
A, Shigehara K, Syuto T, Soh J, Tanabe M,
Taniguchi H, Chiba K, Matsushita K, Mitsui Y,
Yoneyama T, Shirakawa T, Fujii Y, Kumano H,
Ueshiba H, Amano T, Sasaki H, Maeda S,
Mizokami A, Suzuki K, Horie S. Summary of theClinical Practice Manual for Late-Onset
Hypogonadism. Int J Urol 2023. doi:
10.1111/iju.15160. Online ahead of print.
Iki M, FujimoriK, Nakatoh S, Tamaki J, Ishii S,
Okimoto N, Ogawa S. Guideline adherence byphysicians for management of glucocorticoidinduced osteoporosis in Japan: a nationwide healthinsurance claims database study. Osteoporosis Int.
33:1097-1108,2022
Iki M, Fujimori K, Nakatoh S, Tamaki J, Ishii S,
Okimoto N, Kamiya K, Ogawa S. Delayed
initiation of anti-osteoporosis medications
increases subsequent hip and vertebral fractures inpatients on long-term glucocorticoid therapy: a

213

17.

18.

19.

20.

21.

22.

23.

nationwide health insurance claims database study
in Japan. Bone 160:116396,2022
Iki M, Fujimoto K, Nakatoh S, Tamaki J, Ishii S,
Okimoto N, Kamiya K, Ogawa S. Real-world
effectiveness of anti-osteoporosis medications forthe prevention of incident hip and clinical vertebral
fractures in patients on long-term glucocorticoid
therapy: a nationwide health insurance claims
database study in Japan. Bone 166:116605,2023
Imoto S, Suzukawa M, Takeda K, Motohashi T,
Nagase M, Enomoto Y, Kawasaki Y, Nakano E,
Watanabe M, Shimada M, Takada K,
Watanabe S, Nagase T, Ohta K, Teruya K,
Nagai H. Evaluation of tuberculosis diagnostic
biomarkers in immunocompromised hosts based on
cytokine levels in QuantiFERON-TB Gold Plus.
Tuberculosis (Edinb). 2022;136:102242.
Imoto S, Suzukawa M, Takada K, Watanabe S,
Igarashi S, Kitani M, Nagase T, Ohta K.
Immunoglobulin A promotes IL-6 and IL-8
production, proliferation, and migration by thehuman bronchial smooth muscle cells. Cell
Immunol. 2022;381:104612.
Ishii M, Yamaguchi Y, Hamaya H, Iwata Y,
Takada K, Ogawa S, Imura M, Akishita M.
Influence of oral health on frailty in patients with
type 2 diabetics aged 75 years or older. BMC
Geriatr. 22:145,2022
Iwasaki M, Ohara Y, Motokawa K, Hayakawa
M, Shirobe M, Edahiro A, Watanabe Y, Awata
S, Okamura T, Inagaki H, Sakuma N, Obuchi S,
Kawai H, Ejiri M, Ito K, Fujiwara Y, Kitamura
A, Nofuji Y, Abe T, Iijima K, Tanaka T, Son BK,
Shinkai S, Hirano H. Population-based reference
values for tongue pressure in Japanese older adults:
a pooled analysis with over 5,000 participants. J
Prosthodont Res. 2023;67(1):62-69, doi:10.2186/
jpr.JPR_D_21_00272.
Kasajima M, Kusaka S, Matsui H, Tanaka T,
Son BK, Iijima K, Goda K, Kitsuregawa M,
Eggleston K, Bhattacharya J, Hashimoto H.
Frailty and dementia in Japan’s ageing population:
projected needs and economic costs of care. The
Lancet public health. 2022;7(5):e458-e468, doi:
10.1016/S2468-2667(22)00044-5.
Kasajima M, Eggleston K, Kusaka S, Matsui H,
Tanaka T, Son BK, Iijima K, Goda K,

24.

25.

26.

27.

28.

29.

30.

31.

Kitsuregawa M, Bhattacharya J, Hashimoto H.
Projecting prevalence of frailty and dementia andthe economic cost of care in Japan from 2016 to
2043: a microsimulation modelling study. Lancet
Public Health. 2022 May;7(5):e458-e468, doi:
10.1016/S2468-2667(22)00044-5.
Kobayashi A, Azuma K, Takeiwa T, Kitami T,
Horie K, Ikeda K, Inoue S. A FRET-based
respirasome assembly screen identifies spleentyrosine kinase as a target to improve muscle
mitochondrial respiration and exercise performancein mice. Nat Commun. 2023;14(1):312. doi:
10.1038/s41467-023-35865-x.
Kojima T, Hamaya H, Ishii S, Hattori Y,
Akishita M. Association of disability level with
polypharmacy and potentially inappropriate
medication in community dwelling older people.
Arch Gerontol Geriatr. 2023 Mar;106:104873.
Konno D, Ikegaya Y, Sasaki T. Weakrepresentation of awake/sleep states by local fieldpotentials in aged mice. Sci Rep. 12:7766, 2022
Lyu W, Tanaka T, Son BK, Yoshizawa Y,
Akishita M, Iijima K. Associations of nutritionrelated, physical, social factors and their
combinations with sarcopenia in communitydwelling older adults: Kashiwa Cohort Study.
Nutrients. 2022; 14(17): 3544. doi: 10.3390/nu
14173544.
Lyu W, Tanaka T, Son BK, Akishita M, Iijima
K. Associations of multi-faceted factors and their
combinations with frailty in Japanese communitydwelling older adults: Kashiwa cohort study. Arch
Gerontol Geriatr. 2022;102:104734. doi: 10.1016/j.
archger.2022.104734.
Mizumoto J, Son D, Izumiya M, Horita S, Eto M.
Experience of residents learning about social
determinants of health and an assessment tool:
Mixed-methods research. J Gen Med. 2022;00:1-8.
doi: 10.1002/jgf2.559.
Mizumoto J, Mitsuyama T, Kumagaya S, Eto M,
Izumiya M, Horita S. Primary care nurses during
the coronavirus disaster and their struggle:
Qualitative research. J Gen Fam Med. 2022. doi:
10.1002/jgf2.566.
Mizumoto J, Mitsuyama T, Kondo S, Izumiya M,
Horita S, Eto M. Defining the observable
processes of patient care related to social

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32.

33.

34.

35.

36.

37.

38.

determinants of health. Med Educ. 2022 Aug 11.
doi: 10.1111/medu.14915.
Mori H, Izumiya M, Hayashi M, Eto M. Current
perception of social accountability of medical
schools in Japan: A qualitative content analysis.
Med Teach. 2022;Nov2:1-8.
Mori T, Wakabayashi H, Kishima M, Itoda M,
Fujishima I, Kunieda K, Ohno T, Shigematsu T,
Oshima F, Ogawa N, Nishioka S, Momosaki R,
Shimizu A, Saito Y, Yamada M, Ogawa S.
Association between inflammation and functional
outcome in patients with sarcopenic dysphagia. J.
Nutr Health Aging 26:400-406,2022
Moritoyo T, Nishimura N, Hasegawa K, Ishii S,
Kirihara K, Takata M, Kishi SA, UmedaKameyama Y, Kawarasaki S, Ihara R,
Sakanaka C, Wakabayashi Y, Niizuma K,
Tominaga T, Yamazaki T, Hasumi K. A first-inhuman
study
of
the
anti-inflammatory
profibrinolytic TMS-007, an SMTP family
triprenyl phenol. Br J Clin Pharmacol. 2022 Dec
23. doi: 10.1111/bcp.15651. Online ahead of print.
Nagatani M, Tanaka T, Son BK, Kawamura J,
Tagomori J, Hirano H, Shirobe M, Iijima K.
Oral Frailty as a Risk Factor for Mild Cognitive
Impairment in Community-Dwelling Older Adults:
Secondary Analysis of the Kashiwa Study Data.
Exp Gerontol. 2023;172:112075. doi:10.1016/j.
exger.2022.112075
Nakatoh S, Fujimori K, Ishii S, Tamaki J,
Okimoto N, Ogawa S, Iki M. Association ofpharmacotherapy with the second hip fracture
incidence in women: a retrospective analysis of the
National Database of Health Insurance Claims andSpecific Health Checkups of Japan. Geriatr.
Gerontol. Int. 22:930-937,2022
Nakatoh S, Fujimori K, Ishii S, Tamaki J,
Okimoto N, Ogawa S, Iki M. Association between
pharmacotherapy and secondary hip fracture in areal-world setting: a nationwide database study. J
Bone Miner Metab. 41:248-257,2023
Nishimoto M, Tanaka T, Hirano H, Watanabe Y,
Oharav Y, Shirobe M, Iijima K. Severe
periodontitis increases the risk of oral frailty: A six‐year follow‐up study from Kashiwa cohort study.
Geriatrics (Basel). 2023;8(1):25, doi: 10.3390/
geriatrics8010025.

39. Nishioka S, Fujishima I, Kishima M, Ohno T,
Shimizu A, Shigematsu T, Itoda M,
Wakabayashi H, Kunieda K, Ohshima F,
Ogawa S, Fukuma K, Ogawa N, Kayashita J,
Yamada M, Mori T, Onizuka S. Association ofexistence of sarcopenia and poor recovery ofswallowing function in post-stroke patients withsevere deglutition disorder: A multicenter cohort
study. Nutrients 14:4115,2022
40. Nishita Y, Makizako H, Jeong S, Otsuka, R, Kim
H, Obuchi S, Fujiwara Y, Ohara Y, Awata S,
Yamada M, Iijima K, Shimada H, Suzuki T.
Temporal trends in cognitive function amongcommunity-dwelling older adults in Japan:
Findings from the ILSA-J integrated cohort study.
Arch Gerontol Geriatr. 2022 Sep-Oct;102:104718,
doi: 10.1016/j.archger.2022.104718.
41. Nomura K, Ebihara S, Ikebata Y, Umegaki H,
Ooi K, Ogawa S, Katsuya T, Kobayashi Y,
Sakurai T, Miyao M, Yamaguchi K, Akishita M,
The Japan Geriatrics Society Geriatric Medical
Practice Committee. Japan Geriatrics Society“Statement for the Use of Telemedicine in GeriatricCare-Telemedicine as a Complement to In-person
Medical Practice”: Geriatric Medical PracticeCommittee consensus statement. Geriatr. Gerontol.
Int. 22:913-916,2022
42. Sakai K, Nakayama E, Yoneoka D, Sakata N,
Iijima K, Tanaka T, Hayashi K, Sakuma K,
Hoshino E. Association of Oral Function andDysphagia with Frailty and Sarcopenia in
Community-Dwelling Older Adults: A Systematic
Review and Meta-Analysis. Cells. 2022 Jul 14;
11(14):2199, doi: 10.3390/cells11142199.
43. Sato S, Miyazaki S, Tamaki A, Yoshimura Y,
Arai H, Fujiwara D, Katsura H, Kawagoshi A,
Kozu R, Maeda K, Ogawa S, Ueki J,
Wakabayashi H. Respiratory sarcopenia: A
position paper by four professional organizations.
Geriatr. Gerontol. Int. 23:5-15,2023
44. Son BK, Imoto T, Inoue T, Nishimura T, Lyu W,
Tanaka T, Iijima K. Different reversibility ofskeletal muscle mass and strength in elderly
Japanese women after the first wave of COVID-19.
JCSM rapid communication 2023 Feb 27.
DOI:10.1002/rco2.73. Online ahead of print

215

45. Son BK, Imoto T, Inoue T, Nishimura T, Tanaka
T, Iijima K. Social detachment influenced muscle
mass and strength during the COVID-19 pandemic
in Japanese community-dwelling older women J
Frailty Aging 2022;11(2):231-235. doi:10.14283/
jfa.2022.4
46. Sun Y, Iwagami M, Sakata N, Ito T, Inokuchi R,
Uda K, Hamada S, Ishimaru M, Komiyama J,
Kuroda N, Yoshie S, Ishizaki T, Iijima K,
Tamiya N. Development and validation of a risk
score to predict the frequent emergency house calls
among older people who receive regular home
visits. BMC Primary Care. 2022.5;23(132).
47. Suzuki Y, Shiraishi N, Komiya H, Sakakibara M,
Akishita M, Kuzuya M. Potentially inappropriate
medications increase while prevalence ofpolypharmacy/hyperpolypharmacy decreases inJapan: A comparison of nationwide prescribing
data. Arch Gerontol Geriatr. 2022;102:104733.
48. Takahashi K, Tanaka T, Yoshizawa Y, FujisakiSueda-Sakai M, Son BK, Iijima K. Lower urinary
tract symptoms and functional ability in older
adults: A community-based cross-sectional study.
BMC open 2022; 12(4): e054530. doi: 10.1136/
bmjopen-2021-054530.
49. Takase M, Takahashi K, Ogino R, Nitanai R,
Tanaka T, Saisho S, Goto J, Iijima K. Functional
capacity in community-dwelling older adults
maintained by a higher friend network than family
network: Implications from a two-year longitudinal
study. BMC Res Notes, 2022 Oct 11;15(1):319,
doi: 10.1186/s13104-022-06216-8.
50. Tamaki J, Ogawa S, Fujimori K, Ishii S,
Nakatoh S, Okimoto N, Kamiya K, Iki M. Hip
and vertebral fracture risk after initiating antidiabetic drugs in Japanese elderly: a nationwide
study. J Bone Miner Metab. 41:29-40,2023
51. Tanaka T, Yoshizawa Y, Sugaya K, Yoshida M,
Son BK, Lyu W, Tsushita K, Iijima K. Predictive
validity of the Questionnaire for Medical Checkup
of Old-Old for functional disability: using the
National Health Insurance Database System.
Geriatr Gerontol Int. 2023. doi: 10.1111/ggi.
14533.
52. Tanaka T, Son BK, Iijima K. Poor healthbehaviorsamonghouseboundJapanese
community-dwelling older adults due to prolonged

53.

54.

55.

56.

57.

58.

59.

self-restraint during the first COVID-19 pandemic:
A cross-sectional survey. J Frailty Aging
2023;12(1):86-90. doi: 10.14283/jfa.2022.20.
Tanaka T, Son BK, Lyu W, Iijiam K. The impact
of social engagement on the development ofsarcopenia among community-dwelling older
adults: A Kashiwa cohort study. Geriatr Gerontol
Int 2022;22(5):384-391. doi: 10.1111/ggi.14372.
Wakabayashi H, Kishima M, Itoda M,
Fujishima I, Kunieda K, Ohno T, Shigematsu T,
Oshima F, Mori T, Ogawa N, Nishioka S,
Momosaki R, Yamada M, Ogawa S. Prevalenceof hoarseness and its association with severity ofdysphagia in patients with sarcopenic dysphagia. J.
Nutr Health Aging 26:266-271,2022
Watanabe S, Kobayashi K, Suzukawa M,
Igarashi S, Takada K, Imoto S, Kitani M,
Fukami T, Nagase T, Ohta K. Identification of
ANXA2 on epithelial cells as a new receptor for
secretory IgA using immunoprecipitation and mass
spectrometry. Clin Exp Immunol. 2022;208(3):351-360
Yamamoto K, Akasaka H, Yasunobe Y, Shimizu
A, Nomoto K, Nagai K, Umegaki H, Akasaki Y,
Kojima T, Kozaki K, Kuzuya M, Ohishi M,
Akishita M, Takami Y, Rakugi H; Cherry Study
Group. Clinical characteristics of older adults withhypertension
andunrecognizedcognitive
impairment. Hypertens Res. 2022;45(4):612-619.
Yamamoto T, Tanaka T, Hirano H, Mochida Y,
Iijima K. Model to Predict Oral Frailty Based on
Questionnaire: A Cross-Sectional Study. Int J
Environ Res Public Health. 2022 Oct 14;19(20):13244, doi: 10.3390/ijerph192013244.
Yamanaka T, Kidana K, Yamaguchi Y,
Hirahara S, Hirakawa Y, Mizuki M, Arai H,
Akishita M, Miura H. Palliative home care forolder patients with respiratory disease in Japan:
Practices and opinions of physicians. Geriatr
Gerontol Int. 2022;22(11):943-949.
Yakabe M, Hosoi T, Sasakawa H, Akishita M,
Ogawa S. Kampo formula Hochu-ekki-to (BuZhong-Yi-Qi-Tang, TJ-41) ameliorates muscle
atrophy by modulating atrogenes and AMPK invivo and in vitro. BMC Complement Med Ther.
22:341,2022

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60. Yakabe M, Shibasaki K, Hosoi T, Matsumoto S,
Hoshi K, Akishita M, Ogawa S. Validation of thequestionnaire for medical checkup of. old-old(QMCOO) score cutoff to diagnose frailty. BMC
Geriatr. 23:157,2023
61. Yakabe M, Shibasaki K, Hosoi T, Matsumoto S,
Hoshi K, Akishita M, Ogawa S. Effectiveness ofthe questionnaire for medical checkup of old-old(QMCOO) to diagnose frailty in communitydwelling elderly adults. Geriatr. Gerontol. Int. 22:
127-131,2022
62. Yoshizawa Y, Tanaka T, Takahashi K, Fujisaki
M, Son BK, Iijima K. Impact of Health Literacy
on the Progression of Frailty after 4 Years among
Community-Dwelling Older Adults. Int J Environ
Res Public Health. 2022;19(1):394.

Surgical Sciences
1. Surgery

218

Department of Thoracic Surgery
Professor
Nakajima, Jun

Associate Professor
Sato, Masaaki

Lecturer
Konoeda, Chihiro

Assistant Professor
Nagano, Masaaki
Nakao, Keita
Cong, Yue
Yamaya, Takafumi

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).
The Department of Cardiothoracic Surgery has been
divided into two departments, Department of
Cardiovascular Surgery and Department of Thoracic
Surgery in 1995. The mission of the Department ofThoracic Surgery is to cure the patients with diseasesof the thoracic organs through clinical works, basic
and clinical research, and education of the medical

219

students, postgraduates, and the surgical residents in
our university.
Nakajima, Jun has taken over the mission of thedepartment of thoracic surgery as an independent
department for the first time since April 2011 until theend of March, 2023.

Clinical activities
Five staffs (Nakajima J, Sato M, Konoeda C,
Nagano M, and Nakao K), who are certificated as
members of the Japanese Board of General Thoracic
Surgery, are in charge of the Department of Thoracic
Surgery, University of Tokyo Hospital. They
specialize in surgical treatment for diseases of therespiratory and the mediastinal organs and the chest
wall, except for diseases of the esophagus andmammary glands.
Lung cancer is the leading cause of cancer death inour country: In 2020, Ministry of Health, Labour andWelfare documented that number of deaths frommalignant neoplasms was approximately 390 thousandout of 1.37 million total deaths in Japan. Of them, 76
thousand people were killed by malignant tracheal /pulmonary neoplasms. Surgical therapy for non-small
cell lung cancer (NSCLC) is thus the most important
issue in our department. By the practice of treatment
based on EBM, we perform basic training of thoracic
surgery for medical school students, graduate students
and clinical residents, as well as doing theprofessional education for training physicians whowish to become board-certified thoracic surgeons.
We have performed video-assisted thoracoscopy forthe diagnosis and treatment of the thoracic disease
with less surgical invasiveness since 1992 for safer
treatment of older patients with cardiovascular and/or
respiratory complications. We currently conduct a
standard surgery for clinical stage I non-small celllung cancer (NSCLC), that is, lobectomy andlymphadenectomy through thoracoscopy: Since 2015,
more than 90% of patients with NSCLC has
undergone thoracoscopic surgery in our department.
Research on less-invasiveness, oncological advantageof the thoracoscopic surgery is thus actively done.
Robot-assisted lobectomy/segmentectomy with Da
Vinci has applied to lung cancer patients since January
2021.

Pulmonary metastasis represents far advanced
malignant neoplasms of extrathoracic organs.
Pulmonary resection is an option for the treatment of
pulmonary metastasis. We actively perform pulmonary
resection through thoracoscopy on patients withpulmonary metastasis who are eligible for surgicaltherapy through thoracoscopy
Thymic epithelial neoplasms, such as thymoma andthymic carcinoma, show broad spectrum in the degreeof malignancy. They also associated with paraneoplastic syndromes, such as the myasthenia gravis
and the pure red cell aplasia. Although they are
relatively rare diseases, we sought to establish thestrategies on diagnosis and treatment of these diseases,
which are still yet to be determined, from our clinicalexperiences of more than 200 cases with the diseases
in our department. We are now actively participating a
multiinstitutional study on malignant thymic epithelial
neoplasms database led by Japanese Association forresearch on the thymus (JART).
Our hospital has been certified as a lung transplant
centers since March 2014. We have started to registerpatients who are eligible for lung transplantation. We
successfully performed the first case in Tokyo ofliving donor lung transplantation in April 2015: The
patients had suffered from the interstitial pneumonia.
In July 2015, we also succeeded in performing
brain-dead donor bilateral lung transplantation on apatient who had suffered from the pulmonary
hypertension. We have performed 135 lung transplants(including 26 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.

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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
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 after allogeneictransplantation.
(8) Long-term digital monitoring of post-lungtransplant patients(9) Research on extracorporeal membranous oxygenation for bridge use to lung transplantation

Selected publications (2022)
1.

2.

3.

4.

Ijiri N, Sato M, Konoeda C, Nagayama K,
Nakajima J. Basiliximab for early perioperativetransplant-associated thrombotic microangiopathy
after lung transplantation: a case report. Surg
Case Rep. 2022;8(1):187.
Kawashima S, Yoshida D, Yoshioka T,
Ogasawara A, Fujita K, Yanagiya M, et al. Rapid
imaging of lung cancer using a red fluorescentprobe to detect dipeptidyl peptidase 4 andpuromycin-sensitive aminopeptidase activities.
Sci Rep. 2022;12(1):9100.
Morota M, Nagano M, Ijiri N, Yoshiyasu N,
Shinohara Y, Nobori Y, et al. Effect of
intraoperative needle biopsy on the survival ofnonsmall cell lung cancer patients: a propensity
score matching analysis. Surg Today. 2022;
52(10):1497-503.
Nagano M, Sato M, Yanagiya M, Nakao K,
Konoeda C, Kitano K, et al. Number of dye

marks required in virtual-assisted lung mapping.
Gen Thorac Cardiovasc Surg. 2023;71(5):313-20.
5. Sato M, Kobayashi M, Sakamoto J, Fukai R,
Takizawa H, Shinohara S, et al. The role ofvirtual-assisted lung mapping 2.0 combining
microcoils and dye marks in deep lung resection.
J Thorac Cardiovasc Surg. 2022;164(1):243-51.
e5.
6. Shiiya H, Sato M, Shinozaki-Ushiku A, Konoeda
C, Kitano K, Nakajima J. Exacerbation ofSecondary Pulmonary Hypertension by Flat
Chest after Lung Transplantation. Ann Thorac
Cardiovasc Surg. 2022;28(4):298-301.
7. Shinohara Y, Yamamoto K, Ito M, Sakata M,
Koizumi S, Hashisako M, et al. Development andvalidation of the Japanese version of the uMARS(user version of the mobile app rating system).
Int J Med Inform. 2022;165:104809.
8. Sun C, Anraku M, Kawahara T, Karasaki T,
Kitano K, Nagayama K, et al. Respiratory
strength and pectoralis muscle mass as measuresof sarcopenia: Relation to outcomes in resected
non-small cell lung cancer. J Thorac Cardiovasc
Surg. 2022;163(3):779-87.e2.
9. Sun C, Anraku M, Kawahara T, Karasaki T,
Konoeda C, Kitano K, et al. Combination of
Skeletal Muscle Mass and Density Predicts
Postoperative Complications and Survival ofPatients With Non-Small Cell Lung Cancer. Ann
Surg Oncol. 2022;29(3):1816-24.
10. Tian D, Shiiya H, Sato M, Shinozaki-Ushiku A,
Yan HJ, Nakajima J. Pathological tumor long-toshort axis ratio as a prognostic factor in patientswith thymic epithelial tumors. Thorac Cancer.
2022;13(17):2489-98.
11. Tian D, Shiiya H, Takahashi M, Terasaki Y,
Urushiyama H, Shinozaki-Ushiku A, et al.
Noninvasive monitoring of allograft rejection in a
rat lung transplant model: Application of machinelearning-based (18)F-fluorodeoxyglucose positronemission tomography radiomics. J Heart Lung
Transplant. 2022;41(6):722-31.
12. Tian D, Yan HJ, Shiiya H, Sato M, ShinozakiUshiku A, Nakajima J. Machine learning-based
radiomic computed tomography phenotyping ofthymic epithelial tumors: Predicting pathologicaland survival outcomes. J Thorac Cardiovasc Surg.

2212023;165(2):502-16.e9.
13. Yamaguchi H, Sato M, Yamamoto K, Shinohara
K, Yanagiya M, Hashisako M, et al. Availabilityof virtual-assisted lung mapping affects
procedure selection for early-stage lung cancer: a
web-based cross-sectional study. Eur J
Cardiothorac Surg. 2022;63(1).
14. Yamaguchi H, Sato M, Yamamoto K, Ueda K,
Date H, Chen-Yoshikawa T, et al. Virtual-assistedlung mapping in sublobar resection of small
pulmonary nodules, long-term results. Eur J
Cardiothorac Surg. 2022;61(4):761-8.
15. Yanagiya M, Sato M, Ijiri N, Kobayashi K,
Nagano M, Konoeda C, et al. Virtual-assistedlung mapping using dual staining withindocyanine green and indigo carmine enhanced
marking detectability. J Thorac Dis. 2022;14(4):1061-9.
16. Yoshiyasu N, Sato M, Yamaguchi H, Nakajima J.
Risk Factors for Invisible Intraoperative
Markings After Virtual-Assisted Lung Mapping.
Ann Thorac Surg. 2022;114(5):1903-10.
17. Yoshiyasu N, Sato M, Yasui T, Takami M,
Kawahara T, Konoeda C, et al. Thoracic
mediastinal-occupying ratio predicts recovery
and prognosis after lung transplantation. Interact
Cardiovasc Thorac Surg. 2022;35(3).
18. Ando T, Kage H, Shinozaki-Ushiku A, Tatsuno K,
Tsutsumi S, Nagayama K, et al. Composite
Clonal Analysis Reveals Transition of NSCLC
Subtypes Through Accumulation of Gene
Mutations: A Case Report. JTO Clin Res Rep.
2022;3(2):100277.
19. Hanabusa Y, Kubo T, Watadani T, Nagano M,
Nakajima J, Abe O. Successful transcatheter
arterial embolization for a massive hemothorax
caused by acupuncture. Radiol Case Rep. 2022;
17(9):3107-10.
20. Kuriki Y, Yoshioka T, Kamiya M, Komatsu T,
Takamaru H, Fujita K, et al. Development of afluorescent probe library enabling efficient
screening of tumour-imaging probes based on
discovery of biomarker enzymatic activities.
Chem Sci. 2022;13(16):4474-81.
21. Kuroda H, Koyama S, Mun M, Nakajima J, Funai
K, Yoshino I, et al. Survival Outcomes ofComplete Pulmonary Metastasectomy for Headand Neck Squamous Cell Carcinomas. Cancer
Manag Res. 2022;14:3095-103.
22. Sato C, Kubo T, Shibata E, Yanagiya M,
Nakajima J, Abe O. Successful transcatheter
embolization of an unruptured idiopathic
peripheral pulmonary artery aneurysm. Radiol
Case Rep. 2023;18(1):8-10.
23. Sun C, Anraku M, Nakajima J. ASO Author
Reflections: An Evolving Skeletal Muscle
Profiling-Towards Precise Host Phenotype andPrognostic Stratification in Non-small Cell Lung
Cancer. Ann Surg Oncol. 2022;29(3):1825-6.
24. Sun C, Nagaoka K, Kobayashi Y, Maejima K,
Nakagawa H, Nakajima J, et al. Immunotherapies
targeting neoantigens are effective in PD-1
blockade-resistant tumors. Int J Cancer. 2023;
152(7):1463-75.

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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., Hyoe Komae, M.D., Ph.D.,
Tomoyuki Iwase, M.D., Ph.D., Miyuki Shibata, M.D., Ph.D., Takayuki Gyoten, M.D.,
Kazuki Yakuwa, M.D.

Homepage

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

Introduction and Organization
Cardiac surgery in the Department was initiated by
Dr. Seiji Kimoto, who performed ligation of patentductus arteriosus in June, aortic arch aneurysm
resection in July and first-in-Japan Blalock-Taussig
operation for Tetralogy of Fallot in October in 1951.
He also started implantation of alcohol-preserved
aortic homograft for abdominal aortic aneurysm in
1952, and closed commissurotomy for mitral valve
stenosis in 1954. The first open heart surgery (atrial
septal defect closure) was performed in 1955, using
selective brain perfusion cooling method that wasdeveloped in the Department.
Establishment of Department of Thoracic Surgery
in the University of Tokyo Hospital was approved by
the government first in Japan December 15, 1964.
Under the leadership of Professor Kimoto excellent
research works were created especially on pacemakerand artificial heart, and many opinion leaders were
produced. Dr. Masahiro Saigusa, the second Professor,
endeavored to make open heart surgery safer byintroducing new- generation heart-lung machines tothe Department. Dr. Kenichi Asano, the third

Professor, started posterior-leaflet preserving mitralvalve replacement first in Japan. He also dramatically
improved surgical results of Tetralogy of Fallot. Dr.
Akira Furuse, the fourth Professor, modernizedmanagement of extremely busy clinical works. During
this time, the Department was divided into two
Divisions, Cardiovascular and General thoracic, due
to the University policy of Graduate-school.
Dr. Shinichi Takamoto assumed the fifth Professor
in June 1997. He rearranged clinical teams into threegroups (adult cardiac disease, thoracic aortic diseaseand congenital heart disease) to adapt the rapid
progress of cardiovascular surgery.
Dr. Minoru Ono was elected as the sixth Professor
in November 2009. Advanced Heart Failure Center
was open on the 5th Floor of Hospital Building B,
January 2018 to cope with an increasing number ofpatients who require ventricular assist device andheart transplantation treatment. Present staffs are one
Chief Professor, one Associate Professor and three
Lecturer and seven Associates.

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Clinical Activities
Clinical conference starts at 7:15 am in weekdays.
Regular surgery is scheduled on every weekday. Adult
patients are hospitalized in the South Wing of 5th floor,
and pediatric patients in the South Wing of 2nd floor.
Clinics are open Monday through Friday for thefollow-up visit as well as for patient referral.
Case volume in recent years has been over 400,
which is one of the highest in Japan. We are leading inJapan by showing excellent surgical results. There are
10 Board-certified cardiovascular surgeons, each ofwhom has his own subspecialty among adult cardiac,thoracic aortic or congenital heart disease. We are
famous for off- pump coronary artery bypass surgery,mitral valve plasty, heart transplantation, ventricularassist device implantation, aortic valve sparing root
replacement, arch replacement, treatment of extended
thoracic aortic aneurysm and repair of complex
congenital heart diseases, such as Jatene, Fontan and
Norwood operations. Transcatheter aortic valve
replacement was initiated in 2015. Many high-riskvery old patients with aortic valve stenosis weresuccessfully treated.
The University of Tokyo Tissue Bank was founded
in 1997, based on the Department of Cardiovascular
Surgery. The Bank has been actively promoting
procurement, preservation and shipping of humanvalve and blood vessel allograft in Japan. We take thelead in surgical treatment using allograft for severe
active endocarditis or infection of aortic aneurysm or
vascular prosthesis. Surgical treatment using allograft
was approved for health insurance coverage by theGovernment in 2018. As of March 2023, 197 cases ofheart transplantation including 15 pediatric patientsand 413 cases of ventricular assist device (VAD)
implantation
including274
implantable
continuous-flow VADs were performed in The
University Hospital with excellent long-term survival.

Teaching Activities
We have the chair of systematic review of cardiovascular surgery in the spring term at the 2nd grade of
medical course. We expose the students to dailyclinical works as well as research works during thecourse of “Free Quarter” and “Research Lab Visit”,
which are scheduled in the summer and springvacations at 1st and 2nd grade. Joint lectures with the
Cardiology Department are scheduled 3rd through 4th
grades. Each student is assigned one or two
cardiovascular surgical cases in the Regular ClinicalClerkship, in which he/she is required to learn
preoperative patient evaluation and management,
surgical treatment and postoperative care, based onparticipatory practice. There are also fifteen small
key-lectures on cardiovascular surgery. Hands-on
practice is provided during the Advanced ClinicalClerkship one-month course in the last months of 3rd
grade.
We take charge in core surgical curriculum in the“Super-rotation” postgraduate training. We offer a
program in which each resident can learn basic
knowledge of cardiovascular disease and surgery, andhemodynamic and respiratory evaluation as well asbasic surgical techniques and patient management.
Residents who take the course of cardiovascularsurgery are required three-year general surgicaltraining for General Surgery Board certification. We
have well-developed specialty/subspecialty training
programs to allow the residents to pass Cardiovascular
Board Examination by 9-10th postgraduate year.

Research Activities
In order to achieve excellent clinical results and toseek for new possibilities of surgical treatments, it isessential for cardiothoracic surgical department of the
University to have active research programs in clinicaland basic subjects. The Cardiothoracic Department of
the University of Tokyo has created highly active
research programs in the every field of cardiothoracic
surgery, played an internationally leading role andcontributed to its development. A research meeting isheld once a month on a research project for every
member of the department to understand and to makefree thorough discussions of the subject.
Basic and/or clinical research activities are focusedon 1) establishment of recovery and weaning
protocols of left ventricular assist device, 2) basic andclinical research on cryopreserved allograft, 3)application of regenerative medicine to end-stage
heart failure, 4) analysis of cardiomyocytes matured
and differentiated from iPS cells, 5) mechanism
analysis of right heart failure and development of

224

effective pharmacological and mechanical therapy, 6)
development of versatile suture device, 7) clinicalresearch to test the safety and efficacy of artificial
pancreas during open heart surgery.

References
1.

2.

3.

4.

5.

6.

7.

Ikeda N, Yamamoto H, Taketomi A, Hibi T, Ono
M, Niikura N, Sugitani I, Isozumi U, Miyata H,
Nagano H, Unno M, Kitagawa Y, Mori M. The
impact of COVID-19 on surgical procedures inJapan: analysis of data from the National Clinical
Database. Surg Today. 2022 Jan; 52(1): 22-35.
PMID: 34783905.
Aoyama G, Zhao L, Zhao S, Xue X, Zhong Y,
Yamauchi H, Tsukihara H, Maeda E, Ino K,
Tomii N, Takagi S, Sakuma I, Ono M, Sakaguchi
T. Automatic Aortic Valve Cusps Segmentationfrom CT Images Based on the Cascading
Multiple Deep Neural Networks. J Imaging. 2022
Jan 14;8(1):11. PMID: 35049852.
Terakawa K, Yamauchi H, Lee Y, Ono M. A
Novel Knitted Polytetrafluoroethylene Patch for
Cardiovascular Surgery. Int Heart J. 2022;63(1):122-130. PMID: 35095061.
Ando M, Yamauchi H, Gyoten T, Komae H,
Hoshino Y, Itoda Y, Shimada S, Kimura M,
Kinoshita O, Ono M. Association between left
ventricular ejection fraction and mortality after
Bentall procedure. Heart Vessels. 2022 Aug;37(8):1462-1469. PMID: 35124729.
Tsuji M, Kakuda N, Bujo C, Ishida J, Amiya E,
Hatano M, Shimada A, Imai H, Shimada S,
Kinoshita O, Yamauchi H, Ono M, Komuro I.
Sarcopenia and risk of infection in adult hearttransplant recipients in Japan. ESC Heart Fail.
2022 Apr; 9(2): 1413-1423. PMID: 35146960.
Myers PO, Dayan V, Szeto WY, Thourani VH,
Malaisrie SC, Moon MR, Prager RL, Ono M,
Okita Y, Freemantle N, Milojevic M. Joint
surgical associations (EACTS, LACES, ASCVTS,
AATS, and STS) position statement regarding the
VARC-3 definitions for aortic valve clinicalresearch. J Thorac Cardiovasc Surg. 2022 May;
163(5): 1792-1794. PMID: 35307218.
Kida K, Kanaki T, Gao S, Hatanaka D, Iwakami
M, Liu S, Horikawa M, Ono M, Chang D. A

8.

9.

10.

11.

12.

13.

Novel 3D Culture System Using a Chitin-Based
Polysaccharide Material Produces High-Quality
Allogeneic Human UCMSCs with Dispersed
Sphere Morphology. Cells. 2022 Mar 15;11(6):995. PMID: 35326446.
Sato T, Kobayashi Y, Nagai T, Nakatani T,
Kobashigawa J, Saiki Y, Ono M, Wakasa S,
Anzai T. Long-term preservation of functional
capacity and quality of life in advanced heart
failure patients with bridge to transplant therapy:
A report from Japanese nationwide multicenter
registry. Int J Cardiol. 2022 Jun 1; 356: 66-72.
PMID: 35337935.
Kuramitsu K, Yamanaga S, Osawa R, Hibi T,
Yoshikawa M, Toyoda M, Shimata K, Yosuke E,
Ono M, Kenmochi T, Sogawa H, Natori Y, Yano
H, Chen-Yoshikawa T, Yoshida K, Fukumoto T,
Yuzawa K, Egawa H. Impact of COVID-19 on
the Living Donor Liver and Kidney
Transplantation Programs in Japan in 2020.
Transpl Infect Dis. 2022 Jun;24(3):e13845.
PMID: 35505462.
Gyoten T, Amiya E, Kinoshita O, Tsuji M,
Kimura M, Hatano M, Ono M. Myocardial
recovery evaluation from ventricular assist devicein patients with dilated cardiomyopathy. ESC
Heart Fail. 2022 Aug;9(4):2491-2499. PMID:
35535672.
Narita K, Amiya E, Hatano M, Ishida J,
Minatsuki S, Tsuji M, Bujo C, Kakuda N, Isotani
Y, Ono M, Komuro I. Determining the factors forinterhospital transfer in advanced heart failurecases. Int J Cardiol Heart Vasc. 2022 May 14;
40:101035. doi: 10.1016/j.ijcha.2022.101035.
PMID: 35601528.
Kumamaru H, Kakeji Y, Fushimi K, Ishikawa
KB, Yamamoto H, Hashimoto H, Ono M,
Iwanaka T, Marubashi S, Gotoh M, Seto Y,
Kitagawa Y, Miyata H. Cost of postoperativecomplications of lower anterior resection forrectal cancer: a nationwide registry study of 15,
187 patients. Surg Today. 2022 Dec;52(12):1766-1774. PMID: 35608708.
Hayward C, Adachi I, Baudart S, Davis E, Feller
ED, Kinugawa K, Klein L, Li S, Lorts A, Mahr C,
Mathew J, Morshuis M, Müller M, Ono M,
Pagani FD, Pappalardo F, Rich J, Robson D,

225

14.

15.

16.

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Rosenthal DN, Saeed D, Salerno C, Sauer AJ,
Schlöglhofer T, Tops L, VanderPluym C. Global
best practices consensus: Long-term managementof patients with hybrid centrifugal flow left
ventricular assist device support. J Thorac
Cardiovasc Surg. 2022 Oct;164(4):1120-1137.e2.
PMID: 35624053.
Ko T, Nomura S, Yamada S, Fujita K, Fujita T,
Satoh M, Oka C, Katoh M, Ito M, Katagiri M,
Sassa T, Zhang B, Hatsuse S, Yamada T, HaradaM, Toko H, Amiya E, Hatano M, Kinoshita O,
Nawata K, Abe H, Ushiku T, Ono M, Ikeuchi M,
Morita H, Aburatani H, Komuro I. Cardiac
fibroblasts regulate the development of heart
failure via Htra3-TGF-β-IGFBP7 axis. Nat
Commun. 2022 Jun 7;13(1):3275. PMID:
35672400.
Kawamura S, Koizumi S, Umekawa M,
Miyawaki S, Kinoshita O, Ono M, Saito N.
Long-term benefit of mechanical thrombectomy
for acute ischemic stroke in patients with left
ventricular assist device: a single-center
retrospective study. World Neurosurg. 2022
Sep;165: e331-e336. PMID: 35718273.
Kakuda N, Amiya E, Hatano M, Tsuji M, Bujo C,
Ishida J, Yagi H, Saito A, Narita K, Isotani Y,
Fujita K, Ando M, Shimada S, Kinoshita O, Ono
M, Komuro I. Residual Pulmonary Vascular
Resistance Increase Under Left Ventricular
Assist Device Support Predicts Long-Term
Cardiac Function After Heart Transplantation.
Front Cardiovasc Med. 2022 Jun 1;9:904350. doi:
10.3389/fcvm.2022.904350. PMID: 35722119;
PMCID: PMC9198244.
Ono M. Continuous-flow left ventricular assist
device treatment for arrhythmogenic rightventricular cardiomyopathy complicated byadvanced biventricular failure - University ofTokyo experiences. Front Cardiovasc Med. 2022
Oct 5;9:1023191. PMID: 36277799.
Yoshioka D, Toda K, Ono M, Fukushima N,
Shiose A, Saiki Y, Usui A, Wakasa S, Niinami H,
Matsumiya G, Arai H, Sawa Y, Miyagawa S;
Japanese HeartMateII Investigators. Effect ofDiabetes Mellitus on Outcomes in Patients With
Left Ventricular Assist Device - Analysis of Data
From a Japanese National Database. Circ J.

2022 Nov 25; 86(12): 1950-1958.
PMID:
35786688.
19. Gyoten T, Amiya E, Ono M. SurgicalInterventions for Late Aortic Valve Regurgitation
Associatedwith
Continuous
Flow-Left
Ventricular Assist Device Therapy: Experience
Gained and Lessons Learned. Life (Basel). 2022
Dec 29;13(1):94. PMID: 36676043.
20. Karigyo C, Fonseca J, Andrade A, Ono M. A
Cooperative Environment for Ventricular Assist
Device Development and Application: The
Japanese Experience. Braz J Cardiovasc Surg.
2022 Dec 1;37(6):959-960. PMID: 36441959.
21. Ono M. Durable Ventricular Assist Device for
Bridge to Transplantation. In: Fukushima PN,
editor.
Heart
Transplantation.
London:IntechOpen; 2022 [cited 2022 Feb 05].
doi:10.5772/intechopen.102467
22. Nakamura M, Yaku H, Ako J, Arai H, Asai T, ,Ono M, Shiomi H, Tanemoto K; Japanese
Circulation Society Joint Working Group.
JCS/JSCVS 2018 Guideline on Revascularizationof Stable Coronary Artery Disease. Circ J. 2022
Feb 25;86(3):477-588. PMID: 35095031.
23. Ono M, Yamaguchi O, Ohtani T, Kinugawa K,
Saiki Y, Sawa Y, Shiose A, Tsutsui H,
Fukushima N, Matsumiya G, Yanase M;
JCS/JSCVS/JATS/ JSVS Joint Working Group.
2021 Guideline on Implantable Left Ventricular
Assist Device for Patients With Advanced Heart
Failure. Circ J. 2022 May 25;86(6):1024-1058.
PMID: 35387921.
24. Hatano M, Jimba T, Fujiwara T, Tsuji M, Bujo C,
Ishida J, Amiya E, Kinoshita O, Ono M.
Late-onset right ventricular failure after
continuous-flow left ventricular assist device
implantation: case presentation and review of theliterature. J Cardiol. 2022 Aug;80(2):110-115.
PMID: 34974940.
25. Kunibe Y, Ando M, Komae H, Shimada S,
Kinoshita O, Yamauchi H, Ono M. Perigraft
seroma after total aortic arch replacement using
Triplex graft. Gen Thorac Cardiovasc Surg. 2022
Jul;70(7):668-672. PMID: 35349036.
26. Tsuji S, Shimada S, Itoda Y, Yamauchi H, Ono
M. Aortic valve replacement of a quadricuspid
aortic valve with right coronary artery ostium

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adjacent to one of the commissures. J
Cardiothorac Surg. 2022 Jun 7;17(1):146. PMID:
35672828.

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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
Shoh Yajima M.D. Ph.D.

Masayuki Urabe M.D., Ph.D.

Yoshiyuki Miwa M.D. Ph.D

Asami Okamoto M.D., Ph.D.

Shuichiro Oya M.D. Ph.D

Homepage

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228

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 80
gastric and 70 esophageal cancer surgeries are
performed a year, respectively. Hernia surgery is also
performed. Laparoscopic sleeve gastrectomy formorbid obesity has started in June 2016, and thenumber of cases is steadily increasing. All residents
and medical personnel work with high motivation for
the good of the patients.

References
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Itamoto K, Kumamaru H, Aikou S, Yagi K,
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Y.No association between hospital volume and

229

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short term outcomes of some common surgeries:
a retrospective cohort study based on a Japanesenationwide database. Surg Today 52(6): 941-952,
2022
Iwata R, Shiomi S, Aikou S, Yagi K, Yamashita
H, Seto Y. Optimal settings of near-infrared
fluorescence imaging with indocyanine green for
intraoperative detection of lymph node metastasis
in esophageal cancer. Gen Thorac Cardiovasc Sur
70(10): 924-929, 2022
Konishi K, Fujiogi M, Michihata N, Kumazawa
R, Ohbe H, Matsui H, Fushimi K, Ogita M,
Tanabe M, Seto Y, Yasunaga H. Interstitial lungdisorders following postoperative radiotherapy
with concurrent or sequential hormonal therapy
for breast cancer: a nationwide database study inJapan. Breast cancer 29: 688-697, 2022
Konishi K, Fujiogi M, Michihata N, Matsui H,
Tanabe M, Seto Y, Yasunaga H. Association
between body mass index and incidence of breast
cancer in premenopausal women: A Japanesenationwide database study. Breast Cancer Res
and Treat 194: 315-325, 2022
Konishi K, Fujiogi M, Michihata N, Morita K,
Mtsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Association of operative day of theweek with the length of stay and total
hospitalization costs in patients with partial
mastectomy: a nationwide database study inJapan. JMAJ 5: 319-327, 2022
Konishi K, Fujiogi M, Michihata N, Niwa T,
Morita K, Matsui H, Fushimi K, Tanabe M, Seto
Y, Yasunaga H. Impact of body mass index on
short-term outcomes after differentiated thyroid
cancer surgery: a nationwide inpatient databasestudy in Japan. Eur Thyroid J 11(1): e210081.
2022
Konishi K, Fujiogi M, Sato A, N Michihata N,
Kumazawa R, Matsui H, Fushimi K, Tanabe M,
Seto Y, Yasunaga H. Short-Term outcomes
following breast cancer surgery with and without
neoadjuvant chemotherapy: a nationwide
administrative database study in Japan. Ann Surg
Oncol 29: 3000-3010, 2022
Konishi K, Fujiogi M, Sato A, N Michihata N,
Kumazawa R, Matsui H, Fushimi K, Tanabe M,
Seto Y, Yasunaga H. ASO visual abstract:

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short-term outcomes following breast cancer
surgery with and without neoadjuvant chemotherapy: a nationwide administrative databasestudy in Japan. Ann Surg Oncol 29: 3013, 2022
Konishi K, Fujiogi M, Tanabe M, Seto Y,
Yasunaga H.
ASO author reflections:neoadjuvant chemotherapy does not affectshort-term outcomes after breast cancer surgery.
Ann Surg Oncol 29: 3011-3012, 2022
Konishi K, Goto T, Fujiogi M, Michihata N,
Kumazawa R, Matsui H, Fushimi K, Tanabe M,
Seto Y, Yasunaga H. New machine learning
scoring system for predicting postoperative
mortality in gastroduodenal ulcer perforation: A
study using a Japanese nationwide inpatient
database. Surgery171(4): 1036-1042, 2022
Konishi T, Fujiogi M, Michihata N, Ohbe H,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Cost-effectiveness analysis of
trastuzumab monotherapy versus adjuvant
chemotherapy plus trastuzumab in elderly
patients with HER2-positive early breast cancer.
Jpn J Clin Oncol 52: 1115-1123, 2022
Konishi T, Fujiogi M, Shigemi D, Matsui H,
Fushimi K Tanabe M, Seto Y, Yasunaga H.
Risk factors for postoperative bleeding following
breast cancer surgery: A nationwide databasestudy of 477, 108 cases in Japan. World J Surg
46: 3062-3071, 2022
Konishi T, Fujiogi M, Shigemi D, Nishioka K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Surgical and obstetric outcomesof breast cancer surgery during pregnancy: anationwide database study in Japan. Breast
Cancer Res and Treat 195: 289-299, 2022
Konishi T, Takamoto T, Fujiogi M, Hashimoto Y,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Laparoscopic versus open distal
pancreatectomy with or without splenectomy: Apropensity score analysis in Japan. Int J Surg
104: 106765, 2022
Konishi T, Tanabe M, Michihata N, Matsui H,
Nishioka K, Fushimi K, , Seto Y, Yasunaga H.
Risk factors for arm lymphedema following
breast cancer surgery: a Japanese nationwide
database study of 84, 022 patients. Breast cancer
30: 36-45, 2022

230

16. Konishi T, Yoshimoto T, M Fujiogi, H Yamana,
Tanabe M, Seto Y, Yasunaga H. Validity ofoperative information in Japanese administrative
data: a chart review-based analysis of 1221 cases
at a single institution. Surg Today 52;1484-1490,
2022
17. Niwa T, Konishi T, Sasahara A, Sato A,
Morizono A, Harada M, Nishioka K, Fukuoka O,
Makise N, Saito Y, Ando M, Yoshimoto T,
Shikama T, Yamashita S, Tanabe M, Seto
Y.Subcutaneous axillary primary epithelioid
hemangioendothelioma: report of a rare case.
Surg Case Rep 9;8(1): 166, 2022
18. Okamoto A, Aikou S, Iwata R, Oya S, Kawasaki
K, Okumura Y, Yagi K, Yamashita H, Nomura S,
Seto Y. The type of gastrectomy affects skeletal
muscle loss and the long-term outcomes of
elderly patients with gastric cancer: aretrospective study using computed tomography
images. Surg Today 52(5): 812-821, 2022
19. Saito N, Sato Y, Abe H, Wada I, Kobayashi Y,
Nagaoka K, Kushihara Y, Ushiku T, Seto Y,
Kakimi K. Selection of RNA-based evaluation
methods for tumor microenvironment bycomparing with histochemical and flow
cytometric analyses in gastric cancer. Scientific
Reports 20;12(1): 8576, 2022
20. Shiomi S, Yajima S, Yoshimura S, Urabe M, Ri
M, Okumura Y, Yagi K, Aikou S, Nomura S,
Seto Y. Optimal criteria for predicting lymph
node metastasis in esophageal squamous cell
carcinoma by anatomical location using preoperative computed tomography: a retrospective
cohort study. Surg Today 52(8): 1185-1193,
2022
21. Sugawara K, Yagi K, Aikou S, Yamashita H,
Seto Y. Impacts of complications after
esophageal cancer surgery on health-related
quality of life and nutritional status. Gen Thorac
Cardiovasc Surg. doi: 10.1007/s11748-02201846-y, 2022
22. Sugawara K, Yagi K, Okumura Y, Aikou S,
Yamashita H, Seto Y. Survival Prediction
Capabilities of Preoperative Inflammatory andNutritional Status in Esophageal Squamous Cell
Carcinoma Patients. World J Surg 46(3): 639647, 2022

23. Sugawara K, Yamashita H, Urabe M, Okumura Y,
Yagi K, Aikou S, Seto Y.
Combining
nutritional status with TNM stage: aphysiological update on gastric cancer staging for
improving prognostic accuracy in elderly patients.
Int J Clin Oncol 27(12): 1849-1858, 2022
24. Toriumi T, Yagi K, Ri M, Yajima S, Okumura Y,
Aikou S, Yamashita H, Nomura S, Seto Y.
Lymphatic invasion is a prognostic factor of
pathological N0 esophageal squamous cell
carcinoma Dis Esophagus 35(7): doab087.doi:
10.1093/dote/doab087, 2022
25. Urabe M, Yagi K, Shiomi S, Toriumi T,
Okumura Y, Seto Y. Implications ofliver-directed therapy for postoperative hepatic
metastasis from esophageal cancer.J Chest Surg
55(5): 397-404, 2022
26. Yasuda T, Lee HS, Nam SY, Katoh H, Ishibashi
Y, Yamagata Murayama S, Matsui H, Masuda H,
Rimbara E, Sakurazawa N, Suzuki H, Yoshida H,
Seto Y, Ishikawa S, Jeon SW, Nakamura M,
Nomura S. Non-Helicobacter pylori Helicobacter(NHPH) positive gastric cancer. Sci Rep12(1):4811.doi: 10.1038/s41598-022-08962-y, 2022
27. Zhang CD, Takeshima H, Sekine S, Yamashita S,
Liu YY, Hattori N, Abe H, Yamashita H, Fukuda
M, Imamura Y, Ushiku T, Katai H, Makino H,
Watanabe M, Seto Y, Ushijima T. Prediction oftissue origin of adenocarcinomas in theesophagogastric junction by DNA methylation.
Gastric Cancer 25(2): 336-345, 2022
28. Zhang CD, Yamashita H, Okumura Y, Yagi K,
Aikou S, Seto Y. Signature and Prediction of
Perigastric Lymph Node Metastasis in Patientswith Gastric Cancer and Total Gastrectomy: Is
Total Gastrectomy Always Necessary? . Cancers(Basel) 14(14): 3409. doi: 10.3390/cancers
14143409, 2022

231

Hepato-biliary-Pancreatic Surgery
Division and Artificial Organ
and Transplantation Division
Professor and Chairman
Kiyoshi Hasegawa, M.D., Ph.D.

Associate Professor
Nobuhisa Akamatsu, M.D., Ph.D.

Lecturers
Junichi Kaneko, M.D., Ph.D.
Yoshikuni Kawaguchi, M.D., Ph.D.

Homepages

http://www.u-tokyo-hbp-transplant-surgery.jp/

Introduction and Organization
The Hepato-Biliary-Pancreatic (HBP) Surgery
Division, Artificial Organ and Liver Transplantation
Division, Department of Surgery is originated from
Second Department of Surgery (2nd Dept of Surg),
which was established in 1893. This department has ahistory of over 130 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

232

consents, diagnosis, presentation at the conferences,
operative procedures, and postoperative managements.
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 (2022)
1.

2.

3.

4.

5.

Kokudo T, Kokudo N, Hasegawa K. Oncologicalbenefit of anatomic resection for patients with
hepatocellular carcinoma. Surg Today. 2022 Dec
7. Online ahead of print.
Ishizawa T, Akamatsu N, Kaneko J, Arita J,
Hasegawa K. Closure and anastomosis of thepancreas using a four-needle three-loop suture
device. Glob Health Med. 2022 Aug 31;4(4):225229.
Hakoda H, Kiritani S, Kokudo T, Yoshimura K,
Iwano T, Tanimoto M, Ishizawa T, Arita J,
Akamatsu N, Kaneko J, Takeda S, Hasegawa K.
Probe electrospray ionization mass spectrometrybased rapid diagnosis of liver tumors. J
Gastroenterol Hepatol. 2022 Nov;37(11):21822188.
Kokudo T, Ishizawa T, Nagata R, Ichida A,
Mihara Y, Kawaguchi Y, Akamatsu N, Kaneko J,
Arita J, Kokudo N, Hasegawa K. Optimal tumor
numbers in surgical candidates for multiple
hepatocellular carcinomas. Surgery. 2022 Oct;172(4):1174-1178.
Bae SK, Arita J, Akamatsu N, Maki H, Nishioka
Y, Kawahara T, Miyata A, Kokudo T, Nagata R,
Mihara Y, Ichida A, Inagaki Y, Kawaguchi Y,

Ishizawa T, Kaneko J, Tamura S, Tanaka Y,
Moriya K, Hasegawa K. The impact of thecovalently closed circular DNA level onrecurrence of hepatocellular carcinoma after
initial hepatectomy: an analysis of patients withresolved hepatitis B virus infection. HPB(Oxford). 2022 Oct;24(10):1780-1788.
6. Kazami Y, Arita J, Nishioka Y, Kawaguchi Y,
Ichida A, Ishizawa T, Akamatsu N, Kaneko J,
Nakai Y, Koike K, Hasegawa K. Preoperative
Predictive Features of Invasive Carcinoma
Among
Intraductal
Papillary
Mucinous
Neoplasm of the Pancreas. Pancreas. 2022 Jul 1;
51(6):642-648.
7. Maki H, Hasegawa K. Advances in the surgicaltreatment of liver cancer. Biosci Trends. 2022 Jul
20;16(3):178-188.
8. Kiritani S, Kaneko J, Arita J, Ishizawa T,
Akamatsu N, Hasegawa K. Radical Antegrade
Modular Pancreatosplenectomy for Left-Sided
Pancreatic Ductal Adenocarcinoma May Reduce
the Local Recurrence Rate. Dig Surg. 2022;
39(4):191-200.
9. Takahashi R, Akamatsu N, Nakazawa A, Nagata
R, Ichida A, Kawaguchi Y, Ishizawa T, Kaneko J,
Arita J, Hasegawa K. Effect of the response topreoperative treatment for hepatorenal syndromeon the outcome of recipients of living-donor livertransplantation. J Hepatobiliary Pancreat Sci.
2022 Jul;29(7):798-809.
10. Arita J, Ichida A, Nagata R, Mihara Y,
Kawaguchi Y, Ishizawa T, Akamatsu N, Kaneko J,
Hasegawa K. Conversion surgery after
preoperative therapy for advanced hepatocellular
carcinoma in the era of molecular targeted
therapy and immune checkpoint inhibitors. J
Hepatobiliary Pancreat Sci. 2022 Jul;29(7):732740.
11. Watanabe G, Mise Y, Oba M, Saiura A, Inoue Y,
Takahashi Y, Kishi Y, Suyama K, Takayama T,
Noie T, Nishioka Y, Akamatsu N, Arita J, Kokudo
N, Hasegawa K. A multicenter phase II trial
evaluating the efficacy of bevacizumab plus
mFOLFOX6 for R0 surgical resection inadvanced colorectal liver metastases harboring
mutant-type KRAS: NEXTO-mt trial. HPB(Oxford). 2022 Aug;24(8):1245-1251.

233

12. Matsumura M, Hasegawa K, Oba M, Yamaguchi
K, Uetake H, Yoshino T, Morita S, Takahashi K,
Unno M, Shimada Y, Muro K, Matsuhashi N,
Mori M, Baba H, Shimada M, Mise Y,
Kawaguchi Y, Kagimura T, Ishigure K, Saiura A,
Sugihara K, Kokudo N. A randomized controlled
trial of surgery and postoperative modified
FOLFOX6 versus surgery and perioperative
modified FOLFOX6 plus cetuximab in patientswith KRAS wild-type resectable colorectal liver
metastases: EXPERT study. Langenbecks Arch
Surg. 2022 Jun;407(4):1345-1356.
13. Ichida A, Akamatsu N, Nagata R, Mihara Y,
Kawaguchi Y, Bae SK, Ishizawa T, Kaneko J,
Arita J, Hasegawa K. Efficacy and Safety ofLenvatinib for the Treatment of Recurrent
Hepatocellular Carcinoma After Living Donor
Liver Transplantation: A Report of Two Cases.
Anticancer Res. 2022 Feb;42(2):1161-1167.
14. Kawaguchi Y, Fuks D, Vauthey JN, Kokudo N,
Gayet B, Hasegawa K. A novel simple three-level
liver resection classification without compromising the performance to predict surgical andpostoperative outcomes. Eur J Surg Oncol. 2022
Jan;48(1):305-306.
15. Kazami Y, Kaneko J, Keshwani D, Takahashi R,
Kawaguchi Y, Ichida A, Ishizawa T, Akamatsu N,
Arita J, Hasegawa K. Artificial intelligenceenhances the accuracy of portal and hepatic vein
extraction in computed tomography for virtual
hepatectomy. J Hepatobiliary Pancreat Sci. 2022
Mar;29(3):359-368.
16. Watanabe G, Kawaguchi Y, Ichida A, Ishizawa T,
Akamatsu N, Kaneko J, Arita J, Hasegawa K.
Understanding conditional cumulative incidenceof complications following liver resection to
optimize hospital stay. HPB (Oxford). 2022 Feb;
24(2):226-233.
17. Okada Y, Kawaguchi Y, Matsumura M,
Matsubara S, Nakai Y, Ichida A, Ishizawa T,
Akamatsu N, Kaneko J, Arita J, Koike K,
Hasegawa K. A safe sequential treatment
approach for patients who have acutecholecystitis
withsevereinflammation:
Transmural gallbladder drainage followed bylaparoscopic cholecystectomy under the guidanceof fluorescence imaging. Asian J Endosc Surg.

2022 Jan;15(1):230-234.
18. Ishizawa T, McCulloch P, Stassen L, van den Bos
J, Regimbeau JM, Dembinski J, SchneiderKoriath S, Boni L, Aoki T, Nishino H, Hasegawa
K, Sekine Y, Chen- Yoshikawa T, Yeung T,
Berber E, Kahramangil B, Bouvet M, Diana M,
Kokudo N, Dip F, White K, Rosenthal RJ.
Assessingthedevelopment
statusofintraoperative fluorescence imaging for anatomy
visualisation, using the IDEAL framework. BMJ
Surg Interv Health Technol. 2022 Nov 4;4(1):e000156.
19. Karako K, Mihara Y, Arita J, Ichida A, Bae SK,
Kawaguchi Y, Ishizawa T, Akamatsu N, Kaneko J,
Hasegawa K, Chen Y. Automated liver tumor
detection in abdominal ultrasonography with amodified faster region-based convolutional
neural networks (Faster R-CNN) architecture.
Hepatobiliary Surg Nutr. 2022 Oct;11(5):675683.
20. Kiritani S, Arita J, Mihara Y, Nagata R, Ichida A,
Kawaguchi Y, Ishizawa T, Akamatsu N, Kaneko J,
Hasegawa K. Venous invasion and lymphatic
invasion are correlated with the postoperative
prognosis of pancreatic neuroendocrine neoplasm.
Surgery. 2023 Feb;173(2):365-372.

234

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

Assistant Professor
Daisuke Yamada, M.D., Ph.D., Yusuke Sato, M.D., Ph.D.,
Yuta Yamada, M.D., Ph.D., Yoshiyuki Akiyama, M.D., Ph.D.,
Satoru Taguchi, M.D., Ph.D.

AssociateKenji Yoda, M.D., Kanae Yoshida, M.D., Yoichi Fujii, M.D., Ph.D.,
Daiji Watanabe, M.D., Shintaro Takahashi, M.D., Norihide Shirakawa, M.D.,
Hayato Hoshina, M.D., Kenichi Hashimoto, Ph.D.

Homepage

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

Introduction and Organization
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.

Clinical activities
There are 44 beds in the ward (8th floor of the centralward-building). The professor, associate professors,
lecturers and associates are involved in in-patient andout-patient cares and teaching of the students as well
as research activities. Clinical visiting professors aremainly engaged in the teaching. The residents takecare of all the patients on 24-hour a day basis.
Associate staff members team up with the residents on
a man-to-man basis. Elective operations are performedon every weekday (from Monday to Friday). 1753
operations were performed in 2022. The numbers of
main operations are adrenalectomy 12, nephrectomy
20, partial nephrectomy 71, nephroureterectomy 14,
radical cystectomy 18, radical prostatectomy 121,transurethral resection of the bladder tumor (TUR-Bt)
190, transurethral resection of the prostate (TUR-P) 9,
androbot-assisted
surgeries
204(radicalprostatectomy 121, partial nephrectomy 59, radical
cystectomy 17, pyeloplasty 7).
At the weekly professor’s round on Wednesday, dataof all in patients are presented and appropriate

235

treatment strategies are recommended for them. On
Wednesday evening, a clinical conference is held for
discussing cases with difficult problems in detail andthe best treatment is chosen for each case.
In out-patient clinic, services are provided from
Monday to Friday. Patients assigned to specialized
services as renal tumor, adrenal surgery, bladdercancer, prostate cancer, andrology, neurourology,
urolithiasis, kidney transplantation, second opinion,
pediatric urology and female urology receive
sophisticated care on the particular day of the week.
The total number of out-patients was 26,296 patientdays from January 2022 to December 2022.

References
1.

2.

3.

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.

4.

5.

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

6.

7.

Takayama T, Sugihara T, Kameda T, Yamazaki M,
Komatsubara M, Kamei J, Fujisaki A, Ando S,
Fujimura T. Treatment outcome of radium-223
treatment for castration-resistant prostate cancer
and bone metastases at a single university
hospital. Int J Radiat Res, 20(1), 75-81,2022.1.
Jimba M, Matsuzawa Y, Suzuki M, Kitamura T,
Carandang RR, Sieber NL. Risk of increasing thesudden diagnosis of AIDS in Japan during andafter COVID-19 outbreak. JMA J, 5(1), 104-106,2022.1.
Zaitsu M, Takeuchi T, Zaitsu M, Tonooka A,
Uekusa T, Miyake Y, Kobayashi Y, Kobashi G,
Kawachi I. Occupational disparities in tumor
grade and cytosolic HMGB1 expression in renal
cell cancer. J Occup Health, 64(1), e12340,2022.
1.
Oshina T, Taguchi S, Miyakawa J, Akiyama Y,
Sato Y, Kawai T, Fukuhara H, Nakagawa T,
Kume H. Clinicopathological features andoncological outcomes of urothelial carcinoma
involving the ureterovesical junction. Jpn J Clin
Oncol, 52(1), 65-72,2022.1.
Hagiwara K, Sakamoto A, Sasaki K, Kanatani A,
Kimura M, Kaneko T, Takahashi S, Yamada Y,
Nakagawa T. Higher serum alkaline phosphatasevalue indicates the need for bone mineral density
testing in non-metastatic prostate cancer patients
undergoing androgen deprivation therapy. Jpn J
Clin Oncol, 52(1), 73-80,2022.1.
Tohi Y, Kato T, Nakamura M, Matsumoto R,
Sasaki H, Mitsuzuka K, Inokuchi J, Hashine K,
Yokomizo A, Naito H, Hara I, Kawamura N,
Inoue M, Fukuhara H, Maruyama S, Sakamoto S,
Saito T, Egawa S, Kakehi Y, Sugimoto M.
Deferred radical prostatectomy in patients who
initially elected for active surveillance: amulti-institutional, prospective, observational
cohort of the PRIAS-JAPAN study. Int J Clin
Oncol, 27(1), 194-201,2022.1.
Kinjo M, Tanba M, Masuda K, Nakamura Y,
Tanbo M, Fukuhara H. Comparison ofeffectiveness between modified transvaginal
mesh surgery and vaginal pessary treatment in

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8.

9.

10.

11.

12.

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patients with symptomatic pelvic organ prolapse.
Low Urin Tract Symptoms, 14(1), 64-71,2022.1.
Sasaki T, Ebara S, Tatenuma T, Ikehata Y,
Nakayama A, Kato D, Toide M, Yoneda T,
Sakaguchi K, Teishima J, Makiyama K, Kitamura
H, Saito K, Koie T, Koga F, Urakami S, Inoue T.
Prognostic differences among Grade Group 4
subgroupsinrobotic-assisted
radicalprostatectomy. BJUI Compass, 3(5), 392-399,
20221.1.
Kinoshita Y, Katano S, Nishida S, Shimizu T,
Fujimura T, Kume H, Iwami D. Creatinine
reduction ratio on postoperative day 2 predicts
long-term outcomes after living donor kidneytransplantation. Int J Urol, 29(2), 114-120,2022.
2.
Kubo T, Takayama T, Fujisaki A, Nakamura S,
Teratani T, Sata N, Kitayama J, Nakai H, Iwami
D, Fujimura T. Novel high-quality and reality
biomaterial as a kidney surgery simulation model.
PLoS ONE, 17(2), e0263179,2022.2.
Kawai T, Taguchi S, Nakagawa T, Kamei J,
Nakamura Y, Obinata D, Yamaguchi K, Kaneko T,
Kakutani S, Tokunaga M, Uemura Y, Sato Y,
Enomoto Y, Nishimatsu H, Fujimura T, Fukuhara
H, Takahashi S, Kume H. Impact of immunerelated adverse events on the therapeutic efficacy
of pembrolizumab in urothelial carcinoma: amulticenter retrospective study using timedependent analysis. J Immunother Cancer, 10(2),e003965,2022.2.
Matsunaga A, Yoshida M, Shinoda Y, Sato Y,
Kamei J, Niimi A, Fujimura T, Kume H, Igawa Y.
Effectiveness of ultrasound-guided pelvic floor
muscle training in improving prolonged urinary
incontinence
after
robot-assisted
radicalprostatectomy. Drug Discov Ther, 16(1), 37-42,
2022.2.
Takeuchi T, Hattori-Kato M, Okuno Y, Zaitsu M,
Azuma T. Genome-Wide Association Study
Adjusted for Occupational and Environmental
Factors for Bladder Cancer Susceptibility. Genes(Basel), 13(2), 448,2022.2.
Shin Kumagai, Osamu Muraki, Yasukuni
Yoshimura. Evaluation of the effect of levator ani
muscle contraction on post-prostatectomyurinary

15.

16.

17.

18.

19.

20.

21.

incontinence using cine MRI. Neurourol Urodyn,
41(2), 616-625,2022.2.
Yokomizo A, Yonese J, Egawa S, Fukuhara H,
Uemura H, Nishimura K, Nagata M, Saito A, Lee
T, Yamaguchi S, Nonomura N. Real-world use of
enzalutamide in men with nonmetastatic
castration-resistant prostate cancer in Japan. Int J
Clin Oncol, 27(2), 418-426,2022.2.
Tohi Y, Kato T, Yokomizo A, Mitsuzuka K,
Tomida R, Inokuchi J, Matsumoto R, Saito T,
Sasaki H, Inoue K, Kinoshita H, Fukuhara H,
Maruyama S, Sakamoto S, Tanikawa T, Egawa S,
Ichikura H, Abe T, Nakamura M, Kakehi Y,
Sugimoto M. Impact of health-related quality oflife on repeat protocol biopsy compliance on
active surveillance for favorable prostate cancer;
results from a prospective cohort in the Prostate
CancerResearch
International:
ActiveSurveillance (PRIAS)-JAPAN study. Urol Oncol,
40(2), 56.e.9-e15,2022.2.
Mizuno T, Satho N, Horita S, Tsukada H, Takagi
M, Sato Y, Kume H, Nangaku M, Nakamura M.
Oxidized alkyl phospholipids stimulate sodiumtransport in proximal tubules via a non-genomic
PPARγ-dependent pathway. J Biol Chem, 298（3）,101681,2022.3.
Ando S, Kamei J, Yamazaki M, Sugihara T,
Kameda T, Fujisaki A, Kurokawa S, Takayama T,
Fujimura T. Longer preserved urethral length inrobot-assisted radical prostatectomy significantly
contributes to post-operative urinary continence
recovery. BJUI Compass, 3(2), 184-190,2022.3.
Takayama T, Kameda T, Nakano K. Female-onlyUreteral Stent Placement and Replacement
Technique Using Pig-tail Straightener. Dokkyo
Medical Journal, 1(1), 81-83,2022.3.
Nagamoto S, Urakami S, Oka S, Ogawa K, Kono
K, Sakaguchi K, Kinowaki K, Yamada D, Kume
H. Impact of the neutrophil-to-lymphocyte ratio
as a surgical prognostic factor in renal cell
carcinoma with inferior vena cava tumor
thrombus. Asian J Surg, 46(1), 192-200,2022.3.
Makino K, Sato Y, Takenaka K, Yamashita H,
Akiyama Y, Yamada Y, Nakamura M, Kawai T,
Yamada D, Suzuki M, Kume H. Cumulative
incidence and clinical risk factors of radiation

237

22.

23.

24.

25.

26.

27.

28.

cystitis after radiotherapy for prostate cancer.
Urol Int, Online ahead of print,2022.3.
Yoshida, S., Matsushima, H., & Fujii, Y.
Classification of oligometastatic prostate cancer
with additional consideration for hormone
sensitivity. World journal of urology, 40(3),871-873,2022.3.
Akiyama Y, Niimi A, Igawa Y, Nomiya A,
Yamada Y, Sato Y, Kawai T, Yamada D, Kume H,
Homma Y. Cystectomy for patients with
Hunner-type interstitial cystitis at a tertiaryreferral center in Japan. Low Urin Tract
Symptoms, 14(2), 102-108,2022.3.
Mochida Y, Ochiai K, Nagase T, Nonomura K,
Akimoto Y, Fukuhara H, Sakai T, Matsumura G,
Yamaguchi Y, Nagase M. Piezo2 expression andits alteration by mechanical forces in mousemesangial cells and renin-producing cells. Sci
Rep, 12(1), 4197,2022.3.
Nagamoto S, Urakami S, Oka S, Ogawa K, Kono
K, Sakaguchi K, Kinowaki K, Yamada D, Kume
H. Impact of the neutrophil-to-lymphocyte ratio
as a surgical prognostic factor in renal cell
carcinoma with inferior-vena-cava tumor
thrombus. Asian J Surg, 46(1), 192-200,2022.3.
Kaneko T, Yanagida K, Matsui K, Kimura M,
Yamada Y, Ishii K, Kurozumi T, Suzuki T,
Watanabe Y, Kawano H, Sakamoto T, Nakagawa
T. Incidence of genitourinary injuries in pelvic
fractures: a 12-year single-center retrospective
study. Neurourol Urodyn, 41(4), 1025-1030,
2022.4.
Kinoshita Y, Shirakawa K, Sano M, Yokoo T,
Kume H, Kobayashi E. Development of a novel
porcine ischemia/reperfusion model inducing
different ischemia times in bilateral kidneys–
effects of hydrogen gas inhalation. Transl Androl
Urol, 11(4), 430-438,2022.4.
Kamei J, Fujisaki A, Saito K, Sugihara T, Ando S,
Miyagawa T, Takayama T, Fujimura T. Less
invasive and equivalent short-term outcomes withsimultaneous en bloc robot-assisted radical
cystectomy and laparoscopic nephroureterectomy: Comparison with conventional open
radical cystectomy and nephroureterectomy.
Asian J Endosc Surg, 15(2), 255-260,2022.4.

29. Ando S, Nakamura S, Hyuga T, Tanabe K, Nakai
H, Fujimura T. Indigo Carmine Dye–Assisted
Lymphatic-Sparing Microsurgical Subinguinal
Varicocelectomy
AmongChildrenandAdolescents. Indian J Surg, published online,
2022.4.
30. Shishido T, Okegawa T, Hayashi K, Masuda K,
Taguchi S, Nakamura Y, Tambo M, Fukuhara H.
Laparoscopic retroperitoneal lymph nodedissection versus open retroperitoneal lymph
node dissection for testicular cancer: A
comparison of clinical and perioperative
outcomes. Asian J Urol, 9(2), 119-124,2022.4.
31. Kato T, Hirama H, Mitsuzuka K, Maruyama S,
Sasaki H, Saito T, Matsumoto R, Sakamoto S,
Sakai Y, Fukuhara H, Naya Y, Tsukino H, Hara I,
Ogawa O, Hashine K, Fumimasa F, Yokomizo A,
Tohi Y, Kakehi Y, Sugimoto M. Reclassification
prediction of first-year protocol biopsy on active
surveillance of prostate cancer by p2PSA-relatedparameters: from PRIAS-JAPAN. Prostate
Cancer Prostatic Dis, 25(4), 666-671,2022.4.
32. Nomura Y, Okada Y, Nakagawa C, Kurokawa I,
Shigeta M, Fujisawa H, Yoshimura Y. Magnetic
resonance imaging evaluation of the effectivenessof FemiCushion in pelvic organ prolapse. J
Obstet Gynaecol Res, 48(5), 1255-1264,2022.5.
33. Kamasako T, KagaK, Inoue K, HariyamaM,
Yamanishi T. Supervised machine learningalgorithm identified KRT20, BATF and TP63 as
biologically relevant biomarkers for bladderbiopsy specimens from interstitial cystitis/bladderpain syndrome patients. Int J Urol, 29(5), 406412,2022.5.
34. Nakamura Y, Taguchi S, Kinjo M, Tambo M,
Okegawa T, Fukuhara H. Adrenal metastasis innivolumab-treated renal cell carcinoma: a uniqueentity as a sanctuary site. Urol Int, 29(6), 597599,2022.6
35. Teshima T, Kobayashi Y, Kawai T, Kushihara Y,
Nagaoka K, Miyakawa J, Akiyama Y, Yamada
Y, Sato Y, Yamada D, Tanaka N, Tsunoda T,
Kume H, Kakimi K. Principal component
analysis of early immune cell dynamics during
pembrolizumab treatment of advanced urothelial
carcinoma. Oncol Lett, 24(2), 265,2022.6.

238

36. Kinjo M, Masuda K, Nakamura Y, Taguchi S,
Tambo M, Fukuhara H. Does metabolic
syndrome influence the efficacy of mirabegron
treatment in female patients with overactive
bladder? Int Urogynecol J, Online ahead ofprint,2022.6.
37. Kobayashi K, Matsuyama H, Kawai T, Ikeda A,
Miyake M, Nishimoto K, Matsushita Y, Kume
H, Nishiyama H, Fujimoto K, Oyama M, Miyake
H, Azuma H, Inoue K, Mitsui T, Kawakita M,
Oyama C, Mizokami A, Shinohara N, Kuroiwa H.
Bladder cancer prospective cohort study on highrisk non-muscle invasive bladder cancer after
photodynamic diagnosis-assisted transurethralresection of the bladder tumor (BRIGHT study).
Urol Int, 29(7), 632-638,2022.7.
38. Kurokawa S, Kamei J, Sakata K, Sugihara T,
Fujisaki A, Ando S, Takayama T, Fujimura T. The
cutoff value of transitional zone index predicting
the efficacy of dutasteride on subjective
symptoms in patients with benign prostate
hyperplasia. LUTS, 14(4), 261-266,2022.7.
39. Kimura N, Yamada Y, Takeshima Y, Otsuka M,
Akamatsu N, Hakozaki Y, Miyakawa J, Sato Y,
Akiyama Y, Yamada D, Fujimura T, Kume H.
The 'prostate-muscle index': a simple pelvic
cavity measurement predicting estimated blood
loss and console time in robot-assisted radical
prostatectomy. Sci Rep, 12(1), 11945,2022.7.
40. Kimura N, Takayama K, Yamada Y, Kume H,
Fujimura T, Inoue S. Ribonuclease H2 Subunit A
Preserves Genomic Integrity and Promotes
Prostate Cancer Progression. Cancer Res
Commun, 2(8), 870–883,2022.8.
41. Yamanaka T, Takemura K, Hayashida M, Suyama
K, Urakami S, Miura Y. Cabozantinib-induced
serum
creatinekinaseelevation
andrhabdomyolysis: a retrospective study. Reserchsquare, 0.21203/rs.3.rs-1947367, 1-8,202.8.
42. Kaga K, Yamanishi T, Shibata C, Kamasako T,
Kaga M, Fuse M. The efficacy of compression
stocking on patients with nocturia: sundrome
patients -arm pilot study. Cureus, 14(8), e28603,
2022.8.
43. Hakozaki Y, Yamada Y, Kawai T, Nakamura M,
Takeshima Y, Iwaki T, Teshima T, Kinoshita Y,
Fujii Y, Akiyama Y, Sato Y, Yamada D, Suzuki M,

44.

45.

46.

47.

48.

49.

Kashiwagi-Hakozaki M, Ushiku T, Kume H.
Time to castration resistance is a novel
prognostic factor of cancer-specific survival inpatients with nonmetastatic castration-resistant
prostate cancer. Sci Rep, 12(1), 16202,2022.9.
Nakamura M, Kameyama S, Ambe Y, Teshima T,
Izumi T, Tsuru I, Inoue Y, Yoshimatsu T, Inatsu H,
Amakawa R, Kusakabe M, Morikawa T, Shiga Y.
Predictive factors for postoperative renal function
after
off-clamp,
non-renorrhaphy
partialnephrectomy. Transl Androl Urol, 11(9), 12261233,2022.9.
Takada I, Hidano S, Takahashi S, Ogawa H,
Tsuchiya M, Yokoyama A, Sato S, Ochi H,
Nakagawa T, Kobayashi T, Nakagawa S,
Makishima M Authors equally contributed.
Transcriptional coregulator Ess2 controls survivalof post-thymic CD4+ T cells through the Myc
and IL-7 signaling pathways. J Biol Chem,
298(9), 102342,2022.9.
Takada I, Hidano S, Takahashi S, Yanaka K,
Ogawa H, Tsuchiya M, Yokoyama A, Sato S,
Ochi H, Nakagawa T, Kobayashi T, Nakagawa S,
Makishima M. Ess2 controls survival of
post-thymic CD4+ T cells through the Myc andIL-7 signaling pathways. J Biol Chem, 298(9),102342,2022.9.
Azuma T, Kano M, Iwata S, Honda S, Miyoshi Y,
Nishiguchi J. Utility of periodic medical
questionnaires and examinations for immunerelated adverse event screening: A prospective
observational study. PLoS One, 17(9),2022.9.
Tohi Y, Kato T, Miyakawa J, Matsumoto R,
Sasaki H, Mitsuzuka K, Inokuchi J, Matsumura
M, Yokomizo A, Kinoshita H, Hara I, Kawamura
N, Hashimoto K, Inoue M, Teishima J, Kanno H,
Fukuhara H, Maruyama S, Sakamoto S, Saito T,
Kakehi Y, Sugimoto M. Impact of adherence tocriteria on oncological outcomes of radical
prostatectomy in patients opting for active
surveillance: data from the PRIAS-JAPAN study.
Jpn J Clin Oncol, 52(9), 1056-1061,2022.9.
Yamazaki M, Takayama T, Fujita A, Kikuchi T,
Kamimura T, Myoga H, Mayumi S, Yazaki K,
Katano S, Komatsubara M, Kamei J, Sugihara T,
Ando S, Fujimura T. 3D printed kidney model
could be an important educational tool for

239

50.

51.

52.

53.

54.

55.

residents. Asian J Endosc Surg, Online ahed ofprint,2022.10.
Cheng F, Watton PN, Pederzani G, Kurobe M,
Takaoka E, Chapple C, Birder L, Yoshimura N,
Robertson AM. A constrained mixturemicturition-growth (CMMG) model of theurinary bladder: Application to partial bladderoutlet obstruction (BOO). J Mech Behav Biomed
Mater, 134,2022.10.
Takeshima Y, Yamada Y, Takemura K, Kimura N,
Hakozaki Y, Miyakawa J, Taguchi S, Akiyama Y,
Sato Y, Kawai T, Yamada D, Fujimura T, Kume H.
The association between the parameters ofuroflowmetry and lower urinary tract symptoms
in prostate cancer patients after robot-assisted
radical prostatectomy. PLoS ONE, 17(10),2022.
10.
Yamada Y, Taguchi S, Kume H. Surgicaltolerability and frailty in elderly patients
undergoing robot-assisted radical prostatectomy:
A narrative review. Cancers 2022, 14(20), 5061,
2022.10.
Nakamura M, Yamada Y, Sato Y, Honda K,
Yamada D, Kawai T, Akiyama Y, Suzuki M,
Kume H. Preservation of pelvic floor muscles
contributes to early continence recovery after
robot-assisted radical prostatectomy. PLoS One,
17(10),2022.10.
Zhou J, Koizumi N, Nishiyama Y, Kogiso K,
Ishikawa T, Kobayashi K, Watanabe Y,
Fujibayashi T, Yamada M, Matsuyama M,
Tsukihara H, Tsumura R, Yoshinaka K,
Matsumoto N, Ogawa M, Miyazaki H, Numata K,
Nagaoka H, Iwai T, Iijima H. A VS ultrasounddiagnostic system with kidney image evaluation
functions. Int J Comput Assist Radiol Surg,
online ahead of print,2022.10.
Kato D, Ebara S, Tatenuma T, Sasaki T, Ikehata Y,
Nakayama A, Toide M, Yoneda T, Sakaguchi K,
Teishima J, Makiyama K, Inoue T, Kitamura H,
Saito K, Koga F, Urakami S, Koie T. Short-term
oncological and surgical outcomes of robotassisted radical prostatectomy: A retrospective
multicenter cohort study in Japan (the MSUG94
group). Asian J Endosc Surg, 15(4), 745-752,
2022.10.

56. Kawase M, Ebara S, Tatenuma T, Sasaki T,
Ikehata Y, Nakayama A, Toide M, Yoneda T,
Sakaguchi K, Ishihara T, Teishima J, Makiyama
K, Inoue T, Kitamura H, Saito K, Koga F,
Urakami S, Koie T. A Nomogram for Predicting
Prostate Cancer with Lymph Node Involvementin Robot-Assisted Radical Prostatectomy Era: A
Retrospective Multicenter Cohort Study in Japan(The MSUG94 Group). Diagnostics (Basel),12(10), 2545,2022.10.
57. Namiki S, Kawase M, Ebara S, Tatenuma T,
Sasaki T, Ikehata Y, Nakayama A, Toide M,
Yoneda T, Sakaguchi K, Teishima J, Makiyama K,
Inoue T, Kitamura H, Saito K, Koga F, Urakami
S, Koie T. Pelvic Lymphadenectomy May Not
Improve Biochemical Recurrence-Free Survival
in Patients with Prostate Cancer Treated with
Robot-Assisted Radical Prostatectomy in Japan(The MSUG94 Group). Cancers (Basel), 14(23),5803,2022.11.
58. Watanabe M, Taguchi S, Machida H, Tambo M,
Takeshita Y, Kariyasu H, Fukushima K, Shimizu
Y, Okegawa T, Fukuhara H, Yokoyama K.
Clinical validity of non-contrast-enhanced
VI-RADS: Prospective study using 3-T MRI withhigh gradient magnetic field. European
Radiology 2022, 32(11), 7513-7521,2022.11.
59. Sugimoto K, Taguchi S, Kishitani K, Kawai T,
Masuda K, Nakamura Y, Kinjo M, Tambo M,
Miyakawa J, Akiyama Y, Yamada Y, Sato Y,
Yamada D, Nakagawa T, Fukuhara H, Kume H.
Comparison of full-dose gemcitabine/cisplatin,
dose-reduced
gemcitabine/cisplatin,andgemcitabine/carboplatin in real-world patientswith advanced urothelial carcinoma. BMC Urol,22(1), 177,2022.11.
60. Kato T, Yokomizo A, Matsumoto R, Tohi Y,
Miyakawa J, Mitsuzuka K, Sasaki H, Inokuchi J,
Matsumura M, Sakamoto S, Kinoshita H,
Fukuhara H, Kamiya N, Kimura R, Nitta M,
Okuno H, Akakura K, Kakehi Y, Sugimoto M.
Comparison of the medical costs between active
surveillance and other treatments for early
prostate cancer in Japan using data from the
PRIAS-JAPAN study. Int J Urol, 29(11), 12711278,2022.11.

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61. Watanabe M, Taguchi S, Machida H, Tambo M,
Takeshita Y, Kariyasu T, Fukushima K, Shimizu
Y, Okegawa T, Fukuhara H, Yokoyama K.
Clinical validity of non-contrast-enhanced
VI-RADS: prospective study using 3-T MRI withhigh-gradient magnetic field. Eur Radiol, 32(11),7513-7521,2022.11.
62. Kurokawa r, Kato S, Koyama H, Ishida M,
Kurokawa M, Kuroda R, Ushiku T, Kume H, Abe
O. Osteolytic or mixed bone metastasis is notuncommon in patients with high-risk prostatecancer. European Journal of Radiology 2022, 157,
110595,2022.12.
63. Suzuki M, Yamamoto M, Shiratori T, Naito A,
Nakamura M. Evaluation of trends in prescription
drugs for overactive bladder in Japanese patients.
International Journal of Urology, Online ahead ofprint,2022.12.
64. Taguchi S, Kawai T, Nakagawa T, Miyakawa J,
Kishitani K, Sugimoto K, Nakamura Y, Kamei J,
Obinata D, Yamaguchi K, Kaneko T, Yoshida K,
Yamamoto S, Kakutani S, Kanazawa K, Sugihara
Y, Tokunaga M, Matsumoto A, Uemura Y,
Akiyama Y, Yamada, Y, Sato Y, Yamada D,
Enomoto Y, Nishimatsu H, Ishikawa A, Tanaka Y,
Nagase Y, Fujimura T, Fukuhara H, Takahashi S,
Kume H. Improved survival in real-world
patients with advanced urothelial carcinoma: A
multicenter propensity score-matched cohort
study comparing a period before the introductionof pembrolizumab (2003-2011) and a more recent
period (2016-2020). Int J Urol, 29(12), 14621469,2022.12.
65. Sugihara T, Kamei J, Yasunaga H, Sasabuchi Y,
Fujimura T. Prescription of Choreito, a Japanese
Kampo Medicine, with Antimicrobials for
Treatment of Acute Cystitis: A Retrospective
Cohort Study. Antibiotics (Basel), 11(12), 1840,
2022.12
66. Kitamura T, Suzuki M, Shigehara K, Fukuda K,
Matsuyama T, Kume H. Prevalence of humanpapillomavirus types 16/18 and effect ofvaccination among Japanese female general
citizens in the vaccine crisis era. Viruses
67. Suzuki M, Shiratori T, Naito A. Relevant
predisposing factors for voiding in a sitting

position among Japanese male adult patients.
Continence

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Department of Surgical Oncology
Professor
Soichiro Ishihara, M.D., Ph.D.

Associate Professor
Hiroaki Nozawa, M.D., Ph.D.

Lecturer
Kazuhito Sasaki, M.D., Ph.D., Ph.D., Koji Murono, M.D.

Assistant Professor
Shigenobu Emoto, M.D., Ph.D., Hiroyuki Matsuzaki, M.D., Ph.D.,
Yuichiro Yokoyama, M.D., Ph.D., Shinya Abe, M.D., Ph.D., Yuzo Nagai, M.D., Ph.D.,
Yuichiro Yoshioka, M.D., Ph.D., Takahide Shinagawa, 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, one Associate Professor,
two Lecturers and nine Assistant Professors. The
outpatient office is located on the third floor of the
Outpatient Building. The ward is situated on theeighth floor of the Ward Building. The administrative
office and research laboratories are located in the
Administration and Research Building. Current
activities of the Department of Surgical Oncology inclinical practice, education, and research aresummarized as follows.

Clinical activities
The Department of Surgical Oncology provides
comprehensive evaluation, diagnosis, treatment andmanagement for adult patients with both general andoncologic surgical problems, in the ambulatory as wellas inpatient setting. In particular, we are trying to

identify the best way to treat each patient with theleast surgical stress by minimally invasive surgery
such as laparoscopic surgery and robotic surgery (daVinci Surgical System), and preoperative chemoradiotherapy for rectal cancer. The department is also wellknown for its innovative therapy for inflammatory
bowel disease. Department specialists have expertisein biological cancer immunotherapy, chemotherapy
for a variety of malignancies, and radiotherapy forrectal cancer. The outpatient clinic is open from
Monday through Friday, and twenty-four-hour consultation is available for urgent or emergency problems.
The outpatient clinic is specialized in the lower GI
tract. The Department was responsible for 505
surgically treated inpatients in the year of 2022. 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242

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

243

References1.

Murono K, Nozawa H, Kawai K, Sasaki K,
Emoto S, Kishikawa J, et al. Vascular anatomy of
the splenic flexure: a review of the literature.
Surg Today. 2022;52(5):727-735.
2. Tachikawa Y, Kawai K, Ozaki K, Nozawa H,
Sasaki K, Murono K, Emoto S, et al.
CD133(+)HIF-1α(-) Expression After Chemoradiotherapy Predicts Poor Prognosis in Rectal
Cancer. Anticancer Res. 2022;42(4):2033-2043.
3. Nagata H, Kawai K, Oba K, Nozawa H,
Yamauchi S, Sugihara K, Ishihara S.
Laparoscopic Colectomy: A Risk Factor for
Postoperative Peritoneal Metastasis. Clin
Colorectal Cancer. 2022;21(3):e205-e212
4. Okamoto K, Nozawa H, Emoto S, Murono K,
Sasaki K, Ishihara S. Adjuvant Capecitabine andOxaliplatin for Elderly Patients with Colorectal
Cancer. Oncology. 2022;100(11):576-582. F
5. Sonoda H, Kitamura C, Kano K, Anzai H, Nagai
Y, Abe S, et al. Changes in Lysophospholipid
Components in Ulcerative Colitis and Colitisassociated Cancer. Anticancer Res. 2022; 42(5):2461-2468.
6. Noguchi T, Ando T, Emoto S, Nozawa H, Kawai
K, Sasaki K, et al. Artificial Intelligence Programto Predict p53 Mutations in Ulcerative ColitisAssociated Cancer or Dysplasia. Inflamm Bowel
Dis. 2022 1;28(7):1072-1080
7. Okamoto K, Nozawa H, Sasaki K, Murono K,
Emoto S, Ishihara S. Diverting ileostomy is a risk
factor for renal impairment during CAPOX
therapy. Int J Clin Oncol. 2022;27(10):16161623.
8. Komatsu K, Emoto S, Abe S, Nozawa H, Kawai
K, Sasaki K, Murono K, Ishihara S. Perineal
Approach, the Closest Approach to the Pelvic
Floor, in Perineal Hernia Repair After
Abdominoperineal Resection. Dis Colon Rectum.
2022 1;65(9):e907.
9. Okada M, Kawai K, Sasaki K, Nozawa H,
Kaneko M, Murono K, et al. Intervention
Strategies to Reduce Surgical Site Infection Rates
in Patients Undergoing Rectal Cancer Surgery. In
Vivo. 2022; 36(1):439-445.
10. Nozawa H, Kawai K, Sasaki K, Emoto S, Abe S,

11.

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Sonoda H, et al. Predictive factors of survival ofcolorectal cancer patients after para-aortic lymph
node metastasis. Int J Clin Oncol. 2022; 27(3):520-527
Lim S, Kawai K, Nozawa H, Sasaki K, Murono
K, Emoto S, et al. Low Expression of SNAI1 in
Lymph Node Metastasis Indicates Delayed
Recurrence of Colonic Cancer. Anticancer Res.
2022; 42(12):5927-5935.
Yokoyama Y, Emoto S, Nozawa H, Kawai K,
Sasaki K, Murono K, Ishibashi R, Koike K,
Ishihara S. Laparoscopic resection after
self-expanding stent insertion for obstructive
left-sided colorectal cancer: Clinicopathologicalfeatures and outcomes. Scand J Surg. 2022;
111(2): 1457496922109 6191.
Matsunaga K, Sasaki K, Nozawa H, Kawai K,
Murono K, Emoto S, et al. Clinicopathological
Characteristics of Anastomotic Recurrence After
Curative Resection for Colorectal Cancer:
Comparison with Non-Anastomotic Local
Recurrences. Dis Colon Rectum. 2022
Ozaki K, Kawai K, Nozawa H, Sasaki K, Murono
K, Emoto S, Abe H, Ushiku T, Ishihara S. Impactof the viability assessment of lateral lymph nodemetastasis in rectal cancer after neoadjuvant
chemoradiotherapy. Int J Colorectal Dis. 2022;
37(2):467-473.
Kawai K, Nozawa H, Sasaki K, Murono K,
Ishihara S. Hazard function analysis fordevelopment of second primary colorectal cancer
after surgery for primary colorectal cancer. J
Gastroenterol Hepatol. 2022; 37(1):56-62.
Nozawa H, Hata K, Sasaki K, Murono K, Kawai
K, Emoto S, Ishihara S. Laparoscopic vs open
restorative proctectomy after total abdominal
colectomy for ulcerative colitis or familial
adenomatous polyposis. Langenbecks Arch Surg.
2022; 407(4):1605-1612.
Murai S, Kawai K, Sonoda H, Nozawa H, Sasaki
K, Murono K, et a;l. Computed tomographic
colonography versus double-contrast barium
enema for the preoperative evaluation of rectal
cancer. Surg Today. 2022; 52(5):755-762.
Okamoto K, Nozawa H, Sonoda H, Kaneko M,
Ishihara S. Combinatory anti-tumor activities of
1,4-bis[2-(dimethylamino)
ethylamino]-5,8-

244

dihydroxyanthracene-9,10-dione (AQ4) andtemsirolimus against colorectal cancer cells.J
Cancer Res Clin Oncol. 2023;149(8):4689-4699.
19. Kasuga S, Anzai H, Makise N, Sonoda H, Nagai
Y, Abe S, et al. Giant filiform polyposis withhigh-grade dysplasia: A case report and review ofthe literature.Ann Med Surg (Lond). 2022
2;82:104433.
20. Emoto S, Hata K, Nozawa H, Kawai K, Tanaka T,
Nishikawa T, et al. Risk factors for non-reachingof ileal pouch to the anus in laparoscopic
restorative proctocolectomy with handsewn
anastomosis for ulcerative colitis. Intest Res.
2022;20(3):313-320.
21. Abe S, Kawai K, Nozawa H, Sasaki K, Murono
K, Emoto S, et al. Preoperative sarcopenia is apoor prognostic factor in lower rectal cancer
patients undergoing neoadjuvant chemoradiotherapy: a retrospective study. Int J Clin Oncol.
2022;27(1):141-153.
22. Sasaki K, Nozawa H, Kawai K, Murono K,
Emoto S, Kishikawa J, et al. Risk of extracolonicmalignancies and metachronous rectal cancer
after colectomy and ileorectal anastomosis in
familial adenomatous polyposis. Asian J Surg.
2022; 45(1): 396-400.
23. Abe S, Nozawa H, Kawai K, Sasaki K, Murono
K, Emoto S, et al. Poor nutrition and sarcopenia
are related to systemic inflammatory response inpatients with rectal cancer undergoing
preoperative chemoradiotherapy. Int J Colorectal
Dis. 2022;37(1):189-200.
24. Lim S, Nagai Y, Nozawa H, Kawai K, Sasaki K,
Murono K, et al. Surgical outcomes of robotic,
laparoscopic, and open low anterior resection
after preoperative chemoradiotherapy for patientswith advanced lower rectal cancer. Surg Today.
2023;53(1):109-115.
25. Nozawa H, Kawasaki A, Hayashi C, Kawai K,
Sasaki K, Murono K, Emoto S, Ishihara S.
Impact of COVID-19 Outbreak on Stoma
Surgery and Stoma Clinic Service: A
Retrospective Study at a Single Japanese Referral
Hospital. Int J Clin Pract. 2022
4;2022:4789775.
26. Ochiai K, Kobayashi E, Sasaki K, Nozawa H,
Kawai K, Murono K, Sakuma I, Ishihara S.

Stereotactic navigation using registration basedon intra-abdominal landmarks in robotic-assisted
lateral pelvic lymph node dissection. TechColoproctol. 2022; 26(9): 735-743.
27. Abe S, Nozawa H, Sasaki K, Murono K, Emoto S,
Yokoyama Y, et al. Sarcopenia is Associated With
Oncological Prognosis and the Incidence ofSecondary Cancer in Patients With Middle/Lower
Rectal Cancer. Clin Colorectal Cancer. 2023;
22(1):143-152.
28. Nozawa H, Okamoto K, Kawai K, Sasaki K,
Emoto S, Murono K, Sonoda H, Ishihara S.
Anatomical features of inferior mesenteric andleft colic arteries and surgery in colorectal cancer
patients with persistent descending mesocolon.
ANZ J Surg. 2022; 92(7-8):1760-1765.
29. Taira T, Nozawa H, Kawai K, Sasaki K, Murono
K, Emoto S, et al. Prognoses in PathologicallyConfirmed T1 Lower Rectal Cancer Patients withor without Preoperative Therapy: An Analysis
Using the Surveillance, Epidemiology, and End
Results Database. Oncology. 2022; 100(2): 8288.
30. Emoto S, Yokoyama Y, Nozawa H, Kawai K,
Sasaki K, Murono K, et al. Preoperative
diagnosis of obstructive colitis in colorectal
cancer patients who underwent self-expandable
metallic stent insertion as a bridge to surgery.
Asian J Surg. 2022;45(12):2700-2705.
31. Chen Z, Sasaki K, Murono K, Kawai K, Nozawa
H, Kobayashi H, Ishihara S, Sugihara K;
Japanese Society for Cancer of the Colon and
Rectum. Oncologic Status of Obturator Lymph
Node Metastases in Locally Advanced Low
Rectal Cancer: A Japanese Multi-Institutional
Study of 3487 Patients. Ann Surg Oncol. 2022
32. Abe H, Yasunaga Y, Yamazawa S, Nakai Y,
Gonoi W, Nishioka Y, Murono K, Sasaki K, Arita
J, Kawai K, Nozawa H, Hasegawa K, Ishihara S,
Ushiku T. Histological growth patterns ofcolorectal cancer liver metastases: a strong
prognostic marker associated with invasive
patterns of the primary tumor and p53 alteration.
Hum Pathol. 2022; 123:74-83.
33. Abe S, Kawai K, Nozawa H, Sasaki K, Murono
K, Emoto S, et al. Clinical impact of primarytumor sidedness and sex on unresectable245

post-recurrence survival in resected pathologicalstage II-III colorectal cancers: a nationwide
multicenter retrospective study. BMC Cancer.
2022 2;22(1):486.
34. Fukui R, Nozawa H, Sakamoto A, Sasaki K,
Murono K, Emoto S, Ishihara S. Temporalchanges in functional outcomes of stapled andhand-sewn ileal pouch-anal anastomosis forulcerative colitis and familial adenomatous
polyposis. Colorectal Dis. 2023; 25(3):396-403.
35. Murai S, Kawai K, Nozawa H, Sasaki K, Murono
K, Emoto S, et al. Determination of the positional
relationship of the second Houston valve andperitoneal
reflection
using
computed
tomographic colonography and magnetic
resonance imaging. Surg Today. 2023; 53(5):614-620.
36. Hojo D, Murono K, Nozawa H, Kawai K, Hata K,
Tanaka T, Oba K, Ishihara S. Improvement inSurgical Outcomes Using 3-Dimensional Printed
Models for Lateral Pelvic Lymph Node
Dissection in Rectal Cancer. Dis Colon Rectum.
2022 1; 65(4):566-573.
37. Kawazu M, Ueno T, Saeki K, Sax N, Togashi Y,
Kanaseki T, Chida K, Kishigami F, Sato K,
Kojima S, Otsuka M, Kawazoe A, Nishinakamura
H, Yuka M, Yamamoto Y, Yamashita K, Inoue S,
Tanegashima T, Matsubara D, Tane K, Tanaka Y,
Iinuma H, Hashiguchi Y, Hazama S, Khor SS,
Tokunaga K, Tsuboi M, Niki T, Eto M, Shitara K,
Torigoe T, Ishihara S, Aburatani H, Haeno H,
Nishikawa H, Mano H. HLA Class I Analysis
Provides Insight Into the Genetic and Epigenetic
Background of Immune Evasion in Colorectal
Cancer With High Microsatellite Instability.
Gastroenterology. 2022; 162(3): 799-812.
38. Yamada K, Saiki Y, Komori K, Shiomi A, Ueno
M, Ito M, Hida K, Yamamoto S, Shiozawa M,
Ishihara S, Kanemitsu Y, Ueno H, Kinjo T,
Maeda K, Kawamura J, Fujita F, Takahashi K,
Mizushima T, Shimada Y, Sasaki S, Sunami E,
Ishida F, Hirata K, Ohnuma S, Funahashi K,
Watanabe J, Kinugasa Y, Yamaguchi S,
Hashiguchi Y, Ikeda M, Sudo T, Komatsu Y,
Koda K, Sakamoto K, Okajima M, Ishida H,
Hisamatsu Y, Masuda T, Mori S, Minami K,
Hasegawa S, Endo S, Iwashita A, Hamada M,

Ajioka Y, Usuku K, Ikeda T, Sugihara K.
Characteristics of anal canal cancer in Japan.
Cancer Med. 2022; 11(14): 2735-2743.
39. Uranbileg B, Kurano M, Kano K, Sakai E, Arita J,
Hasegawa K, Nishikawa T, Ishihara S, Yamashita
H, Seto Y, Ikeda H, Aoki J, Yatomi Y.
Sphingosine 1-phosphate lyase facilitates cancer
progression through converting sphingolipids toglycerophospholipids. Clin Transl Med. 2022;
12(9):e1056.
40. Kishigami F, Tanaka Y, Yamamoto Y, Ueno T,
Kojima S, Sato K, Inoue S, Sugaya S, Ishihara S,
Mano H, Kawazu M. Exploration of predictive
biomarkers for postoperative recurrence of stage
II/III colorectal cancer using genomic sequencing.
Cancer Med. 2022; 11(18):3457-3470.
41. Fujiyoshi K, Sudo T, Fujita F, Chino A, Akagi K,
Takao A, Yamada M, Tanakaya K, Ishida H,
Komori K, Ishihara S, Miguchi M, Hirata K,
Miyakura Y, Ishikawa T, Yamaguchi T, Tomita N,
Ajioka Y, Sugihara K. Correction to: Risk of first
onset of colorectal cancer associated with alcohol
consumption in Lynch syndrome: a multicenter
cohort study. Int J Clin Oncol. 2022; 27(6):1060.
42. Watanabe J, Kanemitsu Y, Suwa H, Kakeji Y,
Ishihara S, Shinto E, Ozawa H, Suto T,
Kawamura J, Fujita F, Itabashi M, Ohue M, Ike H,
Sugihara K; Japanese Society for Cancer of theColon and Rectum.A multicenter cohort study on
mapping of lymph node metastasis for splenic
flexural colon cancer. Ann Gastroenterol Surg.
2022 18;7(2):265-271.
43. Fujiyoshi K, Sudo T, Fujita F, Chino A, Akagi K,
Takao A, Yamada M, Tanakaya K, Ishida H,
Komori K, Ishihara S, Miguchi M, Hirata K,
Miyakura Y, Ishikawa T, Yamaguchi T, Tomita N,
Ajioka Y, Sugihara K. Risk of first onset ofcolorectal cancer associated with alcohol
consumption in Lynch syndrome: a multicenter
cohort study. Int J Clin Oncol. 2022; 27(6):1051-1059.

246

Department of Vascular Surgery
Associate Professor and Chief of Vascular Surgery
Katsuyuki Hoshina, M.D., Ph.D.

Lecturer
Toshio Takayama, M.D., Ph.D.

Assistant Professor
Ryosuke Taniguchi, M.D., Ph.D., Takuro Shirasu, M.D., Ph.D.,
Masaru Kimura, 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.

247

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.

24820) 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: Okata S, Hoshina K, Hanada K, Kamata H,
Fujisawa A, Yoshikawa Y, Sakai T.
Hemostatic Capability of a Novel TetraPolyethylene Glycol Hydrogel. Ann Vasc
Surg.2022Aug;84:398-404.
doi: 10.1016/j.avsg.2022.01.016. Epub 2022 Mar
4.PMID: 35257910.
2: Tsuyuki S, Hoshina K, Miyahara K, Suhara M,
Matsukura M, Isaji T, Takayama T.
Motion analysis of suturing technique with Leap
Motion Controller<sup>TM</sup>.
Proofofconcept.SciProg.2022AprJun;105(2):368
504221103777.
doi:10.1177/00368504221103777.
PMID:35635261; PMCID: PMC10450291.
3: Hanada K, Hoshina K, Tsuyuki S, Miyahara K,
Suhara M, Matsukura M, Isaji T, Takayama T.
Ten-Hour Simulation Training Improved theSuturing Performance ofMedical Students. Ann
Vasc Surg. 2022 Aug;84:163-168.
doi:10.1016/j.avsg.2021.12.076. Epub 2022 Jan 5.
PMID: 34995745.
4: Ueda Y, Asamoto M, Kariya T, Akai T, Hoshina K,
Uchida K. Ventricular fibrillation during carotid
endarterectomy and bailout stenting: a case report.
JAClinRep.2022Mar31;8(1):26.
doi:10.1186/s40981-022-00517-4.
PMID:35357630; PMCID: PMC8971334.
5: Fujinami T, Ashikaga T, Hoshina K, Sasaoka T,
Kurihara K, Yoshikawa S, Inagaki H, Sasano T.
β-Blockers Reduced the Target Lesion
Revascularization After Percutaneous Coronary
Intervention Using an Everolimus-eluting Stent.
InVivo.2022Jan-Feb;36(1):416-423.
doi: 10.21873/invivo.12719. PMID: 34972743;
PMCID: PMC8765150.
6: Matsubara K, Fukuhara N, Hoshina K,
MiyaharaK, Suhara M, Taniguchi R, Matsukura

M, Takayama T. Specific Features of Patients
Under 40 YearsOld WithSmall-to-Medium-Sized
Arterial Deterioration. Front Surg. 2022 Feb
24;9:808383.
doi:10.3389/fsurg.2022.808383.PMID:35284485;
PMCID: PMC8907261.
7: Shirasu T, Hoshina K, Deguchi JO. Audit andFeedback for Sustained Improvement of Overall
SurgicalOutcomesafterAbdominalAorticAneurys
ms. Eur J
VascEndovascSurg.2022Jul;64(1):137.
doi: 10.1016/j.ejvs.2022.04.043. Epub2022 May
16. PMID: 35589090.
8: Taniguchi R, Ohashi Y, Lee JS, Hu H, Gonzalez L,
Zhang W, Langford J, Matsubara Y, Yatsula B,
Tellides G, Fahmy TM, Hoshina K, Dardik A.
EndothelialCell TGF-β (Transforming Growth
Factor-Beta) Signaling Regulates Venous
Adaptive Remodeling to Improve Arteriovenous
Fistula Patency. Arterioscler Thromb Vasc
Biol.2022Jul;42(7):868-883.
doi: 10.1161/ATVBAHA.122.317676. Epub 2022
May 5.PMID: 35510552; PMCID: PMC9233042.
9: Tsuyuki S, Miyahara K, Hoshina K, Kawahara T,
Suhara M, Mochizuki Y, Taniguchi R, Takayama
T. Motion capture device reveals a quick learning
curve invascular anastomosis training. Surg
Today. 2023 Jul 19.
doi10.1007/s00595-023-02726-5. Epub ahead ofprint. PMID: 37466703.
10: Endo T, Miyahara K, Shirasu T, Mochizuki Y,
Taniguchi R, Takayama T, Hoshina K. Risk
Factors for Incisional Hernia After Open
Abdominal Aortic Aneurysm Repair. In Vivo.
2023Nov-Dec;37(6):2803-2807.
doi: 10.21873/invivo.13393. PMID:37905664;
PMCID: PMC10621461.

249

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
Ayaka Sato M.D., Ph.D.

Asako Sasahara M.D., Ph.D.

Arisa Morizono M.D., Ph.D.

Satoshi Yamashita M.D., Ph.D.

Homepage
Organization
Our section is staffed by one professor, associate
professor, lecturer, and four associates. Official
activities of our units are run on the same schedule as
the Department of Gastrointestinal Surgery.

Clinical Activities
We started our activities in this area in 1987, andour department was established with thereconstruction of our hospital structure in 1997. Thisis a result of the growth of demand nationally andinternationally. It is caused by not only treatment forthe malignant disease but also functional one or giving
more attention to the quality of life.
Professional skills and broader knowledge of theendocrine system are required for this area. Diseases
we treat at our department are breast, thyroid, andparathyroid. In addition to treatment for malignant
cases of these diseases, we perform surgical procedures as well as systemic therapy. We co-work withthe department of internal endocrine medicine andhave about 250 surgical procedures annually.
In breast surgery, more than half of mammary

cancer patients undergo breast-preserving surgery. In
addition, sentinel node navigation surgery has been
adopted, resulting in better postoperative life quality.
Reconstruction surgery for breast cancer is likely toprovide much better QOL. In this field, we havecollaborated with the Department of Plastic Surgery.
Chemotherapy, hormone therapy, and moleculartargeting therapy play essential roles in breast cancer
treatment. We have accumulated a lot of experienceand achievement in this field.
Our clinical themes are 1) establishment of safe
procedures for endocrine surgery without complications; 2) diagnosis and treatment of micro-breast
lesions under ultrasonographic guides; 3) preoperative
diagnosis for thyroid neoplasms and breast tumors.

Research Activities
We investigate broad areas of breast cancer, thyroid
disease, and parathyroid disease. Most of our studies
are performed with other good institutions.
1) Hereditary Breast and Ovarian Cancer syndrome2502) Precision medicine based on Todai OncoPanel
3) Clinical significance of Ki67 in the area of earlybreast cancer.
4) Clinical evaluation for the developing drugs inbreast and thyroid cancer.
5) Studies in the area of sentinel node biopsy inbreast cancer.
6) Studies about the management of the toxic effects
of chemotherapies.
7) Cover makeup studies for cancer patients.
8) Epigenetic changes critical for breast cancer
development.
9) Cancer stem cells in breast cancer.
10) Quantification of HER2 expression using Digital
PCR.
11) Development of molecular target drugs in the areaof TGF beta
12) Analysis of MED12 mutation and TERT promoter
mutation in breast fibroadenoma and phyllodes
tumor.
13) Loss of BRCA1 expression and morphologicalfeatures associated with BRCA1 promoter
methylation status in triple-negative breast cancer.
14) Epidemiological study using nationwide databases
to resolve clinical questions

Publications
1. Konishi T, Fujiogi M, Shigemi D, Matsui H,
Fushimi K, Tanabe M, Seto Y, Yasunaga H.
Risk Factors for Postoperative Bleeding
Following Breast Cancer Surgery: A Nationwide
Database Study of 477,108 Cases in Japan WorldJ Surg. 2022 Dec;46(12):3062-3071.
2. Niwa T, Konishi T, Sasahara A, Sato A, Morizono
A, Harada M, Nishioka K, Fukuoka O, Makise N,
Saito Y, Ando M, Yoshimoto T, Shikama T,
Yamashita S, Tanabe M, Seto Y. Subcutaneous
axillary
primaryepithelioid
hemangioendothelioma: report of a rare case. Surg
Case Rep. 2022 Sep 9;8(1):166.
3. Konishi T, Goto T, Fujiogi M, Michihata N,
Kumazawa R, Matsui H, Fushimi K, Tanabe M,
Seto Y, Yasunaga H. New machine learning
scoring system for predicting postoperative
mortality in gastroduodenal ulcer perforation: A
study using a Japanese nationwide inpatient

database. Surgery. 2022 Apr;171(4):1036-1042.
4. Konishi T, Fujiogi M, Michihata N, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Association of Operative Day of the
Week with the Length of Stay and Total
Hospitalization Costs in Patients with Partial
Mastectomy: A Nationwide Database Study inJapan. JMA J. 2022 Jul 15;5(3):319-327.
5. Konishi T, Fujiogi M, Shigemi D, Nishioka K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Surgical and obstetric outcomes ofbreast cancer surgery during pregnancy: anationwide database study in Japan. Breast Cancer
Res Treat. 2022 Oct;195(3):289-299.
6. Konishi T, Takamoto T, Fujiogi M, Hashimoto Y,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Laparoscopic versus open distal
pancreatectomy with or without splenectomy: Apropensity score analysis in Japan. Int J Surg.
2022 Aug;104:106765.
7. Konishi T, Fujiogi M, Michihata N, Ohbe H,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Cost-effectiveness analysis of
trastuzumab monotherapy versus adjuvant
chemotherapy plus trastuzumab in elderly patientswith HER2-positive early breast cancer. Jpn J Clin
Oncol. 2022 Oct 6;52(10):1115-1123.
8. Konishi T, Fujiogi M, Michihata N, Matsui H,
Tanabe M, Seto Y, Yasunaga H. Association
between body mass index and incidence of breast
cancer in premenopausal women: a Japanesenationwide database study. Breast Cancer Res
Treat. 2022 Jul;194(2):315-325.
9. Konishi T, Yoshimoto T, Fujiogi M, Yamana H,
Tanabe M, Seto Y, Yasunaga H. Validity ofoperative information in Japanese administrative
data: a chart review-based analysis of 1221 cases
at a single institution. Surg Today. 2022
Oct;52(10):1484-1490.
10. Konishi T, Fujiogi M, Michihata N, Kumazawa R,
Ohbe H, Matsui H, Fushimi K, Ogita M, Tanabe
M, Seto Y, Yasunaga H.Interstitial lung disorders
following postoperative radiotherapy withconcurrent or sequential hormonal therapy forbreast cancer: a nationwide database study inJapan. Breast Cancer. 2022 Jul;29(4):688-697.
11. Konishi T, Fujiogi M, Tanabe M, Seto Y,

251

Yasunaga H. ASO Author Reflections:
Neoadjuvant Chemotherapy Does Not Affect
Short-Term Outcomes After Breast Cancer
Surgery.
Ann
Surg
Oncol.
2022
May;29(5):3011-3012.
12. Konishi T, Fujiogi M, Sato A, Michihata N,
Kumazawa R, Matsui H, Fushimi K, Tanabe M,
Seto Y, Yasunaga H.Short-Term Outcomes
Following Breast Cancer Surgery With andWithout
Neoadjuvant
Chemotherapy:A
Nationwide Administrative Database Study inJapan.
Ann
Surg
Oncol.
2022
May;29(5):3000-3010.
13. Konishi T, Fujiogi M, Michihata N, Niwa T,
Morita K, Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Impact of body mass index on
short-term outcomes after differentiated thyroid
cancer surgery: a nationwide inpatient databasestudy in Japan. Eur Thyroid J. 2022 Jan
1;11(1):e210081.

Surgical Sciences
2. Sensory and Motor System Medicine

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

Associate Professor
Sayaka Shibata, M.D., PhD.

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

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

Takuya Miyagawa, M.D., Ph.D.

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

Daisuke Yamada, M.D., Ph.D.

Hospital Lecturer
Tomomi Miyake, M.D.

Asako Yoshizaki, M.D., Ph.D.

Associate
Shunsuke Miura, M.D., Ph.D.

Hikari Boki, M.D., Ph.D.

Jun Omatsu, M.D., Ph.D.

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

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

Ai Kuzumi, M.D., Ph.D.

Satoshi Toyama, M.D., Ph.D.

Websitehttps://dermatology.m.u-tokyo.ac.jp/

Introduction and Organization
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.
As of March 2023, the professor, one associate
professor, five lecturers, two hospital lecturers andseven associates take part in inpatient and outpatientcares as well as research and teaching activities. Fiftytwo doctors who basically belong to our department
are currently out in affiliated hospitals mainly
engaged in clinical works there. Additionally, threestaff members are abroad at present, mainly involvedin advanced research activities in cell biology andmolecular biology.

Clinical Activities
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.

254

Education
We have twenty dermatologists who are studying in
the postgraduate course under the guidance of staff
members of our department.
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.

Akatsuka T, Omatsu J, Miyagawa T, Omori I,
Kawashima H, Oshima N, Sato S. Congenital
midline sinus of the upper lip: Evaluating the useof ultrasonography. Skin Health Dis. 2022 Oct
1;3(1):e170.
2. Sumida H, Asano Y, Shimizu J, Sato S. Edema
localized to the lips as a novel manifestation of
myositis. Int J Rheum Dis. 2023 Apr;26(4):789792. doi: 10.1111/1756-185X. 14543. Epub 2022
Dec 23.
3. Mizuno Y, Shibata S, Ito Y, Taira H, Sugimoto E,
Awaji K, Sato S. Interleukin-26-DNA complexes
promote inflammation and dermal-epidermal
separation in a modified human cryosection
model of bullous pemphigoid. Front Immunol.
2022 Oct 10;13:1013382.
4. Oka K, Miyagawa T, Suga H, Miyagaki T,
Mizuno Y, Kamijo H, Hisamoto T, Omori I, Boki

H, Oka T, Takahashi-Shishido N, Sugaya M,
Sato S. Increased expression of squamous cell
carcinoma antigen 1 and 2 in mycosis fungoides
and Sézary syndrome. Eur J Dermatol. 2022 Jul
1;32(4):464-470.
5. Yoshizaki A, Fukasawa T, Ebata S, YoshizakiOgawa A, Sato S. Involvement of B cells in thedevelopment of systemic sclerosis. Front
Immunol. 2022 Jul 28;13:938785.
6. Ebata S, Yoshizaki-Ogawa A, Sato S, Yoshizaki
A. New Era in Systemic Sclerosis Treatment:
Recently Approved Therapeutics. J Clin Med.
2022 Aug 8;11(15):4631.
7. Norimatsu Y, Yoshizaki A, Yamada T, Akiyama
Y, Toyama S, Sato S. Pemphigus vulgaris withadvanced hypopharyngeal and gastric cancer
following SARS-CoV-2 vaccination. J Dermatol.
2023 Feb;50(2):e74-e75.
8. Fukasawa T, Yoshizaki-Ogawa A, Enomoto A,
Miyagawa K, Sato S, Yoshizaki A. Involvementof Molecular Mechanisms between T/B Cells andIL-23: From Palmoplantar Pustulosis toAutoimmune Diseases. Int J Mol Sci. 2022 Jul
27;23(15):8261.
9. Mizuno Y, Shibata S, Miyagaki T, Ito Y, Taira H,
Omori I, Hisamoto T, Oka K, Matsuda KM, Boki
H, Takahashi-Shishido N, Sugaya M, Sato S.
Serum cell-free DNA as a new biomarker incutaneous T-cell lymphoma. J Dermatol. 2022
Nov;49(11):1124-1130.
10. Sakakibara M, Sumida H, Yanagida K, Miyasato
S, Nakamura M, Sato S. Bitter taste receptor
T2R38 is expressed on skin-infiltrating
lymphocytes and regulates lymphocyte migration.
Sci Rep. 2022 Jul 11;12(1):11790.
11. Fukasawa T, Yoshizaki-Ogawa A, Enomoto A,
Miyagawa K, Sato S, Yoshizaki A.
Pharmacotherapy of Itch-Antihistamines andHistamine Receptors as G Protein-Coupled
Receptors. Int J Mol Sci. 2022 Jun 13;23(12):6579.
12. Kawanabe R, Yoshizaki A, Matsuda KM, Kotani
H, Hisamoto T, Norimatsu Y, Kuzumi A,
Fukasawa T, Ebata S, Yoshizaki-Ogawa A, SatoS. Serum C-X-C Chemokine Ligand 1 Levels in
Patients with Systemic Sclerosis: Relationship ofClinical and Laboratory Observations to Anti-

255

13.

14.

15.

16.

17.

18.

19.

CD20 Monoclonal Antibody Administration. Life
(Basel). 2022 Apr 27;12(5):646.
Matsuda KM, Yoshizaki A, Yamaguchi K,
Fukuda E, Okumura T, Ogawa K, Ono C,
Norimatsu Y, Kotani H, Hisamoto T, Kawanabe
R, Kuzumi A, Fukasawa T, Ebata S, Miyagawa T,
Yoshizaki-Ogawa A, Goshima N, Sato S.
Autoantibody Landscape Revealed by Wet
Protein Array: Sum of Autoantibody Levels
Reflects Disease Status. Front Immunol. 2022
May 4;13:893086.
Ebata S, Oba K, Kashiwabara K, Ueda K,
Uemura Y, Watadani T, Fukasawa T, Miura S,
Yoshizaki-Ogawa A, Yoshihide A, Yoshizaki A,
Sato S. Predictors of rituximab effect on
modified Rodnan skin score in systemicsclerosis: a machine-learning analysis of the
DesiReS trial. Rheumatology (Oxford). 2022
Nov 2;61(11):4364-4373.
Urano-Takaoka M, Sumida H, Miyagawa T,
Awaji K, Nagai K, Omatsu J, Miyake T, Sato S.
Serum Cytokeratin 18 as a Metastatic andTherapeutic Marker for Extramammary Paget's
Disease. Acta Derm Venereol. 2022 Jan 26;102:
adv00636.
Kuzumi A, Yoshizaki A, Chiba K, Mitsuo S,
Matsuda KM, Norimatsu Y, Nagai K, Omatsu J,
Miyake T, Sato S. Genital necrosis withcutaneous thrombosis after COVID-19 mRNA
vaccination. J Eur Acad Dermatol Venereol.
2022 Mar;36(3):e185-e186.
Ikawa T, Ichimura Y, Miyagawa T, Fukui Y,
Toyama S, Omatsu J, Awaji K, Norimatsu Y,
Watanabe Y, Yoshizaki A, Sato S, Asano Y. The
Contribution of LIGHT (TNFSF14) to theDevelopment of Systemic Sclerosis by
Modulating IL-6 and T Helper Type 1
Chemokine Expression in Dermal Fibroblasts. J
Invest Dermatol. 2022 Jun;142(6):1541-1551.e3.
Boki H, Kimura T, Miyagaki T, Suga H, Blauvelt
A, Okochi H, Sugaya M, Sato S. Lymphatic
Dysfunction Exacerbates Cutaneous Tumorigenesis
and Psoriasis-Like Skin Inflammation throughAccumulation of Inflammatory Cytokines. J
Invest Dermatol. 2022 Jun;142(6):1692-1702.e3.
Ebata S, Yoshizaki A, Fukasawa T, YoshizakiOgawa A, Asano Y, Kashiwabara K, Oba K, Sato

S. Percentage of residual B cells after 2 weeks ofrituximab treatment predicts the improvement ofsystemic sclerosis-associated interstitial lungdisease. J Dermatol. 2022 Jan;49(1):179-183.

256

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

Associate Professor
Shimpei Miyamoto, M.D.

Lecturer
Masakazu Kurita, M.D.

Project Lecturer
Yoko Tomioka, M.D.

Associate
Koji Kanayama, M.D.,

Kou Fujisawa, M.D.,

Hitomi Matsutani, M.D., Rui Yang, M.D.,

Homepage

Jun Oba, M.D.,

Kurita Daichi 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 project lecturer, 1 project
lecturer, 6 associates, 3 physicians, and 5 residents.
There are about 100 doctors in the department, but
most are serving in rotation at affiliated hospitals.
The outpatient clinic is located on the 3rd floor of
the outpatients building, while there are wards with
about 16 available beds on the 10th floor in the New
Ward. Our faculty room is located in the Medical
Laboratory Building and laboratory rooms in the East
Laboratory Building.
The present status of the educational, research andclinical activities of the department is as follows.

Clinical Activities
The outpatient clinic is opened every morning from
Monday to Friday. There are several specialized
clinics for facial paralysis, breast reconstruction, headand neck reconstruction, congenital anomalies,
vascular malformations, critical limb ischemia,
lymphedema, keloid, abdominal hernia, and cosmetic
surgery including cosmetic dermatology. Over 1,000
new patients visited our department, including about
800 patients in emergency. About 1,400 surgeries were
performed. Each week, preoperative and postoperative
conferences that all members of the department should
attend are held on Tuesday and Wednesday evening
respectively.

Teaching Activities
In regard to pregraduate education, the department
has the duty of lecturing to 2nd and 4th year medical
students, and also of instructing 4th medical students
in bed side practice. The subjects taken up in thelectures include general concepts of plastic surgery,wound healing, congenital malformations, skin grafts
and flaps, microsurgery, head and neck reconstruction,
hand surgery, craniomaxillofacial surgery, burn andtrauma, cosmetic surgery, and regenerative medicine.

257

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.

References (2022)
1.

2.

3.

Tomioka Y, Sekino M, Gu J, Kurita M, Yamashita
S, Miyamoto S, Iida T, Kanayama K, Yoshimura
K, Nakagawa M, Akazawa S, Kagaya Y, Tanaka
K, Sunaga Y, Ueda K, Kawahara T, Tahara Y,
Okazaki M. Wearable, wireless, multi-sensor
device for monitoring tissue circulation after
free-tissue transplantation: a multicentre clinical
trial. Sci Rep. 2022 Oct 3;12(1):16532.
Shiraishi M, Kurita M, Narushima M, Banda CH,
Okazaki M. Formation of bilateral arteriovenous
malformations. J Vasc Surg Cases Innov Tech.
2022 Jul 2;8(3):441-442.
Dai M, Yamashita S, Okazaki M, Kimori K,
Sanada H, Sugama J. Real-time image-sharing to

educate a patient with lymphoedema on self-care:a case study. Br J Nurs. 2022 Aug 11;31(15):S22-S29.
4. Hongo H, Miyawaki S, Teranishi Y, Mitsui J,
Katoh H, Komura D, Tsubota K, Matsukawa T,
Watanabe M, Kurita M, Yoshimura J, Dofuku S,
Ohara K, Ishigami D, Okano A, Kato M, Hakuno
F, Takahashi A, Kunita A, Ishiura H, Shin M,
Nakatomi H, Nagao T, Goto H, Takahashi SI,
Ushiku T, Ishikawa S, Okazaki M, Morishita S,
Tsuji S, Saito N. Somatic GJA4 gain-of-function
mutationinorbitalcavernous
venousmalformations. Angiogenesis. 2023 Feb;26(1):37-52.
5. Tanaka K, Okazaki M. Basic Concept of Skull
Base Reconstructive Surgery. No Shinkei Geka.
2022 May;50(3):586-594.
6. Tanaka K, Suesada N, Homma T, Mori H,
Tsutsumi T, Asakage T, Okazaki M.
Muscle-penetration method: Cable nerve graftingwith well vascularized surrounding tissue andshortest graft length. J Plast Reconstr Aesthet
Surg. 2022 Jul;75(7):2387-2440.
7. Miyamoto S, Fukunaga Y, Arikawa M, Fujisawa
K, Okazaki M. Crescent-shaped skin paddle for afibular flap: Avoiding skin grafting at the donorsite. Head Neck. 2022 Jul;44(7):1742-1746.
8. Tanaka K, Suesada N, Homma T, Hidaka T, MoriH, Okazaki M, Sugawara T, Tsutsumi T, Asakage
T. Early postoperative complications and theirmeasures after skull base reconstruction: A study
from the standpoint of plastic and reconstructive
surgeons. Auris Nasus Larynx. 2022 Oct;49(5):845-855.
9. Numahata T, Kitamura Y, Okazaki M. Successful
Repair of a Forehead Depression Deformation
due to En Coup de Sabre Using Costal Cartilage
Transplantation. J Craniofac Surg. 2022 Sep 1;
33(6): e585-e586.
10. Du Z, Shen Q, Mito D, Kato M, Okazaki M,
Kurita M. Optimized 3D-printed template designfor production of silicone skin chambers. J
Dermatol Sci. 2022 Jan;105(1):55-57.
11. Hidaka T, Ogawa K, Tomioka Y, Yoshii K,
Okazaki M. The Impact of Brow-Lift on Eyelid
Closure in Patients with Facial Paralysis. Facial

258

12.

13.

14.

15.

16.

17.

Plast Surg Aesthet Med. 2022 Sep-Oct;24(5):385-390.
Yamashita S, Kitamura Y, Fujisawa K, Mito D,
Tomioka Y, Kurita M, Miyamoto S, Iida T,
Okazaki M. Microsurgical Lymphovenous
Anastomosis for Pelvic Lymphoceles after
Gynecological Cancer Surgery. J Plast Reconstr
Aesthet Surg. 2022 Mar;75(3):1142-1149.
Ogawa K, Okazaki M, Mori H, Hidaka T,
Tomioka Y, Tanaka K, Uemura N, Akiyama M.
Comparative Blink Analysis in Patients With
Established Facial Paralysis Using High-Speed
Video Analysis. J Craniofac Surg. 2022 May
1;33(3):797-802.
Hidaka T, Ogawa K, Tomioka Y, Yoshii K, TomioJ, Okazaki M. Change in Eyelid Closure in
Spontaneous Blinking After Static Eyelid
Reconstruction Surgery for Patients With Facial
Paralysis. Ann Plast Surg. 2022 Mar 1;88(3):303307.
Tanaka K, Suesada N, Homma T, Mori H,
Sugawara T, Tsutsumi T, Asakage T, Okazaki M.
The different concepts of surgical managements
between anterior and lateral skull basereconstructions based on surgical purposes. Auris
Nasus Larynx. 2022 Apr;49(2):271-278.
Kanayama K, Kato H, Mori M, Takahi F,
Nakatsukasa S, Okazaki M. Optimal choice ofpunch size for follicular unit excision: A
comparative study of 153 Asian patients. J
Cosmet Dermatol. 2022 Jun; 21(6):2668-2670.
Tanaka K, Suesada N, Homma T, Mori H,
Okazaki M. Reliability of Temporal Vascular
Anastomosis and Techniques for Better
Outcomes. J Reconstr Microsurg. 2022 Jan;38(1):41-46.

259

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

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

Masashi Shiiba, D.D.S., Ph.D.

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

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

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

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

Associate
Natsuko Uchino, D.D.S., Ph.D.

Asako Taniguchi, D.D.S., Ph.D.

Rika Narita, D.D.S., Ph.D.

Yoko Uchida, D.D.S., Ph.D.

Kenichi Kumagai, D.D.S., Ph.D.

Miki Kashiwagi, D.D.S., Ph.D.

Yusuke Tsuda, M.D., Ph.D.

Ryo Maruoka, D.D.S., Ph.D.

Homepage http://plaza.umin.ac.jp/%7Eoralsurg/
Introduction and Organization
Department of Oral and Maxillofacial Surgery,commenced by Dr. Hisashi Ishihara in 1900, is oneof the oldest departments in Graduate School of
Medicine, the University of Tokyo. This department
consists of wide variety of specialists, such as oral
surgeons, orthodontists and prosthodontists. We
handle all diseases in the oral-maxillofacial region,such as congenital anomalies, jaw deformities,
benign and malignant tumors, trauma andinflammation. In particular, we have established andpracticed medical system for cleft lip and palate
since around 2000. In November 2016, weestablished the Cleft Lip and Palate Center, which
we become the center for oral surgeons,orthodontists, and others. Specialists such as
prosthodontists, otolaryngologists, anesthesiologists,obstetricians, pediatricians, pediatric surgeons,speech therapists, nurses, dental hygienists, anddental technicians form a team to deal with illnesses
from all directions and provide multidisciplinary
treatment. Dental care for the patients who havesystemic disorders or under medical control isanother field of our department. Multidisciplinary
treatment teamed by these specialists is characteristicand has performed excellent results in clinical works.
In research fields, all staffs participate in the clinicaland basic research to support the treatment
scientifically and to develop new treatment
protocols, and we have mainly performed theexperimental studies on the regenerative abilities oftissues such as bone, periosteum, cartilage,
perichondrium, vessels, nerve, and skin. At present,
we are focusing on tissue engineering in researchworks especially in bone, cartilage and vessels. The
Department of Tissue Engineering was established at
the University of Tokyo Hospital in October 2001,
and at present Professor Kazuto Hoshi of ourdepartment is concurrently serving as its director.

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The Department of Oral and Maxillofacial Surgery
has Cartilage and Bone Regenerative Medicine and a
Tissue Engineering Department, where assistantprofessors, and graduate students are conducting
basic research on regenerative medicine in the
maxillofacial region.

deformity are treated by utilizing several techniquessuch as distraction technique, autologous bone graft
technique, and the original artificial bone graft
technique in addition to orthognatic surgery. The
original bone graft is made from patient’s three
dimensional images of CT data and this technique is
now applied for patients.

Clinical activities
In the outpatient clinic, we have 12 dental treatment
booths, one operation room and one speech therapy
room. Average number of patients treated at
outpatient clinic is approximately 100 per day.
Our department has two sections mainly; one is oral
and maxillofacial surgery and another is dental andorthodontic dentistry.
In outward dispensary, oral surgery section performs
dental surgeries such as extraction of impacted teeth,
amputation of infected dental root and gingivoplasty
in the operation room. Patients who had been performed surgical treatment are also followed up after
release from the hospital.
Dentistry and orthodontic dentistry performs facial
growth control and tooth movements for patientswith congenital orofacial anomalies such as cleft lip
and palate, jaw deformities and other congenital
deformities. Speech therapy for the patients withcleft lip and palate is also performed by speechtherapists in our department.
Special section for patients of congenital deformities
is on Monday afternoon examined by plastic
surgeon,oral
andmaxillofacial
surgeons,
orthodontists. We also have special sections forpatients with oral cancer and temporomandibular
joint disorder.
In the ward, we have approximately 400 new
inpatients and surgical treatment is performed on
approximately 300 cases per year. The main surgicaltreatments are chiloplasty and palatoplasty for cleft
lip and palate patients, bone grafting in alveolar
cleft, orthognatic surgery of orofacial deformities,
fixation of orofacial fractures, resection of malignant
tumors combined with reconstruction surgery.
Peculiarity of our treatment strategy is teamapproach that consists of oral and maxillofacial
surgeons, orthodontists and prosthodontists. In our
department, patients with congenital dento-facial

Education
Teaching activities are divided into two parts; forundergraduate medical students and for postgraduate
dental students. For undergraduate students, we make5 systematic lectures in their second year of
specialized course, and one lecture and one week
bedside learning in final year. Through thesecurriculums, we demonstrate the characteristics andtreatments of the diseases in oral-maxillofacial
region. Teaching is focused on following points;
congenital anomalies such as cleft lip and palate andbranchial arch syndromes, dentofacial deformities
caused by developmental and acquired problems,
surgical resection and functional reconstruction of
benign and malignant tumors, temporomandibular
joint disorders, inflammation and maxillofacial
trauma. Minimum dental knowledge concerning jaw
movement, tooth pain, periodontal disease,malocclusion and dental restorations are instructed.
For postgraduate dental students, we have two-yearresident course. This course aims to train for a wide
range of dental treatments and to learn about medical
cares. Various specialists instruct dental treatments
for them in outpatient clinic. Dental caries
treatments, periodontal cares and applications ofdentures are instructed. Tooth extractions andorthodontic treatment are instructed by oral surgeons
and orthodontists. Medical cares in the ward aretaught by medical doctors and oral surgeons.
After two-year residential course, research training at
postgraduate school is positively recommended. Ouraim for education of clinician is to raise up
specialists mastered both clinic and research skills.

Research
Our research project consists of clinic and basic
sections. Each research themes are closely related on
the aim of clinical improvement.

261

The main projects are as follows.
Clinical research:
1. Treatment of facial deformities and malocclusionin patients with cleft lip/ palate
2. Research on facial growth in patients withcraniofacial anomalies
3. Reconstruction of oral and maxillofacial area bycustom-made artificial bone (CT bone) (clinical
trial)
4. Transplantation of implant-type tissue-engineered
cartilage for cleft lip-nose patients
5. QOL study of oral health care system inpreparative cancer patients
6. Overcoming eating loss (eat-loss)
7. The association between oral disorders andsystemic diseases
8. Development of surgical assisted systems using
artificial intelligence, computer vision, andaugmented reality
9. Research on the treatment of temporo-mandibular
joint disorder using autologous adipose-derived
mesenchymal stem cells
Basic and experimental research:
1. Regeneration of bone and cartilage with tissueengineering approach
2. Molecular biology of cartilage repair and its
application to cartilage regenerative medicine
3. Development of novel scaffolds for cartilage andbone regeneration
4. In vivo evaluation of tissue-engineered cartilage
and bone
5. Study on the control of mesenchymal celldifferentiation
6. Elucidation of epigenetic abnormalities in oral
cancers and oral premalignant lesions
7. Functional analysis of microRNAs in humandental pulp stem cells
8. Study on the cleft lip and osteonecrosis of thejaw using animal models
9. Elucidation of mechanisms of tissue repair byadipose-derived stem cells and macrophages
10. Analysis of regulatory mechanisms of bone using
a reconstitution system of the cellular network inbone metabolism

Publication(Original articles，Case report)
1. Fan M, Arai M, Tawada A, Chiba T, Fukushima
R, Uzawa K, Shiiba M, Kato N, Tanzawa H,
Takiguchi Y. Contrasting functions of theepithelial stromal interaction 1 gene, in humanoral and lung squamous cell cancers. Oncol Rep.
2022 Jan;47(1):5. doi: 10.3892/or.2021.8216.
PMID: 34738627【peer-reviewed journal】
2. Osaki J, Yamazaki S, Hikita A, Hoshi K.
Hematopoietic progenitor cells specificallyinduce a unique immune response in dental pulp
under conditions of systemic inflammation.
Heliyon. 2022 Feb 5;8(2):e08904. doi:10.1016/j.
heliyon.2022.e08904. PMID: 35198771; PMCID:
PMC8842015.
3. Ma Q, Kobayashi E, Fan B, Hara K, Nakagawa
K, Masamune K, Sakuma I, Suenaga H.
Machine-learning-based approach for predicting
postoperative skeletal changes for orthognathic
surgical planning. Int J Med Robot. 2022 Feb 7;
e2379. doi: 10.1002/rcs.2379. 【peer-reviewed
journal】
4. Komatsu M, Saito K, Miyamoto I, Koike K,
Iyoda M, Nakashima D, Kasamatsu A, Shiiba
M, Tanzawa H, Uzawa K. Aberrant GIMAP2
expression affects oral squamous cell carcinoma
progression by promoting cell cycle andinhibiting apoptosis. Oncol Lett. 2022 Feb;
23(2): 49. doi:10.3892/ol.2021.13167. PMID:
34992682【peer-reviewed journal】
5. Koichiro Sato, Kazutoshi Nakaoka, HarunaYabe, Takanori Eguchi, Kenichi Kumagai, Go
Arai, Yumi Ito, Yoshiki Hamada。Epstein–Barrvirus-infected Plasma Cells Infiltrating Plasma
Cell Mucositis of the Oral Cavity and Larynx,
Journal of Oral and Maxillofacial Surgery,
Medicine, and Pathology (in press) 【peerreviewed journal】
6. Kawakami H, Nishizawa S, Hikita A, Hoshi K.
Histochemical and Morphometrical Analyses of
Scarless Wound Healing in Mouse Fetal Model.
Tokai J Exp Clin Med, 2021 Apr 20; 46(1):3343. PMID: 33835474 【peer-reviewed journal】
7. Uzieliene I, Bagdonas E, Hoshi K, Sakamoto T,
Hikita A, Tachtamisevaite Z, Rakauskiene G,

262

Kvederas G, Mobasheri A, Bernotiene E.
Different
phenotypes
andchondrogenic
responses of human menstrual blood and bonemarrow mesenchymal stem cells to activin A
and TGF-β3. Stem Cell Res Ther, 2021 Apr 29;
12(1):251. doi: 10.1186/s13287-021-02286-w,
PMID: 33926568, Free PMC article【peerreviewed journal】
8. Tonosaki K, Yonenaga K, Ono S, Itai S, Oyama
S, Mizuno T, Watanabe R, Hoshi K. Correction
to: Swallowing evaluation by the Kuchikara
Taberu Balance Chart and videoendscopic
examination reveals that respiratory conditions,chewing, and position are strongly related todysphagia. Odontology, 2021 Apr; 109(2):453454. doi: 10.1007/s10266-020-00575-z, PMID:
33346895, No abstract available 【peerreviewed journal】Ono S, Ishimaru M, Ida Y,
Yamana H, Ono Y, Hoshi K, Yasunaga H.
Validity of diagnoses and procedures inJapanese dental claims data. BMC Health Serv
Res, 2021 Oct 18; 21(1):1116. doi: 10.1186/
s12913-021-07135-3, PMID: 34663302, Free
PMC article 【peer-reviewed journal】
9. Kanda K, Asawa Y, Inaki R, Fujihara Y, Hoshi
K, Hikita A. Requirement of direct contact
between chondrocytes and macrophages for thematuration of regenerative cartilage. Sci Rep,
2021 Nov 18; 11(1):22476. doi: 10.1038/
s41598-021-01437-6, PMID: 34795319, Free
PMC article 【peer-reviewed journal】
10. Shimizu R, Asawa Y, Komura M, Hoshi K,
Hikita A. Superior stemness of a rapidly
growing subgroup of isolated human auricularchondrocytes and the potential for use in
cartilage regenerative therapy. Regen Ther, 2022
Jan 4; 19: 47-57. doi: 10.1016/j.reth.2021.12.
005, eCollection 2022 Mar, PMID: 35059479,
Free PMC article 【peer-reviewed journal】
11. Yonenaga K, Itai S, Hoshi K. Implications forclinical dental practice during the coronavirus
disease pandemic: A scoping review. J
Prosthodont Res, 2022 Jan 11; 66(1): 6-11.
doi:10.2186/jpr. JPR_D_21_00064, Epub 2021
Oct 26, PMID: 34707074, Review
12. Kanda K, Asawa Y, Inaki R, Fujihara Y, Hoshi
K, Hikita A. Author Correction: Requirement of

13.

14.

15.

16.

17.

18.

direct contact between chondrocytes andmacrophages for the maturation of regenerative
cartilage. Sci Rep. 2022 Jan 13; 12(1):967. doi:
10.1038/s41598-021-03460-z, PMID: 35027564,
Free PMC article, No abstract available
Miyamoto Y, Kubota K, Asawa Y, Hoshi K,
Hikita A. Publisher Correction. M1-likemacrophage contr ibutes to chondrogenesis invitro. Sci Rep, 2022 Feb 22; 12(1):3298. doi:
10.1038/s41598-022-07417-8, PMID: 35194120,
Free PMC article, No abstract available.
Ning FL, Lyu J, Pei JP, Gu WJ, Zhang NN, Cao
SY, Zeng YJ, Abe M, Nishiyama K, Zhang CD.
The burden and trend of gastric cancer andpossible risk factors in five Asian countries
from 1990 to 2019. Sci Rep, 2022 Apr 8;
12(1):5980. doi: 10.1038/s41598-022-10014-4,
PMID: 35395871, PMCID: PMC8993926【peer-reviewed journal】
Ma Q, Kobayashi E, Fan B, Hara K, Nakagawa
K, Masamune K, Sakuma I, Suenaga H.
Machine-learning-based approach for predicting
postoperative skeletal changes for orthognathic
surgical planning. Int J Med Robot, 2022 Jun;
18(3):e2379.
doi:
10.1002/rcs.2379【peerreviewed journal】
Kanazawa S, Okada H, Riu D, Mabuchi Y,
Akazawa C, Iwata J, Hoshi K, Hikita A.
Hematopoietic-mesenchymal signals regulate
the properties of mesenchymal stem cells. Int J
Mol Sci, 2022 Jul 26; 23(15):8238. doi:
10.3390/ijms23158238, PMID: 35897814, Free
PMC article
Fujihara Y, Mori Y, Saijo H, Abe T, Susami T,
Haga N, Hoshi K. Long-term dental outcomes inpatients
withfibrodysplasia
ossificans
progressiva: a report of three cases of tooth
extraction. Quintessence Int, 2022 Aug 17;53(8):712-720. doi: 10.3290/j.qi.b3094989,
PMID: 35674162
Tonosaki K, Yonenaga K, Itai S, Oyama S,
Mizuno T, Ono S, Watanabe R, Hoshi K.
Complete lateral positioning enabled feeding ina patient with aspiration pneumonia. Tokai J
Exp Clin Med, 2022 Sep 20; 47(3):105-108.
PMID: 36073279

263

19. Tsuji N, Sakamoto T, Hoshi K, Hikita A.
Spatiotemporal
analysisofosteoblast
morphology and wnt signal-induced osteoblast
reactivation during bone modeling in vitro.
JBMR Plus, 2022 Oct 21; 6(11):e10689. doi:
10.1002/jbm4.10689, eCollection 2022 Nov,
PMID: 36398107, Free PMC article
20. Kato H, Koga M, Kinoshita Y, Hidaka N,
Hoshino Y, Takashi Y, Arai M, Kobayashi H,
Katsura M, Nakamoto Y, Makise N, Ushiku T,
Hoshi K, Nangaku M, Makita N, Fukumoto S,
Ito N. Utility of multimodality approach
including systemic FGF23 venous sampling in
localizing phosphaturic mesenchymal tumors. J
Endocr Soc, 2022 Nov 24; 7(2):bvac181. doi:
10.1210/jendso/bvac181, eCollection 2022 Dec
15, PMID: 36540156, Free PMC article
21. Kato H, Okawa R, Ogasawara T, Hoshino Y,
Hidaka N, Koga M, Kinoshita Y, Kobayashi H,
Taniguchi Y, Fukumoto S, Nangaku M, Makita
N, Hoshi K, Nakano K, Ito N. Effect ofconventional treatment on dental complications
and ectopic ossifications among 30 adults with
XLH. J Clin Endocrinol Metab, 2022 Dec 16:
dgac732. doi: 10.1210/clinem/dgac732, Epubahead of print, PMID: 36524341【peerreviewed journal】(Review articles)
1. Abe M, Mitani A, Yao A, Hoshi K, Yanagimoto
S. Systemic Disorders Closely Associated with
Malocclusion in Late Adolescence: A Review
and Perspective. Int J Environ Res Public
Health. 19(6): 3401, 2022. https://doi.org/10.
3390/ijerph19063401 Published 14 March, 2022
【peer-reviewed journal】
2. Abe M, Mitani A, Yao A, Zong L, Zhang CD,
Hoshi K, Yanagimoto S. Oral Health in Japan:
State-of-the-Art and Perspectives. Int J Environ
Res Public Health. 2022 Jul 6;19(14): 8232.
doi:10.3390/ijerph19148232.PMID: 35886083
Free PMC article. 【peer-reviewed journal】

264

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.

Takumi Matsumoto, M.D., Ph.D.

Hiroshi Kobayashi, M.D., Ph.D.

Specially Appointed Lecturer
Ryota Yamagami, M.D.

Associates
So Kato, M.D., Ph.D.

Hideki Nakamoto, M.D., Ph.D.

Tomofumi Kage, M.D., Ph.D.

Kenta Makabe, M.D., Ph.D.

Hisatoshi Ishikura, M.D., Ph.D.

Junya Miyahara, M.D., Ph.D.

Takafumi Miyake, M.D.

Naoto Kaminaga, M.D., Ph.D.

Yudai Kumanomidoh, M.D.

Kazuhiro Kohata, M.D., Ph.D.

Koichi Okajima, M.D.

Hiroyasu Kodama, M.D.

Takahiro Sasaki, 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 had learned
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 number of
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 the acuteneeds of society from the beginning. Prof. Tashiro
believed that trauma should be treated by orthopedists,
so he provided his pupils with this training. Since
1950’s, the department has increasingly been involvedin the treatment of traffic and industrial accident
victims. Prof. Tashiro and his successor professor Kenji
Takagi devoted themselves to the establishment of an
institute for children with disabilities. The arthroscopy
was developed by Prof. Takagi, and is now considered
to represent a breakthrough in the development ofminimally invasive surgery. We have recently been

265

conducting many studies related to the ossification of
spinal ligaments (OPLL), rheumatoid arthritis,
biomechanics, and the degenerative skeletal disorders
such as osteoporosis and osteoarthritis in response to
the progressive aging of 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 of society,
we have been conducting the teaching, clinical, andresearch activities described below.
Faculty members of the department are one professor,
two associate professors, three lecturers, one speciallyappointed lecture, 13 associates, four medical staff
members, and 12 senior 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, clinical clerkshipprograms to 5th year students and elective clinicalclerkship programs to 6th year medical students.
A comprehensive series of lectures provides basic
knowledge of the physiology, pathology, diagnosis andtreatment of various musculoskeletal disorders. Twelve
consecutive lectures in total cover a whole field of
orthopaedics: basic science, pediatric disorders,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 thephysical assessment classes, we have provided physicaldiagnostic maneuvers and the radiological assessmentof a variety of musculoskeletal diseases. PBL has been
introduced to a small group of students to learn medical
humanity and to develop a practical methodology toresolve 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 of more
intensive exposure to the clinical practice. The students
are attached to a clinical team and are involved in mostof the clinical activities performed by the team.
For postgraduate education, junior residents join our
department for 1-8 months. In 11 doctors-in-training
completed our program during this fiscal year. Since
the training period is short, they are encouraged toexperience emergency cases as often as possible tolearn primary care. For senior residents, 1-year clinicalprograms were conducted in corporation with ouraffiliated hospitals. A postgraduate seminar and a basic
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, bone systemic
disorders, and foot. A total of 34,337 patients visitedthe outpatient clinic in fiscal 2022.
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.
1,345 operations were performed in fiscal 2022.
These include 303 spine surgeries, 58 surgeries forrheumatoid arthritis patients, 128 hip surgeries, 264
knee surgeries (including 36 computer-assisted ACL
reconstructions, 152 computer-assisted TKA/UKA,
255 hand surgeries, 43 foot and ankle surgeries, 36
pediatric surgeries, 134 surgeries for bone and soft

266

tissue tumor, and 106 trauma surgeries.
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 these cases.
This procedure was invented and developed in our
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 system that has
been officially approved as a high-level advanced
medical treatment.
The spine group is now converting open surgeries tominimum invasive surgeries using endoscopic
technique. In 2012, the cervical microendoscopic
Interlaminar decompression through a midline
approach (CMID) was developed, and has beenyielding favorable results in selected patients withcervical myelopathy.
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 the accurate
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 treat-ment 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 thisperiod of analysis, the mechanical properties of thefracture site in vivo are to be evaluated by monitoring
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. Five
endowment departments take an active role in research
activities in close collaboration with our department.
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. Our research
activities cover the generation and differentiation ofchondrocytes, the joint 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

267(NinJa), and other multicenter groups. In 2017, theNPO Tokyo University Spine Group was established,proactively registering all spine surgeries at affiliatedfacilities and sharing surgical outcomes. As of August
2023, 32,440 spine surgeries have been registered.

circuit for response inhibition revealed bytranscranial ultrasound stimulation in humans. Cell
Nagata K, Tozawa K, Miyahara J, Ito Y, Nakamoto
H, Nakajima K, Kato S, Doi T, Taniguchi Y,

Yoshida Y, Ito Y, Ohtomo N, Sakamoto R,

Matsubayashi Y, Tanaka S, Oshima Y. Association

Nakajima K, Nagata K, Okamoto N, Nakamoto H,

Between Preoperative Neuropathic Pain and

Kato S, Taniguchi Y, Matsubayashi Y, Tanaka S,

Patient

Oshima Y. Noninvasive Skin Autofluorescence ofCervical Spinal Cord Decompression Surgery.

Advanced Glycation End Products for Detecting

Global Spine J. 2022 Jun 17. Online ahead of print.

of

the

PosteriorLongitudinal

7.

Reported

Outcome

Measures

After

Oshina M, Tani S, Yamada T, Ohe T, Iwai H,

Ligament in the Thoracic Spine. Spine (Phila Pa

Oshima Y, Inanami H. Limitations of minimally1976). 2022 Nov 4. Online ahead of print.

invasive

Tozawa K, Matsubayashi Y, Kato S, Doi T,

decompression method of posteriorly shifting theTaniguchi Y, Kumanomido Y, Higashikawa A,

nerve root-in cases of large anterior osteophytes in

Yosihida Y, Kawamura N, Sasaki K, Azuma S, Yu

cervical radiculopathy: A retrospective multicenter

J, Hara N, Iizuka M, Ono T, Fukushima M,

cohort study. J Orthop Sci. 2022 Jul 8. Online

Takeshita Y, Tanaka S, Oshima Y. Surgicalahead of print.
8.

posteriorcervicalforaminotomy-aNagata K, Miyahara J, Nakamoto H, Kawamura N,

and posterior decompression with fusion surgery

Takeshita Y, Higashikawa A, Ono T, Fukushima M,

among

2

Okazaki R, Hara N, Kato S, Doi T, Taniguchi Y,

multicenter

Matsubayashi Y, Tanaka S, Oshima Y. Effect ofcohort study. BMC Musculoskelet Disord. 2022

diabetes on patient-reported outcome measures at

Oct 8;23(1):902.

one

Sakamoto R, Nakamoto H, Yoshida Y, Ohtomo N,

spondylotic myelopathy. Sci Rep. 2022 Jun

Nagata K, Kato S, Doi T, Matsubayashi Y,

11;12(1):9684.

patients

degenerativewithMeyerdingspondylolisthesis:

a

grade

Taniguchi Y, Tanaka S, Oshima Y. Does T1 slope

4.

S. A causal role of anterior prefrontal-putamen

6.

outcomes between posterior decompression alone

3.

Kamagata K, Aoki S, Oshima Y, Tanaka S, Konishi

Doi T, Horii C, Tozawa K, Nakarai H, Sasaki K,

Ossification

2.

Nakajima K, Osada T, Ogawa A, Tanaka M, Oka S,

Rep. 2022 Aug 16;40(7):111197.

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Sameshima S, Tanaka S. The Association between

13. Miyahara J, Yoshida Y, Nishizawa M, Nakarai H,

In Vivo Knee Kinematics and Patient-Reported

Kumanomido Y, Tozawa K, Yamato Y, Iizuka M,

OutcomesYu J, Sasaki K, Oshina M, Kato S, Doi T, Taniguchi

Stabilized Total Knee Arthroplasty. J Knee Surg.

Y, Matsubayashi Y, Higashikawa A, Takeshita Y,

2022 Oct;35(12):1342-1348.

duringSquattinginBicruciate-

Ono T, Hara N, Azuma S, Kawamura N, Tanaka S,

19. Inui H, Yamagami R, Kono K, Kawaguchi K,

Oshima Y. Treatment of restenosis after lumbar

Sameshima S, Kage T, Tanaka T, Taketomi S,

decompression surgery: decompression versus

Tanaka S. Comparison of the joint laxity of total

decompression and fusion. J Neurosurg Spine.

knee arthroplasty evaluated by the distraction force

2022 Jan 7;36(6):892-899.

and the varus-valgus force. Knee. 2022 Jan;34:98-

14. Okamoto N, Kato S, Doi T, Nakamoto H,
Matsubayashi Y, Taniguchi Y,

Inanami107.

H,

20. Kono K, Inui H, Tomita T, Yamazaki T, Taketomi

Higashikawa A, Kawamura N, Hara N, Azuma S,

S, Yamagami R, Kawaguchi K, Kage T, Arakawa T,

Takeshita Y, Ono T, Fukushima M, Tanaka S,

Tanaka S. Effect of weight-bearing in bicruciate-

Oshima Y. Influence of Perioperative Antithrombic

retaining total knee arthroplasty during high-Agent Discontinuation in Elective Posterior Spinal

flexion activities. Clin Biomech (Bristol, Avon).

Surgery: A Propensity-Score-Matched Analysis.

2022 Feb;92:105569.

World Neurosurg. 2022 Feb;158:e362-e368.

21. Takei S, Taketomi S, Torii S, Tojima M, Kaneoka

15. Nakarai H, Kato S, Kawamura N, Higashikawa A,

K, Tanaka S. Characteristics of the Kicking Motion

Takeshita Y, Fukushima M, Ono T, Hara N, Azuma

in Adolescent Male Soccer Players Who Develop

S, Tanaka S, Oshima Y. Minimal clinically

Osgood-Schlatter Disease: A Prospective Study.

important difference in patients who underwent

Orthop J Sports Med. 2022 Mar 14; 10(3):decompression alone for lumbar degenerative

23259671221083567.

269

22. Yamagami R, Inui H, Taketomi S, Kono K,

28. Sameshima S, Inui H, Taketomi S, Yamagami R,

Kawaguchi K, Sameshima S, Kage T, Tanaka S.

Kono K, Kawaguchi K, Kage T, Tanaka S. The

Proximal tibial morphology is associated with risk

intraoperative gap differences due to jointof trauma to the posteromedial structures during

distraction

tibial bone resection reproducing the anatomicalarthroplasty are affected by preoperative lower

posterior tibial slope in bicruciate-retaining total

limb alignment and body mass index. Clinknee arthroplasty. Knee. 2022 Jun;36:1-8.

Biomech (Bristol, Avon). 2022 Oct;99:105765.

force

differences

in

total

knee

23. Kawaguchi K, Taketomi S, Mizutani Y, Inui H,

29. Kage T, Inui H, Tomita T, Yamazaki T, Taketomi S,

Yamagami R, Kono K, Kage T, Takei S, Fujiwara

Yamagami R, Kono K, Kawaguchi K, Murakami R,

S, Ogata T, Tanaka S. Dynamic Postural Stability

Arakawa T, Tanaka S. In vivo kinematic

Is Decreased During the Single-Leg Drop Landing

comparison of medial pivot total knee arthroplasty

Task in Male Collegiate Soccer Players Within weight-bearing and non-weight-bearing deep

Chronic Ankle Instability. Orthop J Sports Med.

knee bending. Clin Biomech (Bristol, Avon). 2022

2022 Jul 25;10(7):23259671221107343.

Oct;99:105762.

24. Kono K, Inui H, Kage T, Tomita T, Yamazaki T,

30. Kage T, Taketomi S, Tomita T, Yamazaki T, Inui H,

Taketomi S, Yamagami R, Kawaguchi K, Tanaka S.

Yamagami R, Kono K, Kawaguchi K, Sameshima

Femoral rollback at high-flexion during squatting

S, Arakawa T, Tanaka S. Anterior cruciate

is related to the improvement of sports activities

ligament-deficient

after bicruciate-stabilized total knee arthroplasty:

location of the femur in the medial compartment

an observational study. BMC Musculoskelet

during squatting. J Orthop Res. Dec 20. Online

Disord. 2022 May 26;23(1):496.

ahead of print.

knee

inducesaposterior

25. Takagi K, Taketomi S, Inui H, Yamagami R,

31. Yamagami R, Inui H, Taketomi S, Kono K,

Kawaguchi K, Sameshima S, Kage T, Tahara K,

Kawaguchi K, Sameshima S, Kage T, Arakawa T,

Tanaka S. The effects of initial graft tension on

Tanakafemorotibial relationship following anatomical

kinematics are similar in varus and valgus knees

rectangular tunnel anterior cruciate ligament

during medial pivot total knee arthroplasty. Clinreconstruction using bone-patellar tendon-bone

Biomech (Bristol, Avon). Dec 9. Online ahead ofgraft. Knee. 2022 Aug;37:112-120.

print.

S.

Intraoperative

femoralrotational

26. Nakahira Y, Taketomi S, Kawaguchi K, Mizutani Y,

32. Matsumoto T, Takeda R, Maenohara Y, Chang SH,

Hasegawa M, Ito C, Uchiyama E, Ikegami Y,

Omata Y, Takuo J, Tanaka S. Comparison between

Fujiwara S, Yamamoto K, Nakamura Y, Tanaka S,

suture and staple fixations as internal fixation

Ogata T. Kinematic Differences Between thetechniques for Akin osteotomy. Foot Ankle Surg.

Dominant and Nondominant Legs During a Single-

2022 Jan;28(1):100-106.

Leg Drop Vertical Jump in Female Soccer Players.

33. Matsumoto T, Takeda R, Kasai T, Chang SH, Izawa

Am J Sports Med. 2022 Aug;50(10):2817-2823.

N, Hirose J, Takuo J, Tanaka S. Clinical Outcomes

27. Taketomi S, Inui H, Yamagami R, Nakazato K,

After First Metatarsophalangeal Joint Arthrodesis

Kawaguchi K, Kono K, Sameshima S, Kage T,

by Flat Cut Joint Preparation With Individual

Tanaka S. Lateral posterior tibial slope does not

Adjustment for Sagittal Alignment. J Foot Ankle

affect femoral but does affect tibial tunnel

Surg. 2022 Jan-Feb;61(1):60-66.

widening following anatomic anterior cruciate

34. Matsumoto T, Higuchi J, Maenohara Y, Chang SH,

ligament reconstruction using a Bone-Patellar

Iidaka T, Horii C, Oka H, Muraki S, Hashizume H,

Tendon-Bone graft. Asia Pac J Sports Med

Yamada H, Yoshida M, Nakamura K, Tanaka S,

Arthrosc Rehabil Technol. 2022 Oct 5;30:25-31.

YoshimuraN.

The

discrepancy

between270

radiographically-assessedandself-recognized

41. Takamiya A, Ishibashi Y, Makise N, Hirata M,

hallux valgus in a large population-based cohort.

Ushiku T, Tanaka S, Kobayashi H. Imaging

BMC Musculoskelet Disord. 2022 Jan 4;23(1):31.

characteristics of NTRK-rearranged spindle cell

35. Takeda R, Matsumoto T, Maenohara Y, Omata Y,

neoplasm of the soft tissue: A case report. J Orthop

Inui H, Nagase Y, Nishikawa T, Tanaka S.

Sci. 2022 Jan 13. Online ahead of print.

Increasing trend of radiographic features of knee

42. Kobayashi H, Zhang L, Hirai T, Tsuda Y, Ikegami

osteoarthritis in rheumatoid arthritis patients

M, Tanaka S. Comparison of clinical features andbefore total knee arthroplasty. Sci Rep. 2022 Junoutcomes of patients with leiomyosarcoma of bone

21;12(1):10452.

and soft tissue: a population-based cohort study.

36. Zhang L, Michihata N, Matsui H, Fushimi K,

Jpn J Clin Oncol. 2022 Feb 5;52(2):143-150.

Yasunaga H, Tsuda Y, Tanaka S, Kobayashi H.

43. Kobayashi H, Okuma T, Okajima K, Ishibashi Y,

Preoperative arterial embolization and wound

Zhang L, Hirai T, Ohki T, Ikegami M, Sawada R,

complications after resection of malignant bone

Shinoda Y, Akiyama T, Goto T, Tanaka S. Systemic

tumor in the pelvis: a nationwide database study.

inflammation response index (SIRI) as a predictive

Jpn J Clin Oncol. 2022 Oct 6;52(10):1176-1182.

factor for overall survival in advanced soft tissue

37. Miyamoto K, Kobayashi H, Zhang L, Tsuda Y,

sarcoma treated with eribulin. J Orthop Sci. 2022

Makise N, Yasunaga Y, Ikemura M, Nakai Y,
Shibata E, Ushiku T, Tanaka S. Atypical
Neurofibromatous

Neoplasm

with

Jan;27(1):222-228.
44. Kato H, Koga M, Kinoshita Y, Hidaka N, Hoshino

Uncertain

Y, Takashi Y, Arai M, Kobayashi H, Katsura M,

Biologic Potential in the Posterior Mediastinum ofNakamoto Y, Makise N, Ushiku T, Hoshi K,

a Young Patient with Neurofibromatosis Type 1: A

Nangaku M, Makita N, Fukumoto S, Ito N. Utility

Case Report. Case Rep Oncol. 2022 Nov 8; 15(3):of Multimodality Approach Including Systemic

988-994.

FGF23

38. Hirai T, Kobayashi H, Kobayashi E, Saito M,
Akiyama T, Kikuta K, Nakai T, Endo M,

VenousSampling

inLocalizing

Phosphaturic Mesenchymal Tumors. J Endocr Soc.
2022 Nov 24;7(2):bvac181.

Tsukamoto S, Hakozaki M, Takenaka S, Nishimura

45. Kato H, Okawa R, Ogasawara T, Hoshino Y,

S, Kawashima H, Tanzawa Y, Kawano H, Tanaka

Hidaka N, Koga M, Kinoshita Y, Kobayashi H,

S. Dedifferentiation in low-grade osteosarcoma: aTaniguchi Y, Fukumoto S, Nangaku M, Makita N,

JapaneseGroup

Hoshi K, Nakano K, Ito N. Effect of Conventional(JMOG) study. Int J Clin Oncol. 2022 Nov; 27(11):Treatment on Dental Complications and Ectopic

1758-1766.

Ossifications Among 30 Adults With XLH. J Clin

Musculoskeletal

Oncology

39. Kobayashi H, Zhang L, Hirai T, Tsuda Y, Ikegami
M,

TanakaS.

Clinicalcharacteristics

ofEndocrinol Metab. 2022 Dec 16. 17;108(6):14051414. Online ahead of print.

undifferentiated pleomorphic sarcoma of bone and46. Hoshino Y, Hidaka N, Kato H, Koga M, Taniguchi

the impact of adjuvant chemotherapy on theY, Kobayashi H, Nangaku M, Makita N, Ito N.

affected patients: a population-based cohort study.

Incidence of ossification of the spinal ligaments in

Jpn J Clin Oncol. 2022 May 31;52(6):589-598.

acromegaly patients. Bone Rep. 2022 Oct 17;

40. Kobayashi H, Zhang L, Hirai T, Tsuda Y, Ikegami
M, Tanaka S. Role of adjuvant chemotherapy in

17:101628.
47. Kawai A, Narahara H, Takahashi S, Nakamura T,

undifferentiatedKobayashi H, Megumi Y, Matsuoka T, Kobayashi

pleomorphic sarcoma of soft tissue: a population-

E. Safety and effectiveness of eribulin in Japanese

based cohort study. Int J Clin Oncol. 2022 Apr;patients with soft tissue sarcoma including rare27(4):802-810.

subtypes: a post-marketing observational study.

patients

withlocalized,

271

BMC Cancer. 2022 May 11;22(1):528.

Nagata K, Omata Y, Yano F, Inui H, Moro T,

48. Tabata J, Nakaoku T, Araki M, Yoshino R, Kohsaka

Tanaka S, Saito T. Regulation of osteoarthritis

S, Otsuka A, Ikegami M, Ui A, Kanno SI, Miyoshi

development by ADAM17/Tace

K, Matsumoto S, Sagae Y, Yasui A, Sekijima M,

cartilage. J Bone Miner Metab. 2022 Mar;40(2):Mano H, Okuno Y, Okamoto A, Kohno T. Novel196-207.

Calcium-Binding Ablating

Induce55. Kaneko T, Nakamura S, Hayakawa K, Tokimura F,

Drive

Miyazaki T. Clinical and radiological outcomes ofTumorigenesis. Cancer Res. 2022 Oct 17;82(20):total hip arthroplasty in octogenarian patients using

3751-3762.

a three-dimensional porous titanium cup: aConstitutive

RET

Mutationsin articular

Activity

and

49. Kage H, Kohsaka S, Tatsuno K, Ueno T, Ikegami

retrospective analysis in Japanese patients. Eur J

M, Zokumasu K, Shinozaki-Ushiku A, Nagai S,

Orthop Surg Traumatol. 2022 Nov 22. Online

Aburatani H, Mano H, Oda K. Tumor mutational

ahead of print.

burdenmeasurement

using

comprehensive

56. Miyake T, Uehara K, Kohata K, Miura T, Ohe T,

genomic profiling assay. Jpn J Clin Oncol. 2022

Tanaka S, Morizaki Y. New body surface indexes

Aug 5;52(8):925-929. doi: 10.1093/jjco/hyac063.

for germinal matrix: DIP joint extension boundary

Erratum in: Jpn J Clin Oncol. 2022 Nov 3;52(11):line and dorsal distal interphalangeal crease. J

1358.

Orthop Sci. 2022 Sep 15. Online ahead of print.

50. Ikeuchi H, Hirose T, Ikegami M, Takamochi K,

57. Tani S, Okada H, Onodera S, Chijimatsu R, Seki

Suzuki K, Mano H, Kohsaka S. PreclinicalM, Suzuki Y, Xin X, Rowe DW, Saito T, Tanaka S,

assessment of combination therapy of EGFR

Chung UI, Ohba S, Hojo H. Stem cell-based

tyrosinehighlymodeling and single-cell multiomics reveal gene-

heterogeneous tumor model. Oncogene. 2022 Apr;

regulatory mechanisms underlying human skeletal

41(17):2470-2479.

development. Cell Rep. 2023 Apr 25;42(4):112276.

kinaseinhibitors
doi:

in

a

10.1038/s41388-022-

02263-4. Epub 2022 Mar 19.

58. Tonak HA, Aydin Y, Ozcanyuz B, Ozcanli H,

51. Ishikura H, Nakamura M, Nakamura S, Tanaka T,

Uehara K, Morizaki Y. Psychometric Properties of

Kawano H, Tanaka S. Relationship between the

the Turkish Version of the JHand for the Patient-

Accuracy of the Acetabular Cup Angle and BMI in

Oriented Outcome Measure for Patients with Hand

Posterolateral Total Hip Arthroplasty with CT-

and Elbow Disorders. Eval Health Prof. 2022 Dec

Based Navigation. Medicina (Kaunas). 2022 Jun

12. Online ahead of print.

27;58(7):856.

59. Matsubara T, Soma K, Yamada I, Fujita H,

52. Tanaka T, Moro T, Asai S, Hashikura K, Ishikura
H,

Tanakacup

fixation for intertrochanteric fractures improves

implantations during total hip arthroplasty with or

reduction and lag screw position. PLoS One. 2022

without

Nov 16;17(11):e0276903.

aS.

Comparison

historyofbetween

Yoshitani J, Oka H, Okada H, Tanaka S. Offset nailrotational

acetabularosteotomy. Arch Orthop Trauma Surg. 2022 Nov;
142(11):3539-3547.

60. Kurashige

T,

Nakagawa

T,

Matsubara

T,

Kobayashi M. Modified paratricipital approach

53. Ishikura H, Nakamura M, Oka H, Yonezawa K,

without mobilization of the ulnar nerve prevents

Hidaka R, Tanaka T, Kawano H, Tanaka S. A new

postoperative ulnar neuropathy in distal humerusclassification

fatty

fractures. J Orthop Sci. 2023 Sep;28(5):1113-1117.

infiltration of the gluteus minimus in hip

61. Hojo H, Saito T, He X, Guo Q, Onodera S, Azuma

osteoarthritis using plain computed tomography. J

T, Koebis M, Nakao K, Aiba A, Seki M, Suzuki Y,

Orthop Sci. 2022 Jul;27(4):792-797.

Okada H, Tanaka S, Chung UI, McMahon AP,

systemforevaluating

54. Kaneko T, Horiuchi K, Chijimatsu R, Mori D,

Ohba S. Runx2 regulates chromatin accessibility to272

direct the osteoblast program at neonatal stages.
Cell Rep. 2022 Sep 6;40(10):111315.
62. Omata Y, Okada H, Uebe S, Izawa N, Ekici AB,
Sarter K, Saito T, Schett G, Tanaka S, Zaiss MM.
Interspecies

Single-Cell

RNA-Seq

Analysis

Reveals the Novel Trajectory of Osteoclast
Differentiation and Therapeutic Targets. JBMR
Plus. 2022 May 16;6(7):e10631.
63. Chijimatsu R, Takeda T, Tsuji S, Sasaki K, Kato K,
Kojima R, Michihata N, Tsubaki T, Matui A,
Watanabe M, Tanaka S, Saito T. Development ofhydroxyapatite-coated nonwovens for efficientisolation of somatic stem cells from adipose tissues.
Regen Ther. 2022 Jun 8;21:52-61.
64. Saito T. The superficial zone of articular cartilage.
Inflamm Regen. 2022 May 2;42(1):14.
65. Yano F, Takeda T, Kurokawa T, Tsubaki T,
Chijimatsu R, Inoue K, Tsuji S, Tanaka S, Saito T.
Effects of conditioned medium obtained fromhuman adipose-derived stem cells on skininflammation. Regen Ther. 2022 Apr 16;20:72-77.
66. Kato H, Ansh AJ, Lester ER, Kinoshita Y, Hidaka
N, Hoshino Y, Koga M, Taniguchi Y, Uchida T,
Yamaguchi H, Niida Y, Nakazato M, Nangaku M,
Makita N, Takamura T, Saito T, Braddock DT, Ito
N. Identification of ENPP1 Haploinsufficiency inPatients

With

DiffuseIdiopathic

Skeletal

Hyperostosis and Early-Onset Osteoporosis. J
Bone Miner Res. 2022 Jun;37(6):1125-1135.
67. Watanabe H, Okada H, Hirose J, Omata Y,
Matsumoto T, Matsumoto M, Nakamura M, Saito
T, Miyamoto T, Tanaka S. Transcription Factor
Hematopoietically Expressed Homeobox Protein(Hhex)

Negatively

Regulates

Osteoclast

Differentiation by Controlling Cyclin-Dependent
Kinase Inhibitors. JBMR Plus. 2022 Feb 14; 6(4):e10608.

273

Department of Ophthalmology
Professor
Makoto Aihara, M.D., Ph.D.

Associate Professor
Megumi Honjo, M.D., Ph.D., Ryo Obata, M.D., Ph.D., Takashi Miyai, M.D., Ph.D.

Lecturer
Hitomi Saito, M.D., Ph.D., Hiromasa Sawamura, M.D., Ph.D., Rei Sakata, M.D., Ph.D.,
Rie Tanaka, M.D., Ph.D.

Research Associate
Takashi Ueta, M.D., Ph.D., Keiko Azuma, M.D., Ph.D., Tetsuya Toyono, M.D., Ph.D.,
Taku Toyama, M.D., Ph.D., Yukako Taketani, M.D., Ph.D., Sugimoto Koichiro, M.D.,
Ishiyama Yukako, M.D., Kohdai Kitamoto, M.D., Ph.D., Arai Takahiro, M.D.,
Ono Takashi, M.D., Ph.D., Aoki Shuichiro, M.D., Aoyama Yurika, M.D., Shu Kanhou, M.D.

Homepagehttps://www.todaiganka.jp

Introduction and Organization
The Department of Ophthalmology, University ofTokyo School of Medicine, was founded in 1889.
Since then, the department has contributed to Japanese
ophthalmology not only by educating many eminent
ophthalmologists in Japan but also by producing
significant basic research in ophthalmology.
The department has been active in collaboration with
ophthalmologists around the world, sponsoring
international ophthalmological meetings, educating
fellows from foreign countries, and sending our staff
and fellows abroad.

Clinical activities
Altogether, approximately 2900 new outpatients areseen every year in our hospital, which has a total of 27
beds. Residents work in the ambulatory section andtake care of inpatients. Special services are provided
in units devoted to ophthalmic subspecialties such as
cornea, glaucoma, retina, uveitis, neuro-ophthalmology, orthoptics, diabetic retinopathy, and genetic

and color blindness problems. The staff members
supervise the ambulatory and special services
depending on each one’s specialty.
Most of the inpatients suffer from cataract, glaucoma,
corneal diseases, retinal detachment, diabetic
retinopathy, age-related macular degeneration, uveitis,
ptosis, dry eye and strabismus. Surgeries are
performed in the operating theater of the hospital
under operating microscopes. Approximately 8610
cases underwent operations in our department.
Surgeries can be monitored by TV system, which ismounted on operating microscopes. Since multiple
observers can watch the same images and sharefindings, this system has great potential in training andpromoting discussion.

Education
As an undergraduate course, we give lectures on
corneal physiology, corneal diseases, and corneal
transplantation. In addition, we are engaged inpractical training for medical students on ophthalmological examinations at the outpatient clinic. As a274

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.
13.
14.
15.
16.
17.
18.

Lipid mediators in ocular diseases
Clinical investigation of normal tension
glaucoma
Drug development in IOP reduction of glaucoma
Screening method of glaucoma
Pathophysiology and molecular mechanisms of
diabetic retinopathy
Relationship between visual function and qualityof life in patient with low vision
Investigation of molecular mechanisms of retinal
arteritis and phlebitis
Investigation of gene mutations in primary
vitreoretinal lymphoma and development of newtreatment
Study of mechanisms involving disease-specific
HLA in Behcet's disease
Analysis of structure-function relationships inmacular diseases
Molecular analysis of corneal neovascularization
Gene therapy for corneal dystrophies
Analysis of Meibomian gland with Mibography
Analysis of safety of topical eye drops using
human corneal epithelial cell sheets
Clinical trial of corneal crosslinking for
keratoconus and keratoectasia
Ophthalmic examination of patients withcongenital insensitivity to pain with anhydrosis
Assessment of higher visual functions by fMRI
Relevance between ophthalmic diseases andcortical functions

2.

3.

4.

5.

6.

7.

8.

9.

Liu Y, Yamagishi R, Honjo M, Kurano M,
Yatomi Y, Igarashi K, Aihara M. Role ofAutotaxin in High Glucose-Induced Human
ARPE-19 Cells. Int J Mol Sci. 2022 Aug 16;
23(16):9181.
Fujishiro T, Honjo M, Kawasaki H, Aihara M.
Visual cortex damage in a ferret model of ocular
hypertension. Jpn J Ophthalmol. 2022 Mar;66(2):205-212.
Ono T, Iwasaki T, Terada Y, Miyai T, Mori Y,
Nejima R, Honma T, Aihara M, Miyata K.
Corneal Toxicity After Stinging by a Sea
Anemone, Anthopleura uchidai: A Case Report
With Confirmation by In Vitro Study. Cornea.
2022 Aug 1;41(8):1035-1037.
Suzuki T, Obata R, Inoue T, Ueta Y, Azuma K,
Tate H, Kitamoto K, Otaki C, Hashimoto Y,
Aihara M, Tachi N. Intravenous lipoprostaglandin E1 administration for patients withacute central retinal artery occlusion. BMJ OpenOphthalmol. 2022 May;7(1):e001014.
Nemoto H, Honjo M, Okamoto M, Sugimoto K,
Aihara M. Potential Mechanisms of Intraocular
Pressure Reduction by Micropulse Transscleral
Cyclophotocoagulation in Rabbit Eyes. Invest
Ophthalmol Vis Sci. 2022 Jun 1;63(6):3.
Azuma K, Koumura T, Iwamoto R, Matsuoka M,
Terauchi R, Yasuda S, Shiraya T, Watanabe S,
Aihara M, Imai H, Ueta T. Mitochondrial
glutathione peroxidase 4 is indispensable forphotoreceptor development and survival in mice.
J Biol Chem. 2022 Apr;298(4):101824.
Fujita A, Hashimoto Y, Matsui H, Yasunaga H,
Aihara M. Recent Trends in Treatment andAssociated Costs of Primary Angle-Closure
Glaucoma: A Retrospective Cohort Study.
Ophthalmol Glaucoma. 2022 Oct 15:S25894196(22)00201-0.
Hashimoto Y, Okada A, Matsui H, Yasunaga H,
Aihara M, Obata R. Recent trends in antivascular endothelial growth factor intravitreal
injections: a large claims database study in Japan.
Jpn J Ophthalmol. 2022 Dec 12:1-10.
Chen LW, Ono T, Hashimoto Y, Tsuneya M,
Abe Y, Omoto T, Taketani Y, Toyono T, Aihara

275

10.

11.

12.

13.

14.

15.

16.

M, Miyai T. Regular and irregular astigmatism ofbullous keratopathy using Fourier harmonic
analysis with anterior segment optical coherence
tomography. Sci Rep. 2022 Oct 25;12(1):17865.
Tsuneya M, Chen LW, Ono T, Hashimoto Y,
Kitamoto K, Taketani Y, Toyono T, Aihara M,
Miyai T. UbiA prenyltransferase domaincontaining protein 1 (UBIAD1) variant c.695 A >G identified in a multigenerational Japanesefamily with Schnyder corneal dystrophy. Jpn J
Ophthalmol. 2022 Nov 11.
Sakata R, Fujishiro T, Saito H, Nakamura N,
Honjo M, Shirato S, Miyamoto E, Yamada Y,
AiharaM.
Prostaglandin-Associated
Periorbitopathy Symptom Alleviation After
Switching Prostaglandin F Receptor Agonist toEP2 Receptor Agonist in Patients with Glaucoma.
J Ocul Pharmacol Ther. 2022 Oct 31.
Aoyama Y, Sakata R, Fujishiro T, Honjo M,
Shirato S, Aihara M. Changes in corneal
endothelial cell density after initial Ex-PRESS
drainage device implantation and its relating
factors over 3 years. Eye (Lond). 2022 Jan 10.
Asahina Y, Hashimoto H, Aihara M, Noie T,
Morikawa
T.
Impactof
Neoadjuvant
Chemotherapy on SATB2 Expression in
Colorectal Carcinomas: SATB2 Positivity is
Preserved in Most Cases, but Down-Expressed in
Effective Cases of Chemotherapy. Int J Surg
Pathol. 2022 Mar 27:10668969221088881.
Akiyama K, Ono T, Ishii H, Chen LW, Kitamoto
K, Toyono T, Yoshida J, Aihara M, Miyai T.
Impact of rigid gas-permeable contact lens on
keratometric indices and corneal thickness ofkeratoconus eyes examined with anterior segment
optical coherence tomography. PLoS One. 2022
Jul 8;17(7):e0270519.
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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.

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

Rumi Ueha, M.D., Ph.D.（Swallowing Center）

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

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

Chisato Fujimoto, M.D., Ph.D.

Research Associate
Osamu Fukuoka, M.D.

Hironobu Nishijima, M.D., Ph.D.

Makoto Kinoshita, M.D., Ph.D.

Ryoji Kagoya , M.D., Ph.D.

Takao Goto, M.D.

Kenya Kobayashi, M.D., Ph.D.

Taku Sato, M.D.

Shinji Urata, M.D., Ph. D.

Teru Kamogashira, M.D., Ph.D.

Hajime Koyama, M.D., Ph. D.

Kei Ogawa, 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, swallowing and airway disorders,aphasia, central auditory disorders and head & neckcancers.
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.

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Clinical activities
In the out-patient clinic, general and special services
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 inpatient hospital, 33 beds are prepared forpatients under the supervision of lecturers and seniorresidents from each subspecialty group including head& neck surgery, middle ear surgery and cochlear
implant surgery; voice and swallowing surgery, andparanasal surgery and other minor surgery.
Preoperative and postoperative problems are checkedand discussed by each group, the professor’s andassociate professor’s rounds. Approximately 700
operations are performed annually.
Cochlear implant surgery over 400 cases has been
performed for infants, children and adult patients withprofound hearing loss and is very successful to provide
new hearing. Head and neck surgery is performed to
extirpate malignant tumor with neighboring tissues andreconstruct upper respiratory and swallowing functions
at one stage operation cooperating with plastic
surgeons. Reconstructive surgery of microtia andatresia 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
Serial lectures on otolaryngology head and necksurgery, and special lectures on its current topics areprovided to the fourth year and the fifth/sixth year of
medical students, respectively.
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 professors.

Research activities
Clinical and basic research activities are highly
encouraged. Clinical research, which is supervised bysenior doctors, is very actively pursued even by young
residents. Case reports presentation and writing skills
are regarded as important experience in order todevelop young doctors’ research activity andinvestigate important findings in patients. The clinicalresearch is related to ear surgery, neurotology, audiology, head and neck surgery, laryngology, bronchoesophagology and rhinology and is related to caseresearch, clinical statistics and clinical electrophysiology. Basic research is also encouraged to solve
essence of clinical problems and to elucidate basic
phenomena or anatomical and cellular structures. Our
research topics cover:1) Morphology and neurophysiology of the inner ear
focusing on sensory neural deafness2) Speech perception and language development indeaf children3) Liquid biopsy of perilymph via round window
membrane
4) Prediction of hearing outcome in tympanoplasty
using machine learning5) Analysis of balance disorders using vestibularfunction tests6) Development of novel examination methods forbalance disorders
7) Development of novel therapeutic methods forbalance disorders by galvanic vestibular
stimulation
8) Predicting and elucidating the pathogenesis ofvestibular disorders using machine learning9) Elucidation of the pathogenesis of vestibular
migraine
10) Development of novel therapeutic methods for
persistent postural-perceptual dizziness
11) Elucidation of the mechanism of postural control
in patients with vestibulopathy using mathematicalmodels12) Hair cell physiology and pathology andintroduction of hair cell regeneration in the279

auditory and vestibular end organ
13) Clinical neurophysiology of the facial nerves
focusing on degeneration and regeneration inpatients
14) Analyses of development, regeneration and aging
in olfactory neural system
15) Pathophysiology of olfactory dysfunction16) Computer fluid dynamics of intranasal airflow17) Metabolic conversion of odorant molecules bynasal mucus18) Analysis of eosinophilic chronic sinusitis using
human samples and animal models
19) Swallowing impairment in patients with lungtransplants20) Swallowing mechanisms using pathological andelectrophysiological analysis and VR system21) Evaluation of swallowing physiology withpharyngo-esophageal high-resolution manometry22) Esophageal Motility in Neuromuscular Disorders23) Esophageal Motility in systemic sclerosis24) Gene expression analysis of recurrent respiratory
papillomatosis25) Kinetics of vocal cord movement using high-speed
video system
26) 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.

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Tanaka K, Onoe T, Okano S, Imamura Y, Ariizumi
Y, Hayashi R. Human papillomavirus-relatedoropharyngeal carcinoma. Jpn J Clin Oncol. 52(7):700-6.2022.
Saito Y, Yoshimoto S, Kitayama M, Hayashi T,
Yamamura K, Kobayashi K, Fukuoka O, Nibu KI,
Yamasoba T. Elective neck dissection for T3T4N0 laryngeal carcinoma: evidence from Japan's
National Head and Neck Cancer Registry. Int J
Clin Oncol. Epub 2022.
Sakai T, Saito Y, Tateishi Y, Yamazawa S, Fukuoka
O, Kobayashi K, Omura G, Akashi K, Yoshida M,
Ando M, Ebihara Y, Yamasoba T. Tumor-stroma
ratio can predict lymph-node metastasis in
cT1/2N0 oral tongue squamous cell carcinoma
independent of tumor budding grade. Int J Clin
Oncol.27(12):1818-27.2022.
Sakata A, Kashio A, Koyama H, Uranaka T,
Iwasaki S, Fujimoto C, Kinoshita M, Yamasoba T.
Long-Term Progression and Rapid Decline in
Hearing Loss in Patients with a Point Mutation at
Nucleotide 3243 of the Mitochondrial DNA. Life
(Basel).12(4)2022.

283

56. Shinya Y, Shin M, Hasegawa H, Koizumi S, Kin
T, Kondo K, Saito N. Endoscopic endonasal
transpetroclival approach for recurrent bilateral
petroclival meningioma. Neurosurg Focus Video.
6(2):V7.2022.
57. Sugaya T, Ueha R, Sato T, Goto T, Yamauchi A,
Yamasoba T. Safety of surgical tracheostomy
under continued antithrombotic therapy: A
retrospective cohort study. Clin Otolaryngol.
47(1):88-93.2022.
58. Sugito R, Yamauchi A, Sato T, Goto T, Ueha R,
Nito T, Yamasoba T. Sex-and Age-Based
Etiological Analysis of 2901 Patients With
Dysphonia in a Japanese Tertiary Medical Institute.
Journal of voice : official journal of the VoiceFoundation. Epub 2022.
59. Suto A, Ueha R, Ogura T, Maeda E, Tatebayashi
M, Shimada D, Koyama M, Sato T, Goto T,
Yamauchi A, Yamasoba T. Swallowing computed
tomography and virtual reality as novel imaging
modalities for the diagnosis of clicking larynx:
Two case reports. Auris Nasus Larynx. Epub 2022.
60. Suzuki N, Katoh M, Koda K, Kuriyama M,
Nagano G, Yasuhara K. Idiopathic common
carotid artery laceration: A case report. Clin Case
Rep.10(11):e6551.2022.
61. Takeuchi M, Ahn J, Lee K, Takaki K, Ifukube T,
Yabu K-I, Takamichi S, Ueha R, Sekino M.
Hands-Free Wearable Electrolarynx using Linear
Predictive Coding Residual Waves and Listening
Evaluation. Advanced Biomedical Engineering.
11:68-75.2022.
62. Tokimura R, Hashimoto Maeda M, Mitsutake A,
Sakai S, Suzuki F, Sugasawa K, Fujimoto C,
Ishiura H, Toda T. Isolated Paravermal
Hyperintensities in Neuronal Intranuclear
Inclusion Disease. Neurology.98(22):938-9.2022.
63. Tsunoda K, Nagai R, Kobayashi R, Takazawa M,
Wasano K, Kondo K. Tone Enhancement ElectroFiberscope Combined with Strobe Light Source
and Re-analysis Past Images-Tone Enhancement
Dynamic Stroboscope. Laryngoscope. 132(11):2206-8.2022.
64. Uchida Y, Nishita Y, Otsuka R, Sugiura S, Sone M,
Yamasoba T, Kato T, Iwata K, Nakamura A. Aging
Brain and Hearing: A Mini-Review. Front Aging
Neurosci.13:791604.2022.

65. Ueha R, Ito T, Furukawa R, Kitabatake M, OujiSageshima N, Ueha S, Koyama M, Uranaka T,
Kondo K, Yamasoba T. Oral SARS-CoV-2
Inoculation Causes Nasal Viral Infection Leading
to Olfactory Bulb Infection: An Experimental
Study. Front Cell Infect Microbiol. 12:924725.
2022.
66. Ueha R, Ito T, Ueha S, Furukawa R, Kitabatake M,
Ouji-Sageshima N, Uranaka T, Tanaka H,
Nishijima H, Kondo K, Yamasoba T. Evidence forthe spread of SARS-CoV-2 and olfactory celllineage impairment in close-contact infection
Syrian hamster models. Front Cell InfectMicrobiol.12:1019723.2022.
67. Umekawa M, Shinya Y, Hasegawa H, Kawashima
M, Shin M, Katano A, Minamitani M, Kashio A,
Kondo K, Saito N. Stereotactic radiosurgery
ensures an effective and safe long-term control ofKoos grade IV vestibular schwannomas: a singlecenter, retrospective, cohort study. J Neurooncol.
159(1):201-9.2022.
68. Urata S, Okabe S. Three-dimensional mousecochlea imaging based on the modified Sca/eS
using confocal microscopy. Anat Sci Int. 2023.
69. Yamakawa K, Nishijima H, Kubota A, Naruse H,
Baba S, Fujimaki Y, Kondo K, Toda T, Yamasoba
T. Clinical and electrophysiological findings offacial palsy in a case of hereditary gelsolin
amyloidosis. Auris Nasus Larynx. Epub 2022.

284

Department of
Rehabilitation Medicine
Professor
Toru Ogata, M.D.
※The following information is the same as that of the previous year for certain reasons.

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285

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 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
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4.

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8.

Goto M, Haga N, Takedani H: Physical activity
and its related factors in Japanese people withhaemophilia. Haemophilia 25: e267-e273, 2019
Mano H, Fujiwara S, Haga N: Body knowledge inchildren with congenital lower limb deficiency.
Pediatr Int 61(2): 158-165, 2019
Matsushita M, Kitoh H, Mishima K, Yamashita S,
Haga N, Fujiwara S, Ozono K, Kubota T, Kitaoka
T, Ishiguro N: Physical, mental and social
problems of adolescent and adult patients withachondroplasia. Calc Tissue Int 104(4): 364-372,
2019
Nakahara Y, Kitoh H, Nakashima Y, Toguchida J,
Haga N: The longitudinal study of activities ofdaily living and quality of life in Japanese patientswith fibrodysplasia ossificans progressiva. Disabil
Rehabil 41(6): 699-704, 2019
Taya M, Amiya E*, Hatano M, Maki H, Hosoya Y,
Ishida J, Bujo C, Tsuji M, Konishi Y, Yokota K,
Haga N, Komuro I: Inspiratory muscle training foradvanced heart failure with lamin-related muscular
dystrophy. J Cardiol Cases 2019, jccase 20(6):232-234, 2019.9
Yamoto K, Saitsu H, Nishimura G, Kosaki R,
Takayama S, Haga N, Tonoki H, Okumura A,
Horii E, Okamoto N, Suzumura H, Ikegawa S,
Kato F, Fujisawa Y, Nagata E, Takada S, Fukami
M, Ogata T: Comprehensive clinical andmolecular studies in split hand/foot malformation:
identification of two plausible candidate genes(LRP6 and UBA2). Eur J Hum Genet 27: 18451857, 2019
Yoshida M, Matsunaga A, Igawa Y, Fujimura T,
Shinoda Y, Aizawa N, Sato Y, Kamei J, Kume H,
Homma Y, Haga N, Sanada H*: May preoperative
ultrasound-guided pelvic floor muscle training
promote early recovery of urinary continence after
robot-assisted radical prostatectomy? Neurourol
Urodyn 38(1): 158-164, 2019
Ogura K, Uehara K, Akiyama T, Shinoda Y, Iwata
S, Tsukushi S, Kobayashi E, Hirose T, Yonemoto T,
Endo M, Tanzawa Y, Nakatani F, Kawano H,
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musculoskeletal oncology patients. J Orthop Sci
24(3): 539-547, 2019
Fujimura T, Igawa Y, Aizawa N, Niimi A, Yamada
Y, Sugihara T, Kamei J, Sato Y, Matsunaga A,
Yoshida M, Shinoda Y, Fukuhara H, Nakagawa T,
Homma Y, Kume H: Longitudinal change ofcomprehensive lower urinary tract symptoms andvarious types of urinary incontinence during
robot-assisted radical prostatectomy. Neurourol
Urodyn 38(4): 1067-1075, 2019
Shinoda Y, Sawada R, Yoshikawa F, Oki T, Hirai T,
Kobayashi H, Matsudaira K, Oka H, Tanaka S,
Kawano H, Haga N: Factors related to the qualityof life in patients with bone metastases. Clin Exp
Metastasis 36(5): 441-448, 2019
Shinoda Y, Kobayashi H, Kaneko M, Ohashi S,
Bessho M, Hayashi N, Oka H, Imanishi J, Sawada
R, Ogura K, Tanaka S, Haga N, Kawano H:
Prediction of the pathological fracture risk during
stance and fall-loading configurations formetastases in the proximal femur, using acomputed tomography-based finite element
method. J Orthop Sci 24(6): 1074-1080, 2019
Morita K, Miura K, Fujimoto M, Yamamori H,
Yasuda Y, Kudo N, Azechi H, Okada N,
Koshiyama D, Shiino T, Fukunaga M, Watanabe Y,
Ikeda M, Kasai K, Hashimoto R: Eye‐movement
characteristics of schizophrenia and theirassociation with cortical thickness. Psychiatry Clin.
Neurosci. 73: 508–9, 2019
Morita K, Miura K, Kasai K, Hashimoto R: Eyemovement characteristics in schizophrenia: A
recent update with clinical implications. Neuropsychopharmacol Rep. Epub ahead of print, 2019
Morita K, Miura K, Fujimoto M, Yamamori H,
Yasuda Y, Kudo N, Azechi H, Okada N,
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Schizophr. Res. 209: 255–62, 2019

Surgical Sciences
3. Vital Care Medicine

288

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

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

Project Associate Professor
Maiko Hasegawa, M.D., Ph.D.

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

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

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

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

Masaaki Asamoto, M.D, Ph.D.,

Michiko Ushio, M.D.

Yoshiteru Mori, M.D.,

Project Lecturer
Takuma Hiraiwa, M.D.

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

Ken Kuwajima, M.D., Ph.D.,

Ayako Hirai, M.D.,

Yoko Hoshino, M.D.,

Yuko Araki, M.D.,

Takamitsu Ikeda, M.D., Ph.D.,

Masaki Iwakiri, M.D.,

Yuji Ueda, M.D.,

Tomoaki Nakamura, M.D.,

Yuho Tamai, M.D.,

Kazuhito Mietani, M.D., Ph.D.,
Reo Inoue, M.D., Ph.D.,

Miyako Nagaya, M.D.,

Kenji Watanabe, M.D.,

Ryosuke Doi, M.D.,

Kento Omi, M.D.,

Yuki Odawara, M.D.,Gen Kawashima, M.D.,

Yoshika Sudo, M.D.,

Junko Tsukamoto, M.D.,
Chiharu Kushida, M.D.,

Yaeko Yokoshima, M.D.

Homepage https://www.ut-anes.org/
Introduction and Organization
The Department of Anesthesiology was establishedin 1952 and is the oldest department of anesthesiology
in Japan. As of March 1, 2023, the Department ofAnesthesiology consists of Professor Kanji Uchida;
Associate Professor Masahiko Sumitani; Project
Associate Professor Maiko Hasegawa; Lecturers
Nobuko Ito, Masahiko Bougaki, Yoshiteru Mori, Gaku
Kawamura, Taro Kariya, Masaaki Asamoto, Michiko
Ushio; Project Lecturer Takuma Hiraiwa; 22

Associates, 11 anesthesiology residents, and 7
graduate students. The outpatient clinic is located on
the 2nd floor of Outpatient Clinic Building and the 3rd
floor of Central Clinical Service Building 2, theinpatient units are located on the 9th floor south of
Inpatient Building A, and the offices and laboratories
are located on Clinical Research Building East,
Central Building South, and the 4th floor of ClinicalResearch Building A. The current activities of ourdepartment in clinic, education, and research are289

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
University of Tokyo Hospital. The number ofsurgeries at the University of Tokyo Hospitalincreased as a result of the doubling of the number ofoperating rooms to 23 when the Central Clinical
Service Building 2 became operational in January
2007, and the annual number of surgical cases reached11,323 (8,831 managed by the anesthesiologists) in
FY2019. In FY2020, the number of cases decreased
due to the impact of the COVID-19 pandemic.
However, from FY2021, there has been a recovery
trend, and in FY2022 (Apr 2022 – Mar 2023), the total
number of surgeries reached 11,460 cases, with 8,408
cases managed by the anesthesiologists, returning to
the pre-COVID levels. The number of surgeries forpatients with many complications and elderly patientshas been increasing every year, and in addition, heart,
liver, and lung transplants from brain-dead donors
have been performed.
Because many patients with severe and complicatedconditions, both surgically and medically, are treatedat the University of Tokyo Hospital, we routinely
provide anesthesia for patients with many
preoperative comorbidities, including transplant
recipients with end-stage organ failure. We contributeto a good postoperative recovery by performing a
careful preoperative assessment, optimizing thepatient's condition preoperatively, and performing
appropriate intraoperative anesthetic management. In
the operating rooms, we are also well-prepared torespond quickly to medical or surgical emergencies
that may occur during surgery.
For preoperative patients, we provide outpatient andinpatient preoperative consultation service every
weekday for more detailed preoperative evaluation forcomplicated cases, and took care of 1,378
preoperative patients in FY2022. We have actively
engaged in the Perioperative Management Center
Program and are designing and implementing asystem for more efficient and appropriate

perioperative patient management. Starting fromFY2022, we significantly expanded the preoperativeevaluations by anesthesiologists in the outpatient basis.
This expansion includes 4,810 outpatient preoperativeevaluation visits (in addition to 193 consultations fororal care) and 1,099 evaluations for inpatients, allconducted in the outpatient booths, which marks asignificant shift from predominantly conducting
preoperative evaluations on the inpatient wards. 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 tosafe postoperative management and recovery. The
number of postoperative intensive care patients takencare of by the staff members of our department was
1,119 in FY2022.
We have also established an obstetric anesthesia
team to improve the safety and comfort of perinatalcare. The obstetric anesthesia outpatient clinic is
opened once or twice a week to evaluate the anesthetic
risk of pregnant women, and the number of visitors in
FY2022 was 315. The number of neuraxial labor
analgesia was 321 in FY2022.
As an outpatient clinic, the Pain Relief Center (Pain
Clinic) is open every weekday. For patients withvarious pain disorders (including those hospitalized inother departments), we focus on not only the sensory
factors of pain but also the biopsychosocial factors,
and conduct multidisciplinary pain evaluation andtreatment, including neurological, neuropsychiatricand psychiatric evaluations, in cooperation withmultiple departments. The number of outpatients in
FY2022 was 4,994, of which 258 were first-timepatients. The number of active beds was 1, and thenumber of inpatients was 11. There were 137 requests
for pain consultation for inpatients in FY2022.
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.

290

Education
We give lectures for fourth-year medical students
and provide clinical education (Clinical Clerkship) for
fifth and sixth-year medical students on a
person-to-person basis with our faculty staff members.
The lectures of the FY2022 were: History andmechanisms of anesthesia, Inhalational anesthesia,
Intravenous anesthesia, Regional and local anesthesia,
Preoperative evaluation, Management of the
cardiovascular system in anesthesia, Intraoperative
monitoring, Airway management in anesthesia,
Postoperative management, and Pain clinic.
The major content of the Clinical Clerkship consistsof (1) surgical anesthesia clerkship, (2) pain clinic
clerkship, and (3) short lectures. In the surgicalanesthesia clerkship, students participate inpreoperative examinations, planning of anesthesia
management, and onsite anesthesia management tolearn the basic knowledge of examination and testing
techniques as well as physiology and pharmacology
necessary for perioperative management in a clinicalsetting. Pain clinic clerkship aims to deepen
understanding of the causes of various intractablepains and therapeutic methods focusing onpharmacotherapy, nerve block therapy, exercise
therapy, and cognitive-behavioral therapy. The shortlectures cover seven topics: General anesthesiology,
Airway maintenance and intubation, Central venous
access placement, Subarachnoid spinal anesthesia,
Peripheral
nerve
block,
Postoperative
ICU
management, and Pain clinic. Practical training using
a simulator is also provided for tracheal intubation,
central venous puncture, and subarachnoid spinal
anesthesia. As a summary of the Clinical Clerkshipeducation, we ask the students to submit reports onanesthesia cases and reports on anesthetics andcardiovascular drugs, with presentations anddiscussions on the contents.
For post-graduate education, we accepted a total of
111 junior residents of PGY1 and 2 from the General
Education Center as rotators (1-2 months for eachrotator) in FY2022. The training includes anesthesia
management,
preoperative
andintraoperative
management, and basic skills and knowledge inemergency and resuscitation settings. For the 11
anesthesiology residents of PGY3+, faculty staffs

teach and supervise daily clinical anesthesia,
postoperative ICU care, obstetric anesthesia, and pain
clinic. The anesthesiology residents are encouraged togive presentations at scientific meetings, including theJapanese Society of Anesthesiologists (JSA) annual
meetings, and publish papers. Anesthesiology
residents achieve JSA board certification by the end of
the training. In addition, journal clubs and case studies
are organized to cultivate a professional attitude in
residents and develop their competency to perform
care and research as independent anesthesiologists.

Research
Our department has seven research groups. The
research fields include respiratory, cardiovascular,
pain, nervous, and immune systems.
Our ongoing and recent major research subjects are:
 A role of cytokine signaling in acute lunginjury; Transpulmonary pressure during mechanicalventilation;
 Exploring risk factors of perioperative
exacerbation of interstitial lung disease; Modification of immune system byanesthesia;
 Apoptotic signal transduction induced bysepsis or ischemia-reperfusion injury; A role of lipid mediators in the formation of
hyperalgesia; A role of spinal microglial cells in thedevelopmentof
inflammation-mediatedneuropathic pain; Cognitive-behavioral therapy on chronic pain; Analysis of electroencephalography during
general anesthesia;
 Exploring relationship between postoperativedelirium and blood-brain barrier dysfunction;
 Clinical significance of fatty acid metabolites
in general anesthesia;
 Retrospective analyses on perioperative
management of left ventricular assisting
device implantation or heart transplantation;
 Physiology and molecular biology ofleft/right heart failure of animal models; Invention and validation of new anesthetic
procedures with emerging technologies;

291



Epidemiological survey and outcome study
with large administrative database.

Medicine (Baltimore). 2022;101(30):e29906.

1. Ando M, Sumitani M, Fuyuki M, Abe H, Shinoda
Y, Matsubayashi Y, et al. Imaging featuresinferring symptom onset due to spinal metastasis
progression: a preliminary study. Ann Palliat Med.
2022;11(7):2247-56.
2. Asahara M, Ito N, Hoshino Y, Sasaki T, Yokomizo
T, Nakamura M, et al. Role of leukotriene B4(LTB4)-LTB4 receptor 1 signaling in postincisional nociceptive sensitization and local
inflammation in mice. PLoS ONE. 2022; 17(10):e0276135.
3. Edamura T, Sumitani M, Hayakawa K, Inoue R,
Abe H, Tsuchida R, et al. Different profiles of thetriad of lysophosphatidylcholine, lysophosphatidic
acid, and autotaxin in patients with neuropathic
pain diseases: a preliminary observational study.
Pain Ther. 2022;11(4):1439-49.
4. Hoshino Y, Okuno T, Saigusa D, Kano K,
Yamamoto S, Shindou H, et al. Lysophosphatidic
acid receptor1/3 antagonist inhibits the activation
satellite

glial

levels of apolipoprotein A-I and E are associatedwith postoperative delirium: A post hoc analysis.

PublicationsofOgata T, Shimojo N, Kurano M, et al. Serum

cells

and

reduces

acutenociceptive responses. FASEB J. 2022;36(4):e22236.
5. Kasahara S, Takahashi N, Matsudaira K, Oka H,
Takatsuki K, Yabuki S. Psychometric properties ofthe multidimensional pain inventory: Japanese
language version (MPI-J). Pain Physician. 2022;
25(1):E105-E112.
6. Kasahara S, Matsudaira K, Sato N, Niwa SI.
Attention ‐ deficit/hyperactivity disorder andcentralized pain: A review of the case of John F.
Kennedy. Clin Case Rep. 2022;10(10):e6422.
7. Kasahara S, Takao C, Matsudaira K, Sato N, Tu
TTH, Niwa SI, et al. Case report: Treatment of
persistent atypical odontalgia with attention
deficit hyperactivity disorder and autism spectrum
disorder with risperidone and atomoxetine. Front
Pain Res (Lausanne). 2022;3:926946.
8. Mietani K, Hasegawa-Moriyama M, Inoue R,

9. Mietani K, Hasegawa-Moriyama M, Yagi K,
Inoue R, Ogata T, Kurano M, et al. Preoperative
detection of serum phosphorylated neurofilament
heavy

chain

subunitpredicts

postoperativedelirium: a prospective observational study. J
Gerontol Geriatr. 2022;70(3):1-9.
10. Mietani K, Hasegawa-Moriyama M, Yagi K,
Inoue R, Ogata T, Shimojo N, et al. Elevation ofserum plasminogen activator inhibitor-1 predicts
postoperative delirium independent of neuraldamage: a sequential analysis. Sci Rep. 2022;12(1):17091.
11. Saita K, Sumitani M, Nishizawa D, Tamura T,
Ikeda K, Wakai K, et al. Genetic polymorphism ofpleiotrophin is associated with pain experience inJapanese adults: Case-control study. Medicine(Baltimore). 2022;101(37):e30580.
12. Ueda Y, Asamoto M, Kariya T, Akai T, Hoshina K,
Uchida K. Ventricular fibrillation during carotid
endarterectomy and bailout stenting: a case report.
JA Clin. 2022;8(1).
13. Uranbileg B, Kurano M, Sumitani M, Ito N, Kano
K, Aoki J, et al. Lysophosphatidic acids in
cerebrospinal fluids: potential biomarkers andtherapeutic targets for neuropathic pain. Medical
Mass Spectrometry. 2022;6(2):85-92.
14. Ushio M, Uchida K. The quest for meticulous
patient care, even in the challenging COVID-19
era,

is

a

trait

inheritedbyprofessional

anesthesiologists. J Anesth. 2022;36(6):669-70.

292

Department of Emergency andCritical Care Medicine
Professor
Kent Doi, M.D.

Lecturer
Takehiro Matsubara, M.D.

Project Lecturer
Miyuki Yamamoto, M.D.

Research Associate
Toshifumi Asada, M.D., Hitomi Nakamura, M.D. Jinsuke Mizuno, M.D.
Atsushi Shimada, M.D. Yuko Sato, M.D. Eri Endo, M.D.
Keiko Gyoten, M.D. Hiromi Matsuda, M.D. Tomohiko Shirokoshi, M.D.

Project Research Associate
Mio Shikama, M.D.

Homepage

http://uteccm.umin.jp/

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
medical care center in December 2010.

293

Clinical activities
Our clinical activities are divided into three
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.
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, acutekidney injury, sepsis, MOF, shock), post-operative
patients, and tertiary emergency patients, placing anemphasis on evidence-based medical therapy.
3) 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
In the systematic lectures of M2, the latest findings
related to the field of emergency medicine, such as
general emergency medicine, basics of initialemergency care, cardiopulmonary resuscitation, initialtrauma care, and disaster medicine, are lectured andintroduced.
In M3, students are in charge of general medicine

and participate in actual practice of emergency general
medicine in the emergency department, and in M4,
students practice emergency and intensive care
medicine and receive lectures on disaster medicine inaddition to practical training on critical care in theintensive care unit.
Since 2004, post-graduate clinical training has
become mandatory and all residents are required toreceive training in the emergency department. In
accordance with the training guidelines of the Ministryof Health, Labour and Welfare, residents learn andpractice comprehensive emergency medicine thatcovers primary to tertiary care in the emergency
department. In addition, initial clinical trainees are also
assigned to the intensive care unit, where they are
educated to understand intensive care from theviewpoint of pathophysiology and internal medicine.
In 2006, we started the second semester of clinicaltraining, and are educating the residents in applied
crisis medicine such as initial trauma care,
cardiopulmonary resuscitation, multiple organ failure,shock, and mechanical assistance for various organ
failures, etc.

Research activities
Our clinical studies revealed that organ network
disruption could be observed by network analysis withclinical parameters and new biomarkers of ICU patients.

References
1.

2.

3.

Abe M, Shiga H, Tatsumi H, Endo Y, Kikuchi Y,
Suzuki Y, Doi K, Nakada TA, aagafuchi H,
Hattori N, Hirohashi N, Moriguchi T, Yamaga O,
Nishida O. Results of the 2018 Japan Society for
Blood Purification in Critical Care survey: current
status and outcomes. Ren Replace Ther. 2022;
8(1):58.
Kurano M, Jubishi D, Okamoto K, Hashimoto H,
Sakai E, Morita Y, Saigusa D, Kano K, Aoki J,
Harada S, Okugawa S, Doi K, Moriya K, Yatomi
Y. Dynamic modulations of urinary sphingolipid
and glycerophospholipid levels in COVID-19 andcorrelations with COVID-19-associated kidney
injuries. J Biomed Sci. 2022 Nov 10;29(1):94.
Kurano M, Okamoto K, Jubishi D, Hashimoto H,
Sakai E, Saigusa D, Kano K, Aoki J, Harada S,

294

4.

5.

6.

7.

8.

Okugawa S, Doi K, Moriya K, Yatomi Y.
Dynamic modulations of sphingolipids andglycerophospholipids in COVID-19. Clin Transl
Med. 2022 Oct;12(10):e1069.
Matsuura R, Honda K, Oki R, Hamasaki Y, Doi K,
Nangaku M. Screening and Management for
Intracranial Aneurysms in Japanese Patients WithADPKD. Kidney Int Rep. 2022 Jun 1;7(8):18931896.
Yamamoto M, Watanabe Y, Doi K. Reddishpurple
effluent
fluid
inducedbyhydroxocobalaminincontinuous
renalreplacement therapy. Acute Med Surg. 2022 Jul
25;9(1):e773.
Ohashi-Fukuda N, Fukuda T, Doi K. Association
between time to advanced airway management
and survival during pediatric out-of-hospital
cardiac arrest. Resusc Plus. 2022 Jun 24;11:
100260.
Miyamoto Y, Iwagami M, Aso S, Uda K, Fushimi
K, Hamasaki Y, Nangaku M, Yasunaga H, Doi K.
Postoperative outcomes of cancer surgery inpatients with and without kidney failure withdialysis therapy: a matched-pair cohort study. Clin
Kidney J. 2022 Jan 13;15(6):1137-1143.
Agarwal R, Hauske SJ, Wheeler DC, Doi K,
Elsaesser A, Ritter I, Steubl D, Wanner C.
Empagliflozin and incidence of events consistent
with acute kidney injury: Pooled safety analysis in
more than 15 000 individuals. Diabetes Obes
Metab. 2022 Jul;24(7):1390-1393.

Health Sciences and Nursing
1. Health Sciences

296

Department of Mental HealthProfessor
Daisuke Nishi, M.D., Ph.D.

Lecturer
Natsu Sasaki, M.D., Ph.D.

Homepagehttps://mhpn.m.u-tokyo.ac.jp/

Introduction and Organization
The department was firstly established as
Department of Fourth Clinical Medical Nursing in
School of Health Care and Nursing in 1957. When the
School of Health Care and Nursing was reorganized as
the School of Health Sciences in 1965, the department
was renamed Department of Mental Health. In 1992,
as School of Health Sciences became The School of
Health Science and Nursing, Department of Mental
Health became Department of Mental Health andPsychiatric Nursing. As the result of the shift to thechair system of the Graduate School of Medicine in
1996, two departments were established, Departmentof Mental Health and Department of PsychiatricNursing. Faculty, staff, and students of two
departments have been working cooperatively eversince. Since 2007, Department of Mental Healthbecame a part of School of Public Health, with aperspective of “public mental health.”
The department currently has faculty members
introduced above, an associate professor, a project
lecturer, a research associate, part-time lecturers, atechnical specialist, visiting research fellows, 5
doctoral course students, 6 master course students, andsecretaries.
The department has two major objectives: one is toteach mental health to undergraduate and graduate
students in order to produce global leaders in researchand practice in this field. The other is to conductcutting-edge research in the fields of mental health.
All of the activities of the department are conductedin collaboration with staff members in the departments,
other departments within the University of Tokyo, andinstitutions within and outside Japan.

Teaching activities
The department is responsible for giving lectures onmental health; mental disorders; clinical and healthpsychology; and psychometry and behavior evaluation
to undergraduate students. Other than lectures, thedepartment provides students opportunities toexperience mental health activities in relevant mental
health settings.
The department provides graduate courses onmental health I and II, featuring epidemiology andpractice in mental health and occupational mental
health, respectively. The department also provided a
1.5 hour seminar every Wednesday evening for 20
weeks in each semester (40 weeks per year) for
graduate students and research students, withpresentations of research plans and progress, andliterature review by graduate students, as well as
presentation of and lectures by guest speakers.

Research activities
The department conducts research on mental healthepidemiology, perinatal mental health, traumatic stressand resilience, and mental health in the workplace. In
the field of mental health epidemiology, we are in
charge of the survey in Japan of a large-scaleinternational collaborative study (the World Mental
Health Survey), which is being conducted under the
initiative of Harvard University. In perinatal mental
health, we are working with companies to prevent
perinatal depression. For traumatic stress, we are297

working to evaluate the effectiveness of traumainformed care and to promote its implementation. For
mental health in the workplace, we are developing
programs to prevent depression in the workforce. In
addition, we are working on suicide prevention,
disaster mental health, and international mental healthin collaboration with researchers from domestic andinternational institutions and universities. Many ofthese studies are conducted in collaboration withresearchers from domestic and international
institutions and universities.

References
1.

2.

3.

4.

5.

Nishi D. Desire for Shorter Life Expectancy
From a Mental Health Perspective. J Epidemiol.
released online September 30. Epub ahead ofprint.
Nishi D, Imamura K, Watanabe K, Obikane E,
Sasaki N, Yasuma N, Sekiya Y, Matsuyama Y,
Kawakami N. The preventive effect ofinternet-based cognitive behavioral therapy forprevention of depression during pregnancy and in
the postpartum period (iPDP): a large scalerandomized controlled trial. Psychiatry Clin
Neurosci. 2022 Nov;76(11):570-578. Epub 2022
Sep16.
Shiba K, Daoud A, Kino S, Nishi D, Kondo K,
KawachiI.
Uncovering
heterogeneous
associationsofdisaster-related
traumatic
experiences with subsequent mental healthproblems: A machine learning approach.
Psychiatry Clin Neurosci. 2022 Apr;76(4):97105.
Tsuno K, Okawa S, Matsushima M, Nishi D,
Arakawa Y, Tabuchi T. The effect of social
restrictions, loss of social support, and loss ofmaternal autonomy on postpartum depression in
1 to 12-months postpartum women during the
COVID-19 pandemic. J Affect Disord. 2022 Jun
15; 307:206-214.
Obikane E (*), Sasaki N (*), Imamura K,
Nozawa K, Vedanthan R, Cuijpers P, Shimazu T,
Kamada M, Kawakami N, Nishi D. Usefulness of
Implementation Outcome Scales for Digital
Mental Health (iOSDMH): Experiences from Six
Randomized Controlled Trials. International

Journal of Environmental Research and Public
Health. 2022; 19(23) (*) These authors
contributed equally to this work.
6. Sasaki N, Ikeda M, Nishi D. Long-term influenceof unintended pregnancy on psychologicaldistress: a large sample retrospective crosssectional study. Archives of women’s mental
health. 2022:1-9.
7. Sasaki N, Imamura K, Watanabe K, Hidaka Y,
Ando E, Eguchi H, Inoue A, Tsuno K, Komase Y,
Iida M, Otsuka Y, Sakuraya A, Asai Y, Iwanaga
M, Kobayashi Y, Inoue R, Shimazu A, Tsutsumi
A, Kawakami N. The impact of workplace
psychosocial factors on menstrual disorders andinfertility: a protocol for a systematic review andmeta-analysis. Systematic reviews. 2022;11(1):195.
8. Sasaki N, Kuroda R, Tsuno K, Imamura K,
Kawakami N. COVID-19 vaccination did not
improve employee mental health: A prospective
study in an early phase of vaccination in Japan.
Neuropsychopharmacol Rep. 2022;42(2):230-2.
9. Sasaki N, Kuroda R, Tsuno K, Imamura K,
Kawakami N. The effect of job strain andworksite social support on reported adverse
reactions of COVID-19 vaccine: A prospective
study of employees in Japan. Journal ofoccupational health. 2022;64(1): e12356.
10. Sasaki N, Tabuchi T, Okubo R, Ishimaru T,
Kataoka M, Nishi D. Temporary employment andsuicidal ideation in COVID-19 pandemic in
Japan: A cross-sectional nationwide survey.
Journal of occupational health. 2022;64(1):e12319.
11. Hidaka Y, Kawakami N, Watanabe K, and Nishi
D. The association between premenstrual
syndrome before pregnancy and antenatal
depression: A cross‐sectional study withpre-recorded information. Psychiatry and Clinical
Neurosciences Reports 2022, 1(3), p.e27.
12. Imamura K, Sasaki N, Sekiya Y, Watanabe K,
Sakuraya A, Matsuyama Y, Nishi D, Kawakami
N. The Effect of the Imacoco Care
Psychoeducation
Websiteon
Improving
Psychological Distress Among Workers During
the
COVID-19
Pandemic:Randomized

298

Controlled Trial.JMIR Form Res. 2022 Mar 10;
6(3): e33883.
13. Iida M, Watanabe K, Yeo SA, Yasuma N, Nishi D.
& Kawakami N. Association of Personal Values
in Adolescence with Subjective Health Status,
Meaning in Life, and Life Satisfaction in
Adulthood: A Cross‐sectional Study with
Retrospective Recall. Japanese PsychologicalResearch.2022.
14. Kessler, R. C., Kazdin, A. E., Aguilar-Gaxiola, S.,
Al-Hamzawi, A., Alonso, J., Altwaijri, Y. A.,
Andrade, L. H., Benjet, C., Bharat, C., Borges, G.,
Bruffaerts, R., Bunting, B., Caldas de Almeida, J.
M., Cardoso, G., Chiu, W. T., Cía, A., Ciutan, M.,
Degenhardt, L., de Girolamo, G., de Jonge, P., deVries, Y. A., Florescu, S., Gureje, O., Haro, J. M.,
Harris, M. G., Hu, C., Karam, A. N., Karam, E.
G., Karam, G., Kawakami, N., Kiejna, A.,
Kovess-Masfety, V., Lee, S., Makanjuola, V.,
McGrath, J. J., Medina-Mora, M. E.,
Moskalewicz, J., Navarro-Mateu, F., Nierenberg,
A. A., Nishi, D., Ojagbemi, A., Oladeji, B. D.,O’Neill, S., Posada-Villa, J., Puac-Polanco, V.,
Rapsey, C., Ruscio, A. M., Sampson, N. A., Scott,K. M., Slade, T., Stagnaro, J. C., Stein, D. J.,
Tachimori, H., ten Have, M., Torres, Y., Viana, M.
C., Vigo, D. V., Williams, D. R., Wojtyniak, B.,
Xavier, M., Zarkov, Z., Ziobrowski, H. N., and
the WHO WMH survey collaborators. Patterns
and correlates of patient-reported helpfulness oftreatment for common mental and substance use
disorders in the WHO World Mental Health
Surveys. World Psychiatry. 2022 Jun;21(2):272286.
15. Hazumi M, Okazaki E, Usuda K, Kataoka M,
Nishi D. Relationship between attitudes toward
COVID-19 infection, depression and anxiety: across-sectional survey in Japan. BMC Psychiatry.
2022;22(1):798. Published 2022 Dec 19.
16. Hazumi M, Usuda K, Okazaki E, Kataoka M,
Nishi D. Differences in the Course of Depression
and Anxiety after COVID-19 Infection between
Recovered Patients with and without a
Psychiatric History: A Cross-Sectional Study. Int
J Environ Res Public Health. 2022 Sep 8;19(18):11316.

17. Sasaki N, Inoue A, Asaoka H, Sekiya Y, Nishi D,
Tsutsumi A, Imamura K. The Survey Measure of
Psychological Safety and Its Association with
Mental Health and Job Performance: A Validation
Study and Cross-Sectional Analysis. Int J
Environ Res Public Health. 2022 Aug 11;19(16):9879.
18. Sasaki N, Akiyama H, Kawakami N, Nishi D.
Preconception menstrual cycle disorder andantenatal depression: A cross-sectional study withpre-recorded information. J Psychosom Obstet
Gynaecol. 43(4):411-418, 2022.10.
19. Carrozzino D, Christensen KS, Patierno C,Woźniewicz A, Møller SB, Arendt ITP, Zhang Y,
Yuan Y, Sasaki N, Nishi D, Berrocal Montiel C,
Ceccatelli S, Mansueto G, Cosci F. Cross-culturalvalidity of the WHO-5 Well-Being Index andEuthymia Scale: A clinimetric analysis. J Affect
Disord. 2022 Aug 15; 311:276-283. Epub 2022
May 21.
20. Sarris J, Ravindran A, Yatham LN, Marx W,
Rucklidge JJ, McIntyre RS, Akhondzadeh S,
Benedetti F, Caneo C, Cramer H, Cribb L, deManincor M, Dean O, Deslandes AC, Freeman
MP, Gangadhar B, Harvey BH, Kasper S, Lake J,
Lopresti A, Lu L, Metri NJ, Mischoulon D, Ng
CH, Nishi D, Rahimi R, Seedat S, Sinclair J, Su
KP, Zhang ZJ, Berk M. Clinician guidelines forthe treatment of psychiatric disorders withnutraceuticals and phytoceuticals: The World
Federation of Societies of Biological Psychiatry(WFSBP) and Canadian Network for Mood andAnxiety Treatments (CANMAT) Taskforce.
World J Biol Psychiatry. 2022 Jul;23(6):424-455.
Epub 2022 Mar 21.
21. Bruffaerts R, Harris MG, Kazdin AE, Vigo DV,
Sampson NA, Chiu WT, Al-Hamzawi A, Alonso J,
Altwaijri YA, Andrade L, Benjet C, de Girolamo
G, Florescu S, Haro JM, Hu CY, Karam A,
Karam EG, Kovess-Masfety V, Lee S, McGrathJJ, Navarro-Mateu F, Nishi D, O’Neill S,
Posada-Villa J, Scott KM, Have MT, Torres Y,
Wojtyniak B, Xavier M, Zarkov Z, Kessler RC;
WHO World Mental Health Survey Collaborators.
Perceived helpfulness of treatment for social
anxiety disorder: findings from the WHO World
Mental Health Surveys. Soc Psychiatry Psychiatr

299

22.

23.

24.

25.

26.

27.

28.

29.

Epidemiol. 2022 Oct;57(10):2079-2095. Epub
2022 Mar 9.
Kataoka M, Kotake R, Asaoka H, Miyamoto Y,
Nishi D. Reliability and Validity of the Japanese
Versionof
the
Attitudes
RelatedtoTrauma-Informed Care (ARTIC-10) Scale. J
Trauma Nurs. 2022 Nov-Dec 01;29(6):312-318.
Asaoka H, Koido Y, Kawashima Y, Ikeda M,
Miyamoto Y, Nishi D. Association between
clinical decision for patients with COVID-19 andpost-traumatic stress symptoms among healthcare
professionals during the COVID-19 andemic.
Environmental and Occupational Health Practice.
2022; 4(1)Asaoka H, Sasaki N, Imamura K, Kuroda R,
Tsuno K, Kawakami N. Effects of workplacemeasures against COVID-19 on psychologicaldistress of full-time employees: A 12-monthprospective study in the COVID-19 pandemic.
Scand J Work Environ Health. 2022;48(6):468478.
Obikane E, Watanabe K, Nishi D, Kawakami N.
Adverse childhood experiences and personalvalues in adolescence: a cross-sectional study
using community adult samples in Japan. Pediatr
Int. 2023 Jan;65(1): e15370. Epub ahead of print.
Kataoka M, Hazumi M, Usuda K, Emi Okazaki E,
Nishi D. Association of preexisting psychiatricdisorders with post-COVID-19 prevalence: across-sectional study. Scientific reports, 2023 Jan,13(1)Iwanaga M, Nishi D, Obikane E, Kawakami N.
Age of victimization and moderating role ofsocial support for the relationship between
school-age bullying and life satisfaction in
middle-age. Scand J Public Health. 2023 Feb
2;14034948221148788. Online ahead of print.
Obikane E, Nishi D, Ozaki A, Shinozaki T,
Kawakami N, Tabuchi T. Association between
Poverty and Refraining from Seeking Medical
Care during the COVID-19 Pandemic in Japan: A
Prospective Cohort Study. Int J Environ Res
Public Health. 2023 Feb 2;20(3):2682.
Kazdin, A. E., Wu, C.-S., Hwang, I., PuacPolanco, V., Sampson, N. A., Al-Hamzawi, A.,
Alonso, J., Andrade, L. H., Benjet, C., Caldas-deAlmeida, J.-M., de Girolamo, G., de Jonge, P.,

Florescu, S., Gureje, O., Haro, J. M., Harris, M.
G., Karam, E. G., Karam, G., Kovess-Masfety, V.,
Lee, S., McGrath, J. J., Navarro-Mateu, F., Nishi,D., Oladeji, B. D., Posada-Villa, J., Stein, D. J.,Üstün, T. B., Vigo, D. V., Zarkov, Z., Zaslavsky,
A. M., Kessler, R. C., and the WHO World
Mental Health Survey collaborators. (2021).
“Antidepressant use in low- middle- andhigh-income countries: a World Mental Health
Surveys report.” Psychological Medicine 2023
Mar; 53(4): 1583-1591.

300

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

Associate Professor
Koji Oba, Ph.D.

Assistant Professor
Yasuhiro Hagiwara, Ph.D., M.P.H.

Homepage

http://www.epistat.m.u-tokyo.ac.jp/en/

Introduction and Organization
The Department of Epidemiology andBiostatistics evolved from the Department of
Epidemiology in 1992. Since then, we have been
responsible for providing educational courses on
methodology of epidemiologic research and biostatistics to undergraduate students. We belong to
Graduate School of Medicine as Departments ofBiostatistics/ Epidemiology and Preventive Health
Sciences, providing education for undergraduate aswell as graduate-school students and consultation toclinical researchers.
Unfortunately, education programs for biostatistics and epidemiological methodology are notsufficient in Japanese universities and graduate
schools compared to the situation in the US andEuropean countries. Nevertheless, the necessity forcollaboration among biostatisticians and clinicalresearchers/ epidemiologists has been claimed inrecent years. Hence, the central missions of oureducational courses are devoted to provide students
expert knowledge and extensive experience inbiostatistics and epidemiology to take part in clinical/
epidemiological research as biostatisticians or
methodologists. We do not only focus on practicalaspects on statistical analysis in medical research but
also place emphasis on the methodological principles
of biostatistics/epidemiology.
Our main research area is the development ofmethodology for clinical/epidemiological research. Of
course, it requires keeping in touch with real clinical/
epidemiological problems. So, another indispensable
research area is a support for real-world clinical andepidemiological studies including clinical trials. To
achieve these requirements simultaneously, a nonprofit organization the Japan Clinical Research
Support Unit was established in 2001 by the former
faculty members in our department. This organization
J-CRSU had provided research support andcoordination in design, data management, andstatistical analysis in many projects inside/outside theuniversity. Our experience in J-CRSU is the basis of
our supportive activities for clinical research that wework through today.

Teaching activities
 Undergraduate Courses
1) Epidemiology (2 credits)
2) Biostatistics (2 credits; named “Statistics” inmedical doctor course)

3013) Applied Mathematics (2 credits)
4) Biostatistics Practice (1 credit)
5) Practical Examples in Clinical andEpidemiologic Research (1 credit)
6) Medical Data Analysis, and its Practice (1 credit
each)7) Theoretical Epidemiology (2 credits) School of Public Health (Graduate School)
1) Statistical Analysis of Medical Research(2 credits)
2) Practice of Biostatistics (2 credits)3) Design of Medical Research (2 credits) Doctoral Courses (Graduate School)
1) Biostatistics (4 credits)
2) Epidemiology and Preventive Health Sciences(4 credits)
3) Introduction to Medical Statistics(2 credits; for the School of Medicine)
The faculty of the department had provided
lectures in a series of educational courses organizedby “The Clinical Bioinformatics Research Unit” in
2002-2007.

Research activities
1. Methodology for designing and analyzing clinical
trials: Interim analysis
 Adaptive designs
 Multiplicity
 Data management of large-scale multicenter
clinical trials
2. Methodology of Biostatistics and theoreticalepidemiology:
 Analysis of longitudinal (time-to-event and/or
repeated measures) data
 Analysis of missing/incomplete data Causal inference Semiparametric modeling
3. International collaboration of individual-levelmeta-analysis on gastric cancer
4. Coordination and data analysis of collaborative
epidemiological/clinical research:
 Japan Arteriosclerosis Longitudinal Study Japan Diabetes Collaborative Study Chronic Kidney Disease Japan Cohort
5. Validity/reliability studies of QOL questionnaires
and other rating scales
6. Pharmacoeconomic assessment of medical technology
We had been supporting some of the above
collaborative clinical/epidemiologic studies, whichaims to support investigator- initiated studies and toprovide education to researchers and support staffs.
Currently, we are officially conducting a consultation
for design and analysis of clinical trials assisted by theClinical Research Promotion Center of the Universityof Tokyo Hospital.
The University of Tokyo participated in "Support
Programfor
Biostatisticians,"
anindustrygovernment-academia collaborative project launchedby the Japan Agency for Medical Research andDevelopment (AMED) in FY2016, and has been
participating in its successor, "Promotion Program for
Biostatisticians,"
since
FY2021(principal
investigator: Professor Matsuyama). Both projects are
aimed at fostering biostatisticians at clinical research
institutes and research centers in Japan, and aredesigned and implemented for master course andone-year post-graduate education/training programs.
Our department is also officially participating in these
programs, and will provide more and moreeducational/practical supports to future biostatisticianson the basis of our rich experience in biostatisticaleducation and support in variety of research.

References
1.

2.

Takeuchi Y, Iwagami M, Ono S, Michihata N,
Uemura K, Yasunaga H. A post-marketing safetyassessment of COVID-19 mRNA vaccination forserious adverse outcomes using administrative
claims data linked with vaccination registry in acity of Japan. Vaccine. 2022;40;7622–7630.
Kikawa Y, Hagiwara Y, Fujisawa T, Araki K,
Iwamoto T, Sangai T, Shien T, Takao S,
Nishimura R, Takahashi M, Toyama T, Aihara T,
Mukai H, Taira N. Health-related quality of lifeand estimation of the minimally importantdifference in the Functional Assessment of

302

3.

4.

5.

6.

7.

8.

9.

Cancer Therapy-Endocrine Symptom score inpostmenopausal ER+/HER2- metastatic breast
cancer with low sensitivity to endocrine therapy.
PLoS One. 2022;17:e0278344.
Ebata S, Yoshizaki A, Oba K, Kashiwabara K,
Ueda K, Uemura Y, Watadani T, Fukasawa T,
Miura S, Yoshizaki-Ogawa A, Okiyama N,
Kodera M, Hasegawa M, Sato S. Safety andefficacy of rituximab in systemic sclerosis(DESIRES): open-label extension of adouble-blind, investigators-initiated, randomised,
placebo-controlled trial. Lancet Rheumatol.
2022;4:e546–e555.
Oba K, Kagiwada Y, Kamada M, Miki R, Kondo
Y, Kamakura T, Yamagami T, Fujita T, Tsuchida
Y. Evaluating the feasibility of a remote-based
training program supported by information andcommunications technology in the older adults
living at home. BMC Geriatr. 2022;22:574.
Watanabe J, Maeda H, Nagasaka T, Yokota M,
Hirata K, Akazawa N, Kagawa Y, Yamada T,
Shiozawa M, Ando T, Kato T, Mishima H,
Sakamoto J, Oba K, Nagata N. Multicenter,single-arm, phase II study of the continuous useof panitumumab in combination with FOLFIRI
after FOLFOX for RAS wild-type metastatic
colorectal cancer: Exploratory sequential
examination of acquired mutations in circulatingcell-free DNA. Int J Cancer. 2022;151:2172–
2181.
Nagata H, Kawai K, Oba K, Nozawa H,
Yamauchi S, Sugihara K, Ishihara S.
Laparoscopic colectomy: a risk factor for
postoperative
peritoneal
metastasis.
Clin
Colorectal Cancer. 2022;21:e205–e212.
Kemmochi M, Nawa Y, Ohno S, Sawashita Y,
Terada H, Oba K. Analysis of the radial and ulnar
arteries using ultrasound and a vascularvisualization device in children. Paediatr Anaesth
2022;32:747–753.
Sawamoto R, Oba K, Matsuyama Y. Bayesian
adaptive randomization design incorporating
propensity score-matched historical controls.
Pharm Stat. 2022;21:1074–1089.
Ebata S, Oba K, Kashiwabara K, Ueda K,
Uemura Y, Watadani T, Fukasawa T, Miura S,
Yoshizaki-Ogawa A, Yoshihide A, Yoshizaki A,

Sato S. Predictors of rituximab effect on
modified rodnan skin score in systemic sclerosis:
a machine learning analysis of the DESIRES trial.
Rheumatology (Oxford). 2022;61:4364–4373.
10. Ebata S, Yoshizaki A, Fukasawa T, YoshizakiOgawa A, Asano Y, Kashiwabara K, Oba K, Sato
S. Increased red blood cell distribution width in
the first year after diagnosis predicts worseningof systemic sclerosis-associated interstitial lungdisease at 5 years: a pilot study. Diagnostics(Basel). 2021;11:2274.
11. Hagiwara Y, Shiroiwa T. Estimating value-based
price and quantifying uncertainty around it inhealth technology assessment: frequentist andBayesian approaches. Med Decis Making. 2022;
42:672–683.
12. Ishimaru M, Ono S, Morita K, Matsui H,
Hagiwara Y, Yasunaga H. Prevalence, incidence
rate and risk factors of medication-related
osteonecrosis of the jaw (MRONJ) in patientswith osteoporosis and cancer: a nationwide
population-based study in Japan. J Oral
Maxillofac Surg. 2021;80:714–727.
13. Matsumoto H, Igarashi A, Hagiwara Y,
Yamamoto-Mitani N. Relational Design for
Dementia and Job Significance (ReDeSign):
study protocol for a randomized controlled trialof an online dementia training for retail workers.
Contemp Clin Trials Commun. 2022;26:100896.
14. Abe S, Kawai K, Nozawa H, Sasaki K, Murono
K, Emoto S, Kishikawa J, Ishii H, Yokoyama Y,
Nagai Y, Anzai H, Sonoda H, Oba K, Ishihara S.
Preoperative sarcopenia is a poor prognostic
factor in lower rectal cancer patients undergoingneoadjuvant chemoradiotherapy: a retrospective
study. Int J Clin Oncol. 2022;27:141–153.
15. Machida H, Matsuo K, Oba K, Aoki D, Enomoto
T, Okamoto A, Katabuchi H, Nagase S, Mandai
M, Yaegashi N, Yamagami W, Mikami M.
Association between hospital treatment volume
and survival of women with gynecologic
malignancy in Japan: a JSOG tumor registrybased data extraction study. J Gynecol Oncol.
2022;33:e3.
(Only main publications)

303

Department of Biomedical Ethics &Department of Health Promotion
Sciences
Professor
Akira Akabayashi, M.D., Ph.D.

Associate Professor
Yoshiyuki Takimoto, M.D., Ph.D.

Lecturer
Eisuke Nakazawa, Ph.D.

Research Associate
Makoto Udagawa, MA

Homepage

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

Introduction and Organization
The former Department of Health Administration wasestablished in 1967 and Dr. Tsuneo Tanaka became its
first professor in 1974. He devoted himself to thedevelopment of the community health care system inJapan and published numerous papers concerning thesocial theory of health administration and data
management systems for community health care. He
also contributed to the establishment of the School of
Health Sciences. In 1985, Dr. Atsuaki Gunji became
the second professor of the department. During Dr.
Gunji’s tenure, two major research projects were
undertaken. One was “The effects of physical activity
and inactivity on health.” From 1990, a 20-day bed
rest human experimental study was conducted every
year in the context of an international cooperative
research project that was supported by government
grants. The other project concerned health caresystems, especially health care economics and thequality of hospital care.
In 1996, the Department of Health Administration developed into two departments: the Department
of Health Economics and the Department of Health

Promotion Sciences. Both were established as
departments of the Graduate School of Medicine. In
1998, Dr. Yasuki Kobayashi became the professor of
the Department of Health Economics. He conducted
research into health care delivery systems in Japan. In
2001, he moved to the Department of Public Health.
From 1996 to 2002, Dr. Kiyoshi Kawakubo tookcharge of the Department of Health Promotion
Sciences as the associate professor.
In June 2002, Dr. Akira Akabayashi became
professor of the Department of Health Economics.
Professor Akabayashi’s area of research is biomedical
ethics. In April 2003, the Department of Health
Economics was restructured and named the Department of Biomedical Ethics. From 2007, Dr. Jung Su
Lee became the associate professor and took charge of
the Department of Health Promotion Sciences. In
2017, Dr. Yoshiyuki Takimoto acceded to the chair of
the Department of Health Promotion Sciences. In
2019, the Department of Health Promotion Sciences
was consolidated into the Department of Biomedical
Ethics.
Staff members of the department include a304

professor, an associate professor, a lecturer, anassociate, and a technical specialist. All five members,
two project researchers, twelve lecturers from otherorganizations, and ten visiting researchers contributeto department teaching and research activities.
We have six department graduate students. Fourof 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3058) Historical analyses for the term “bioethics” in theJapanese context
9.

References
1.

2.

3.

4.

5.

6.

7.

8.

Akabayashi A, Nakazawa E, Ino H. Could
artificial intelligence hijack author contributions?
Nature. 606(7915):653. doi: 10.1038/d41586022-01697-w.
Arai N, Takimoto Y, Nakazawa E, Ishimura T,
Yokoyama N, Hara M, Ozeki-Hayashi R,
Akabayashi A. Psychosocial and ethicalbehaviors and attitudes of health care
professionals in the clinical setting of living
kidney donors: A qualitative study. Transplant
Proc. 2022 Sep; 54(7):1750-1758. doi: 10.1016/j.
transproceed.2022.04.026.
Dowa Y, Takimoto Y, Kawai M, Shiihara T.
Hospital Ethics Committees in Japan: Current
Status From an Exploratory Survey 2012-2015.
Am J Prev Med Public Health. 2022; 8(5): 1-6.
Ino H, Nakazawa E. Over-the-counter drug
misuse and dependence: Public health ethics’
foray into fight against the codeine crisis.
Pharmacy. 2022; 10(6):155. doi: 10.3390/
pharmacy10060155.
Kato H, Nakazawa E, Mori K, Akabayashi A.
Disclosure of spousal death to patients withdementia: Attitude and actual behavior of caremanagers. Eur J Investig Health Psychol Educ.
2023; 13(2):419-428. doi: 10.3390/ejihpe
13020031.
Komada MT, Lee JS, Watanabe E, Nakazawa E,
Mori K, Akabayashi A. Factors of influenza
vaccine inoculation and non-inoculation behavior
of community-dwelling residents in Japan:
Suggestions for vaccine policy and public healthethics after COVID-19. Vaccine X. 2023 Apr;
13:100245. doi: 10.1016/j.jvacx.2022.100245.
Kono M, Arai N, Takimoto Y. Identifying
practical clinical problems in active euthanasia: A
systematic literature review of the findings incountries where euthanasia is legal. Palliat
Support Care. 2023 Jan 9:1-9. doi: 10.1017/
S1478951522001699.
Miwa E, Shoji E, Nakazawa E, Akabayashi A.
Family care relationships in reproductive justice.

10.

11.

12.

13.

14.

15.

16.

Women. 2022; 2(4):339-345. doi: 10.3390/
women2040031.
Mori T, Deasy Y, Mori K, Nakazawa E,
Akabayashi A. An exploratory quantitative studyof factors associated with dissatisfaction withJapanese healthcare among highly skilled foreign
professionals living in Japan. BioMed. 2022;
2(4):431-441. doi: 10.3390/biomed2040034.
Muraoka K, Takimoto Y, Nakazawa E, Tsuji T,
Liu M. Stroke survivors' experiences and needs
during the decision-making process considering
rehabilitation options: A pilot descriptive study inJapan. Prog Rehabil Med. 2022 May 13; 7:20220024. doi: 10.2490/prm.20220024.
Nagai H, Nakazawa E, Akabayashi A. The
creation of the Belmont Report and its effect on
ethical principles: a historical study. Monash
Bioeth Rev. 2022 Dec; 40(2):157-170. doi:
10.1007/s40592-022-00165-5.
Oikawa M, Takimoto Y, Akabayashi A. Attitudesof the public toward consent for biobank researchin Japan. Biopreserv Biobank. 2022 Dec 19. doi:
10.1089/bio.2022.0041.
Ozeki-Hayashi R, Nakazawa E, Truog R,
Akabayashi A. Initiation and withdrawal ofinvasive
ventilationforpatients
withamyotrophic lateral sclerosis: A narrative
literature review. J. 2022; 5(3):402-409. doi:
10.3390/j5030027.
Sato H, Fujita M, Tsuchiya A, Hatta T, Mori K,
Nakazawa E, Takimoto Y, Akabayashi A.
Disclosing a diagnosis of autism spectrum
disorder without intellectual disability topediatric patients in Japan in early diagnostic
stages and associated factors: a cross-sectional
study. Biopsychosoc Med. 2022 Aug 20; 16(1):18.
doi: 10.1186/s13030-022-00247-0.
Takahashi S, Nakazawa E, Ichinohe S,
Akabayashi A, Akabayashi A. Wearable
technology for monitoring respiratory rate andSpO2 of COVID-19 Patients: A systematic
review. Diagnostics (Basel). 2022 Oct 21; 12(10):2563. doi: 10.3390/diagnostics12102563.
Takeshita K, Nagao N, Kaneda H, Miura Y, Kinjo
T, Takimoto Y. Report on the establishment of theconsortium for hospital ethics committees inJapan and the first collaboration conference of306

hospital ethics committees. Asian Bioeth Rev.
2022 Sep 6; 14(4):307-316. doi: 10.1007/s41649022-00219-0.
17. Takimoto Y. Indications for involuntary
hospitalization for refusal of treatment in severe
anorexia nervosa: a survey of physicians andmental health care review board members inJapan. J Eat Disord. 2022 Nov 21; 10(1):176. doi:
10.1186/s40337-022-00703-w.
18. Takimoto Y. International comparison ofphysicians' attitudes toward refusal of treatment
by patients with anorexia nervosa: a case-based
vignette study. J Eat Disord. 2022 Jun 23; 10(1):86. doi: 10.1186/s40337-022-00613-x.
19. Takimoto Y. Key components of the mental
capacity assessment of patients with anorexia
nervosa: a study of three countries. J Eat Disord.
2022 Jul 26; 10(1):110. doi: 10.1186/s40337-02200633-7.
20. Takimoto Y, Nabeshima T. Ethical healthcare
attitudes of Japanese citizens and physicians:
Patient-centered or family-centered? AJOB
Empir Bioeth. 2022 Dec 28; 1-10. doi: 10.1080/
23294515.2022.2160511.
21. Takimoto, Y, Shimanouchi, A. Ethics Guideline
Development for Neuroscience Research
involving Patients with Mental Illness in Japan.
Asian Bioeth Rev. 2023 Feb. https://doi.org/10.
1007/s41649-023-00240-x.
22. Takimoto Y, Udagawa M. Development andevaluation of remote supervision in clinical ethics
consultation training. Clin Ethics. 2022. doi:
10.1177/14777509221144568.
23. Udagawa M, Takimoto Y. Practical training using
immersive roleplay and an intensive course on
clinical ethics consultation in Japan. BMC Med
Ethics. 2022 Nov 24; 23(1):118. doi: 10.1186/
s12910-022-00861-1.
24. Urade M, Fujita M, Tsuchiya A, Mori K,
Nakazawa E, Takimoto Y, Akabayashi A. Factsand recommendations regarding when medical
institutions report potential abuse to childguidance centers: A cross-sectional study. Pediatr
Rep. 2022 Nov 2; 14(4):479-490. doi: 10.3390/
pediatric14040056.

Health Sciences and Nursing
2. Preventive and Administrative Nursing

308

Department of
Nursing Administration /Advanced Clinical Nursing
Associate Professor
Aya Kitamura, Ph.D., R.N.

Assistant Professor
Naoko Ichikawa, Ph.D., R.N
Ryohei Kida, Ph.D., R.N.
Tamaki Isobe, Ph.D., R.N

Homepage http://nurs-adm.umin.jp/
Introduction and Organization
The Department of Nursing Administration /Advanced Clinical Nursing has 60 years of history andtradition. It was first established in 1954 as the
Department of Fundamental Nursing at the School of
Health Care and Nursing. The School of Health Careand Nursing was composed of two basic medical
departments and six nursing departments. When it was
reorganized as the School of Health Sciences in 1965,
only one nursing department remained. Renamed theDepartment of Nursing, it was responsible for nursing
education. In 1992, the School of Health Sciences
became the School of Health Sciences and Nursing, andtwo new departments of nursing were established; theDepartment of Nursing then became the Department ofFundamental Nursing. As a result of the shift to the chairof the Graduate School of Medicine in 1996, two
departments were established: the Department of
Nursing Administration and the Department ofAdvanced Clinical Nursing. Our department is
responsible for undergraduate fundamental nursing
education.

Teaching activities
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 basic nursing
skills and nursing organization management through a309

series of critique of scientific articles and discussions.
Basic Nursing Skills (2 credits, lecture)
This course covers the basics of assessing clients’
health, including physical examination skills andpractices in fundamental nursing skills, which areessential for providing nursing care with physiologicaland psychosocial integrity. Students learn about thenursing process through case discussions.
Practicum: Basic Nursing Skills(2 credits, practicum)
Under instructors’ supervision, students have theopportunity to apply their fundamental knowledge andnursing skills in a variety of settings. Students willassess clients’ health and needs by applying the nursing
process.
Nursing Administration (1 credit, lecture)
This course introduces students to the roles of nurse
administrators/managers in all types of healthcare
settings, such as institutions, organizations, andcommunities as well as political settings. Students willlearn the fundamental theories and practices of nursing
administration/management by analyzing current issues
in healthcare and nursing.
Practicum: Nursing Administration(1 credit, practicum)
Students participate in a nursing administrative
practicum in units or divisions in hospitals. They willlearn about care delivery systems, such as staffing andpatient classification systems, nursing informatics, andbudgetary issues (e.g., cost effectiveness and quality
improvement).

Graduate Courses
In the graduate program, our department oversees
lectures and seminars for Nursing Administration andAdvanced Clinical Nursing.
Advanced Clinical Nursing I (2 credits)
During this course, students acquire the necessary
knowledge and perspectives to conduct research that
focuses on advanced nursing technologies ororganizations through discussion and a critical analysisof relevant advanced nursing professions or organization

management theories, the environment surrounding
nursing science and nursing practice, and politicaldecision making.
SeminarWe have an accredited departmental seminar where
members discuss their own research project plans.

Research activities
Our research scope is wide, ranging fromindividual nursing care technologies to thecare-related environment and the systems andorganizations that support the nursing profession.
We aim to elucidate the mechanisms underlying
them and relationships to patient outcomes, thereby
creating technologies and systems that maximize thefull power of nursing.
Area of Nursing Administration
In the area of nursing administration, we areworking to elucidate the complex phenomena oforganizations and workers from various perspectives,
such as research to improve the job psychologicalstate of working nurses, research to contribute tonursing policies, and research on future careerdevelopment, to realize a society in which thesustainability of nursing organizations can beachieved. Studies on the job psychological state ofnurses cover topics related to factors and outcomes
related to nurses' intention to continue working, suchas organizational commitment, work engagement,
and sense of personal-job fit. Research contributing tonursing policy includes support for potential nurses toreturn to work, appropriate work environment
management, including working hours, education ofnursing managers and outcomes, and clinicalimplementation of evidence-based practice. In thearea of research on future career development, we areconducting research on the employability of nurses.
Area of Advanced Clinical Nursing
In the area of advanced clinical nursing, research is
being conducted to develop new nursing techniques,aiming at visualization of nursing techniques andclarifying the mechanisms that provide the basis forcare. Specifically, they visualize care effects using

310

echo, thermography, and pressure sensors anddevelop care methods suitable for the target
population. In addition, they are working to generate
evidence for new nursing techniques based on
fundamental research, including animal experiments.
Our main research themes
Developing and verifying novel nursing
technologies and devices

Developing and verifying novel services
systems
Nursing administration skills, including theability to mobilize individuals and groups toachieve missions and goalsOrganizational dynamics and diversityCareer development support and empowerment
for nurses

Quality of health care and nursing, including
investigating the relationship among structures,processes, and outcomes

6.

7.

8.

References
1.

2.

3.

4.

5.

Kida R. & Takemura Y. Working conditions andfatigue in Japanese shift work nurses: A
cross-sectional survey. Asian Nursing Research.
2022: 16(2), 80-86.
Susuki T, Kida R, Takemura Y, Ichikawa N, Kunie
K, & Koyanagi H. Work-related communication
mediates the relationship between perceived
diversity climate and psychological empowerment
among part-time nurses: a cross-sectional study.
Journal of Nursing Management, 2022; 30(2)Sawada S, Takemura Y, Isobe T, Koyanagi H, &Kida R. Perceived Impact of nurse turnover on theorganization: A Delphi study on managers of
nursing. Journal of Nursing Management. 2022.
30(7)Kida R, Takemura Y, Inoue M, Ichikawa N &Koyanagi H. Nursing Management for the
Temporary Lodging Facilities in Japan in the Early
Stages of the COVID-19 Pandemic: A MultipleCase Study. Japan Journal of Nursing Science.
20(1)Sugama J, Ishibasi M, Ota E, Kamakura Y, Saitoh
E, Sanada H, Nakayama T, Nomura T, Yamada M,
Nakagami G, Sato N, Shibata S, Hase T, Fukada J,

Miki T, Arita M, Urai T, Okawa Y, Kitamura A,
Dai M, Takahashi T, Tamai N, Tobita I, Noguchi H,
Matsumoto M, Miura Y, Mukai K, Mugita Y,
Yoshida M, Kurachi M, Shirasaka T, Yamane Y.
Japanese clinical practice guidelines for aspirationand pharyngeal residual assessment during eating
and swallowing for nursing care. Japan Journal of
Nursing Science. 2022:e12496.
Takemura Y, Inoue M, Ichikawa N, Kida R,
Koyanagi H, Ikezaki S, and Ikeda M. Key
Strategies for Managing Nursing Care under the
COVID-19 Pandemic: A Multiple Case Study of
Nursing Directors. Journal of Nursing Management.
2022. 30(8).
Takizawa C, Minematsu T, Nakagami G, Kitamura
A, Koudounas S, Kunimitsu M, Sanada H.
Expression levels of NPPB, ITGB6, CPNE4,
EML5, and ITSN1 in fresh exudates swabbed fromcritically colonized and infected full-thickness
wounds in rats. International Wound Journal. 2022.
The Fact-finding Committee of the JapaneseSociety of Pressure Ulcers, Konya C, Takeuchi Y,
Nakagami G, Kitamura A, Morita K, Ishizawa M,
Abe Y, Higuchi H, Mizuki T, Motegi S, Shoju S,
Shimada K, Tanaka K, Kawakami S, & Sanada H.
Nationwide time-series surveys of pressure ulcer
prevalence in Japan. Journal of Wound Care. 2022;
31(Sup12):S40-S47.

311

Department of Family Nursing
Professor
Mari Ikeda, Ph.D., R.N., P.H.N., C.C.P.

Lecturer
Sachiko Kita, Ph.D., R.M.W, R.N., P.H.N.

Assistant Professor
Mayumi Morisaki, Ph.D., R.N., P.H.N.

Homepage

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

Introduction and Organization
This department was established in 1992. Three
faculty members currently serve the department: aprofessor, a lecturer, and an assistant professor.
Enrolled at present are 1 doctoral student, and 1
administrative staff.

Education
1. Graduate Courses, School of Health Sciences andNursing (credit hours)
Advanced Family Nursing I (2)Advanced Family Nursing II (2)Laboratory and/or Field Work on Family Nursing(16)
Practicum in Translational Research Nursing (2)2. Undergraduate Courses for Students in the Schoolof Integrated Health Sciences (credit hours)
Family Health (2)Health Communication (1)3. Undergraduate Courses for Nursing Students in the
School of Integrated Health Sciences (credit hours)
Pediatric and Child Health Nursing (4)Clinical Practicum in Pediatric and Child HealthNursing (2)Integrated Clinical Practicum in Nursing (1)Research
Our department research family with healthproblems, developmental task or encounter withchanges in the community to which the family belongs.
We aim to reveal the fluctuation that have occurred in
the family system and create family support. Our
on-going, specific research theme include thefollowing:
1. Mental health and childcare Support during
family formation;
2. Development and dissemination of nursing carefocusing on attachment styles;
3. Family violence and gender-based violence
4. QOL for cancer patients and their families;
5. Development of a Pediatric Quality of Life (QOL)
Inventory for children with chronic illness andtheir parents;
6. Lifetime support for survivors of childhood
cancer and their families: treatment and care in
their late effects, special needs education, andworking;
7. Transitional care for children, adolescent andyoung adult with childhood-onset chronic
diseases;
8. Research about prevention of deterioration of
postpartum depression, child abuse and neglect;
9. Support for bereavement from family members.
Regarding the "Development and dissemination ofnursing care focusing on attachment style," we havebeen disseminating the Attachment Style Interview(ASI) developed by Professor Bifilco in the UK which
is translated into Japanese version as ASI-J. We also

312

completed a translated version of the ASI-J for
children between 2019 and 2021, and conducting its
reliability and validity studies. Currently, we areconducting online training of the ASI-J for researchers,
clinical practitioners, and graduate students.
Regarding research on family violence, we havedeveloped a scale to measure family polyvictimization which means the co-occurrence ofdifferent types of violence, such as intimate partner
violence, child abuse and elder abuse. In addition, we
have developed a Training program for Child Abuse
Prevention for citizens (TCAP-C) and tested theeffectiveness. Since 2017, we have been conducting
an international collaboration study with international
scholars from eleven countries, to identify trauma
recovery pathways after gender-based violence.
Studies focusing on transition such as “Transitionalcare for children, adolescent and young adult withchildhood-onset chronic diseases” in patients withchild chronic diseases has been conducted since 2016.
We established a transition outpatient clinic in the
University of Tokyo Hospital in June 2016 and havebeen providing transitional cares for patients withcongenital heart disease, epilepsy, chromosomal
abnormality, hematologic disease, and endocrine
disease in the clinic. We also developed the tool “My
Health Passport” in order for patients to summarize
the information about their disease and share theirexperiences with others (e.g., friends and coworkers)
and established evidence of its effectiveness. We
collaborate with the evidence-based clinic, with regard
to research, practice and graduate education.
In addition, we hold bimonthly family nursing
research seminar, whereby deeper understanding offamily nursing practice and research are promoted. In
this we aim to enhance the quality of clinical practiceand research in family nursing and contribute to theestablishment of the science of family nursing.

Publications
1.

Tobe H, Sakka M, Kita S, Ikeda M, Kamibeppu
K. The Efficacy of a Resilience-Enhancement
Program for Mothers Based on Emotion
Regulation: A Randomized Controlled Trial in
Japan. International Journal of Environmental
Research and Public Health. 2022; 19(22):14953.

2.

3.

4.

5.

6.

7.

8.

9.

http://doi.org/10.3390/ijerph192214953
Sasaki N, Ikeda M, Nishi D. Long‑term influenceof unintended pregnancy on psychologicaldistress: a large sample retrospective cross‑sectional study. Archives of Women’s Mental
Health. 2022 Dec; 25(6): 1119-1127. DOI:
10.1007/s00737-022-01273-1
Kita S, Kamibappu K, Saint Arnault D.“Knitting
together the lines broken apart”: Recovery
process to integration among Japanese survivorsof intimate partner violence. International Journalof Environmental Research and Public Health.
2022; 30; 19(19): 12504.
Takemura Y, Inoue M, Ichikawa N, Kida R,
Koyanagi H, Ikezaki S, Ikeda M. Key strategies
for managing nursing care under the COVID-19
pandemic: A multiple-case study of nursing
directors. Journal of Nursing Management. 2022
Nov; 30(8): 4042-4053. http://doi.org/10.1111/
jonm.13844
Koutra K, Burns C, Sinko L, Kita S, Bilgin H,
Saint Arnault D. Trauma recovery rubric: A
mixed-method analysis of trauma recovery
pathways in four countries. International Journalof Environmental Research and Public Health.
2022；19(16).
Iwasaki T, Kou A, Harasawa N, MorishitaKawahara M, Yamagata C, Moriya H, Ikeda M,
Nagae H. Exploring the Attitudes and Needs ofAdvance Care Planning Practice Among theWorking Generation. Tokyo Women’s Medical
University Journal. 2022; 6. https://doi.org/
10.24488/twmuj.2022004
Kita S, Zeynep O, Saint Arnault D. Initial testingof components of the Cultural Determinants ofTrauma Recovery (CDTR) Theory among
American Gender-Based Violence survivors:
Structural equation modeling. Journal ofAdvanced Nursing, 2022；79（4）：1476-1492.
Muramoto M, Kita S, Tobe H, Ikeda M,
Kamibeppu K. The association between selfcompassion in the postnatal period and difficult
experiences with COVID-19 pandemic-relatedchanges during pregnancy: An observational
study for women at 1 month postnatal in Japan.
Japan Journal of Nursing Science, 2022; e12494.
Morisaki-Nakamura M, Suzuki S, Kobayashi A,313

Kita S, Sato I, Iwasaki M, Hirata Y, Sato A, Oka
A, Kamibeppu K. Efficacy of a Transitional
Support Program Among Adolescent Patients
With Childhood-Onset Chronic Diseases: A
Randomized Controlled Trial. Frontiers in
Pediatrics. 2022.
10. Sato I, Soejima T, Ikeda M, Kobayashi K,
Setoyama A, Kamibeppu K. Reliability andvalidity of the Japanese version of the PediatricQuality of Life Inventory Infant Scales. Journalof Patient-Reported Outcomes, 2022；6(10).
11. Hayakawa A, Sato I, Kamibeppu K, Ishida Y,
Inoue M, Sato A, Shiohara M, Yabe H, Koike K,
Adachi S, Atsuta Y, Yamashita T, Kanda Y,
Okamoto S. Impact of chronic GVHD on QOL
assessed using visual analogue scale in survivors
after pediatric HSCT and those depending on
QOL raters: a cross-sectional observational study
in Japan. International Journal of Hematology.
2022; 115(1):123-128.

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Department ofCommunity Health Nursing /Public Health Nursing
Associate Professor
Kyoko Yoshioka-Maeda, Ph.D., R.N., P.H.N.

Assistant Professor
Chikako Honda, Ph.D., R.N., P.H.N.
Hiroshige Matsumoto, Ph.D., R.N., P.H.N.

Homepagehttps://chiikikango.m.u-tokyo.ac.jp/

Introduction and Organization
The Department of Community Health Nursing wasestablished in June 1992. The educational program forthe public health nurse license has been established in
the master's program of the graduate school since2014. Our department is also in charge of thisprogram.

Teaching activities
Our department aims to educate public health nurses
with a research mindset and researchers with a publichealth nurse mindset. In the undergraduate program,
we teach basic methods and theories of healthpromotion for individuals, families, and specificpopulations living in the community. The titles are as
follows: Home Health Nursing, Community HealthNursing, Home Health Nursing Practice. There is a
total of four credits of lecture and two credits ofpracticum.
In the graduate program, we teach about the advanced
methods and theories in community health nursing
and public health nursing. The titles are as follows:
Advanced Community Health Nursing I, II, Advanced
Community Health Nursing Seminar I, II and PracticeI, II. There are a total of 12 credits: 4 credits of lectureand 8 credits of exercises and practical training.
We also offer an additional nine types of lecture/practical training as a part of the education programfor public health nurse licenses. The titles are as
follows: Skills for Public Health Nursing I, II, Public
Health Nursing I, II, III, Ⅳ, Public Administration for
Nurses, Public Health Nursing Practice I, II. There are
13 credits of lecture and five credits of practicum.
We also supervise undergraduate/graduate students
with their thesis.

Research activities
We conduct research to improve health and quality oflife by understanding the nursing needs of people
living in the community and those receiving care athome on an individual basis, as well as the needs offamilies, groups, and the community as a whole. In an
aging society with a declining birth rate, it isimportant to support the independence of the older
adults and prevent the need for nursing care. In
addition, we aim to create community care systems
that enable people with physical and mental
disabilities to live well in their own familiar
communities. It is also essential to support children
throughout the community so that they can grow anddevelop healthily. Our research we are engaged in315contributes to the creation of a society that is
conducive to a comfortable living environment,
addressing the evolving needs of society and thetimes.
Our research is supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Ministry of
Health, Labour and Welfare, and other foundations.
Ongoing research projects in our department are listed
below.
1. Improving public health nursing practice andbuilding care systems
 Algorithms and evaluation methods for publichealth nursing activities using informationand communication technology
 Comprehensive community care systems
2. Development, evaluation and dissemination ofprograms to solve health problems at different stagesof life Programs to protect the health of community
residents
 Injury prevention for infants and toddlers
 Dementia education programs in thecommunity
3. Study on the development of professional
competencies and skills of public health nurses
 Policy making and project development by
public health nurses
 Elucidation of skills and tacit knowledge of
public health nurses
4. Cutting-edge issues that do not fit into conventionalframeworks
 VR-based home visit learning materials fornursing students
5. The "Zero Missed Hip Dislocations in Infants"
Project
To achieve our goal of preventing missed hip
dislocation in newborns and infants, we're working
together with experts in nursing, medicine, andengineering. Our goal is to develop a screening systemthat can be used by public health nurses and midwives

during their visits to newborns. We are also focusing
on developing a comprehensive community-based
approach to early treatment of this condition.

References
1. Yoshioka-Maeda, K., Katayama, T., Shiomi, M.,
Hosoya, N., Fujii, H., & Mayama, T. (2022).
Feasibility of an educational program for publichealth nurses to promote local healthcare planning:
protocol for a pilot randomized controlled trial.
Pilot and Feasibility Studies, 8(1), 92.
2. Yoshioka-Maeda, K., Fujii, H., Kageyama, M., &Takamura, S. (2022). Factors of parental preparationof children with mental illnesses for their
independent living after their own death. Healthcare,10(12), 2360.
3. Yoshioka-Maeda, K., Honda, C., Sumikawa, Y.,
Okamoto, Y., Shimada, M., Fujii, H., ... & Otsuki, M.
(2022). Developing a virtual reality simulation
program for improving nursing students’ clinicalreasoning skills in home settings: A protocol paper.
Nursing Reports, 12(4), 968-979.
4. Honda, C., Yoshioka-Maeda, K., Fujii, H.,
Iwasaki-Motegi, R., & Yamamoto-Mitani, N. (2022).
Evaluation of infant injury prevention education
provided during antenatal classes after two years: A
pilot prospective cohort study. International journalof environmental research and public health, 19(12),7195.
5. Matsumoto, H., Igarashi, A., Sakka, M., Takaoka,
M., Kugai, H., Ito, K., & Yamamoto-Mitani, N.
(2022). A two-step model for encouraging thegeneral public to exhibit helping behaviors toward
people living with dementia. Innovation in Aging,
6(3), igac023.
6. Matsumoto, H., Hagiwara, Y., Yamamoto-Mitani, N.,& Igarashi, A. (2022). A randomized control trial forredesign: a dementia-friendly mobile microlearning
training for store workers in Japan. The
Gerontologist, gnac182.
7. Yokobori, H., Iwasaki‐Motegi, R., Naruse, T., &Yamamoto‐Mitani, N. (2022). Public health nurses’
activities toward child abuse prevention before
childbirth in Japan. Public health nursing, 39(6),1346-1354.

Health Sciences and Nursing
3. Clinical Nursing

317

Department of GerontologicalHome Care and Long-term Care
Nursing/Palliative Care Nursing
Professor
Noriko Yamamoto-Mitani, Ph.D., R.N.

Associate Professor
Ayumi Igarashi, Ph.D., R.N.

Assistant Professor
Mariko Sakka, Ph.D., R.N.
Yuka Sumikawa, Ph.D., R.N.

Homepagehttps://longtermcare.m.u-tokyo.ac.jp/en/home-en/

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 was 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. Students complete their master’s thesis or
doctoral dissertation by developing a researchquestion from their own scientific interests regarding
nursing practice for older people or adults in thechronic stage.
In education, we emphasize the critical thinking
process as a researcher who conducts unique andoriginal research: from cultivating perspectives as a
researcher to coming up with original research topics,
developing research topics into unique researchquestions/ hypotheses, choosing appropriate researchmethods, and developing valid research protocols.

Research
In research, we aim to contribute to the development of nursing science and improvement in thequality of nursing practice through collaborative
research with clinicians. Specifically, we aim todevelop new nursing knowledge grounded onJapanese culture, as needed in tomorrow’s aged
society. Faculty members conduct studies on various
topics in the field of adult and gerontological nursing.
Regarding methods, besides conventional statisticalmethods, we often utilize qualitative methods tounderstand the experiences of individual patients
and/or nurses and to conceptualize and theorize them.

318

1) Quality assurance and improvement for long-termcare for older people
The goal of long-term care nursing is to allow older
adults to live as high-quality lives as possible, evenwith diseases/disabilities; the paradigm of long-termcare is different from that of acute care which
typically aims to have the patients recover promptly
from disease conditions. There has not been enoughattention to long-term care nursing in today’s
healthcare practice; there has been little research on
quality assurance and improvement in the long-termcare field in Japan. In this department, we have been
conducting multiple studies on long-term care infacilities and homecare nurse agencies regarding carequality assurance and improvement.
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 the qualityof long-term care, including home care nursing. We
have been developing them as a part of the 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 providers working at long-term carefacilities and homecare nurse agencies are limited
compared to those working at critical hospitals.
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 a long time, it
has not had a standardized method. We aim to develop
a protocol for conducting a case study that contributes
to developing nursing science.
3) Establishment of support systems for older people
in the integrated community care
In the Japanese aged society, establishing a local
structure supporting the life of older people in thecommunity is an urgent need. In collaboration withdifferent stakeholders, we strive to create programs

that aim to build a dementia-friendly community(DFC). As part of this effort, we developed andevaluated a dementia awareness program for local
residents that uses virtual reality (VR) technology toprovide a first-person experience from the perspectiveof a person with dementia. As a next step, we are
expanding the scope of the program from local
residents to nurses working at healthcare institutions,nursing students, and children, and are modifying andevaluating the program to suit each target group.
4) Creating a workplace that supports care-workbalance
In a super-aging society, the number of people caring for family members while working is increasing.
Therefore, we are working on the development of
e-learning programs to create a workplace that supports the balance between nursing care provision andwork. Through e-learning, we are developing content
that allows students to learn not only about nursing
care, but also about how to respond as colleagues andsuperiors, and how to create a workplace. In the next
fiscal year, we plan to intervene through an e-learning
program developed as workplace training for companies and local governments and evaluate its effect.
5) Examination of care provision systems for the
future spread of infectious diseases such as
COVID-19
The COVID-19 pandemic has had many effects on
nursing, medical, and long-term care systems
worldwide. We conduct research from the following
two perspectives, targeting Japan and overseas. The
first perspective is to grasp the actual situation of
COVID-19 response in long-term care facilities
worldwide. The second perspective is to examine thesupport systems and issues of home-visit nursing
stations and public health centers for COVID-19 homecare patients in Japan. In order to prepare for the next
infectious disease crisis, we aim to grasp the actual
situation of the care system during the spread of
emerging
infectious
diseases
andproposecountermeasures.
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

319

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.
8.

Publications
1.

2.

3.

4.

5.

6.

7.

Matsumoto H, Igarashi A, Hagiwara Y,
Yamamoto-Mitani N. Relational Design for
Dementia and Job Significance (ReDeSign):
Study protocol for a randomized controlled trialof an online dementia training for retail workers.
Contemp Clin Trials Commun. 2022 Jan 21;
26:100896. doi: 10.1016/j.conctc.2022.100896.
Yokobori H, Iwasaki-Motegi R, Naruse T,
Yamamoto-Mitani N. Public Health Nurses'
Activities toward Child Abuse Prevention before
Childbirth in Japan. Public Health Nurs. 2022;
39(6):1346- 1354. doi: 10.1111/phn.13122
Sari DW, Noguchi-Watanabe M, Sasaki S,
Yamamoto-Mitani N. Dietary Patterns of 479
Indonesian Adults and Their Associations with
Sodium and Potassium Intakes Estimated by Two
24-h Urine Collections. Nutrients. 2022; 15;
14(14):2905. doi: 10.3390/nu14142905
Honda C, Yoshioka-Maeda K, Fujii H,
Iwasaki-Motegi
R,
Yamamoto-MitaniN.
Evaluation of Infant Injury Prevention Education
Provided during Antenatal Classes after Two
Years: A Pilot Prospective Cohort Study. Int J
Environ Res Public Health. 2022; 11;19(12):7195.
doi: 10.3390/ijerph19127195
Iwasaki-Motegi R, Yoshioka-Maeda K, Honda C,
Yamamoto-Mitani N. Prefectural public healthnurses' support in human resource developmentof municipal public health nurses in Japan. Nihon
Koshu Eisei Zasshi. 2022; 15;69(6):417-423. doi:
10.11236/jph.21-078
Ho LYW, Kwong EWY, Song MS, Kawakami A,
Boo S, Lai CKY, Yamamoto-Mitani N.
Decisionmaking preferences on end-of-life carefor older people: Exploration and comparison ofJapan, the Hong Kong SAR and South Korea in
East Asia. J Clin Nurs. 2022; 31(23-24):34983509. doi: 10.1111/jocn.16178
Matsumoto H, Hagiwara Y, Yamamoto-Mitani N,
Igarashi A. A randomized control trial for

9.

10.

11.

12.

13.

14.

ReDeSign:
Adementia-friendly
mobilemicrolearning training for store workers in Japan.
Gerontologist. 2022; doi: 10.1093/geront/gnac
182
Yoshioka-Maeda K, Honda C, Sumikawa Y,
Okamoto Y, Shimada M, Fujii H, Iwasaki-Motegi
R, Miura T, Otsuki M. Developing a Virtual
Reality Simulation Program for Improving
Nursing 3 Students’ Clinical Reasoning Skills in
Home Settings: A Protocol Paper. Nurs Rep. 2022.
12(4): 968-979. doi: 10.3390/nursrep12040093.
Eltaybani S, Yasaka T, Fukui C, Inagaki A,
Takaoka M, Suzuki H, Maruyama M, Igarashi A,
Noguchi-Watanabe M, Sakka M, Weller C,
Yamamoto-Mitani N. Family-oriented interventions in long-term care residential facilities
for older people: A scoping review of thecharacteristics and outcomes. Nurs Forum. 2022;
57(5):800-818. doi:10.1111/nuf.12768
Naruse T, Kynoch K, Sumikawa Y, Ramis MA,
Tuckett AG. Effectiveness of social activity
interventions on sleep among older people: asystematic review protocol. JBI Evid Synth. 2022.
18(0): 1-6. doi: 10.11124/JBIES-21-00231
Eltaybani S, Suzuki H, Igarashi A, Sakka M,
Amamiya Y, Yamamoto-Mitani N. Long-termcare facilities’ response to the COVID-19
pandemic: A protocol of a cross-sectional,
multi-site, international survey. Nurs Open. 2022;
9(5):2506-2517. doi:10.1002/nop2.1264
Eltaybani S, Kiyomi K, Kato R, Inagaki A,
Shinohara M, Yamamoto-Mitani N. Effectivenessof home visit nursing for older people onpatient-related clinical outcomes: an umbrella
review protocol. JBI Evid Synth. 2022;20(8):2071-2078. Published 2022 Aug 1. doi:10.11124/
JBIES-21-00343.
Masuda A, Sakka M, Kitamura S, Igarashi A,
Noguchi-Watanabe M, Araki A, YamamotoMitani N. Collaborative visits by hospital
specialist nurses with homecare nurses: A
nationwide, cross-sectional, web-based survey.
Journal of International Nursing Research. 2(2023), No. 1 pp. e2021-0011-e2021-0011. doi:
10.53044/jinr.2021-0011.
Matsumoto H, Igarashi A, Sakka M, Takaoka M,
Kugai H, Ito K, Yamamoto-Mitani N. A two-step320

model for encouraging the general public to
exhibit helping behaviors towards people livingwith dementia. Innov Aging. 2022. doi:
10.1093/geroni/igac023
15. Iwasaki-Motegi R, Yoshioka-Maeda K, Honda C,
Yamamoto-Mitani N. Prefectural public healthnurses' support in human resource developmentof municipal public health nurses in Japan. Nihon
Koshu Eisei Zasshi. 2022. doi: 10.11236/jph.21078.

321

Department ofMidwifery and Women's HealthProfessor
Megumi Haruna, Ph.D., R.N.M.

Lecturer
Kaori Yonezawa, Ph.D., R.N.M.

Assistant Professor
Emi Sasagawa, 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, 1 JSPS
postdoctoral fellowship for overseas researcher, 17
graduate students (8 in master’s courses, 9 in doctoral
courses), and 10 visiting researchers.

Teaching activities
We have graduate and undergraduate courses.
1. Graduate Courses, School of Health Sciences andNursing1) Advanced Midwifery and Women’s Health I(2 credits, lectures)
2) Advanced Midwifery and Women’s Health II(2 credits, lectures)
2. Graduate Courses, School of Health Sciences andNursing for midwifery
1) Midwifery I (2 credits, lectures)
2) Midwifery II (2 credits, lectures)
3) Midwifery III (2 credits, lectures)
4) Midwifery IV (2 credits, lectures)

5) Midwifery V (2 credits, lectures)
6) Midwifery VI (1 credit, lectures)
7) Clinical Practicum of Administration for
Midwifery (1 credit, practices)8) Clinical Practicum in Midwifery I(2 credits, practices)9) Clinical Practicum in Midwifery II(8 credits, practices)
3. Undergraduate Courses of Nursing, School of
Health Sciences and Nursing
1) Maternal-Newborn Nursing (2 credits, lectures)
2) First AID course (1 credit, lecture)3) Clinical Practicum in Maternal-Newborn
Nursing (2 credits, practices)

Research activities
Our research activities encompass the field ofmaternal and child health emphasizing on the
promotion of women’s health and quality of life at
every stage of life.
We aim to conduct the following research projects:
1. Creating evidence of health guidance during
pregnancy
1) Healthy lifestyle: Adequate maternal nutrition,

322

weight management, exercise, physical activity,
sleep, and mental health are needed to ensure ahealthy lifestyle among pregnant women.
We aim to conduct the Japan Pregnancy, Eating,
Activity, Cohort Study (J-PEACH study) toprovide evidence for appropriate healthguidance. It investigates maternal body weight,
glucose and lipid metabolite biomarkers,
nutritional intakes, and physical activities tooptimize weight management and a healthy
lifestyle during pregnancy to prevent adverse
perinatal outcomes including low birth weight.
2. Development of a support system for reliablechildbirth1) Midwifery care for positive childbirth experiences
This study evaluates the care provided by
midwife-led system and in-hospital midwifery
clinic with the aim of building a positive andefficient midwifery care for a positive birthexperience for the mother.
2) “Fear of childbirth” and psychosocial factors
among pregnant Japanese womenThis study aims to identify the psychosocial risk
factors of intense fear of childbirth.
3) Development of assessment methods of birthcanal using transperineal ultrasonography
This study aims to develop the objective
assessment methods of birth canal and theassociation of birth canal and delivery modeusing transperineal ultrasonography.
4) Development of the strategy for safe delivery in
El Salvador
To reduce the maternal mortality ratio in El
Salvador, a program for humanized childbirth
based on scientific evidence that leads tomaternal safety and comfort during childbirth isdeveloped.
5) Evaluation of learning efficacy of Virtual
Reality on midwifery education
Collaborative research between the Universityof the Sunshine Coast, Queensland, Australia
and the Waikato Institute of Technology, New
Zealand is conducted to create and evaluate
educational content related to midwifery using
virtual reality technology. Furthermore, a 360°

camera is being used to create teaching materials
and to study its effectiveness in midwifery
education.
6) Development and effectiveness of an online
Japanese version of mindfulness-based childbirthand parenting programThis study aims to develop a short online
Japanese version of the Mindfulness-BasedChildbirth and Parenting (MBCP) program andto investigate the program’s effectiveness on
women’s prenatal mental health.
3. Development of a support system for postpartum
body management
1) Pelvic floor disorders among postpartum womenThis study evaluates the effect of pelvic floor
muscle training in prevention of postpartum
pelvic floor disorders (e.g., urinary incontinence). Furthermore, this study aims to develop
and implement a pelvic floor muscle training
program.
4. Development of a support system for women’s
health1) Health Support for working mothers and womenThis study investigates the cadences of daily lifeand conditions of sleep such as excessive
daytime sleepiness and other related factors
among working mothers. Furthermore, it also
explores factors associated with work
engagement among working pregnant women.
2) Support for breastfeeding mothers and babies
This study aims to develop the Japanese versionof the Infant Breastfeeding Assessment Tool
(IBFAT), to assess the instinctive feeding
behavioral reflexes of newborns, and explore
factors affecting the IBFAT.
5. Creating evidence of health guidance for neonatalskin care1) Development of an effective skin careintervention to prevent neonatal skin problems.
This study investigates the effect of following amoisturizing skincare routine on improving skinbarrier functions among healthy neonates.
Moreover, we will investigate the relationshipbetween newborns’ skin problems and allergies

323(i.e., food allergy or atopic dermatitis).
2) Effect of skincare on skin barrier function andnormal bacterial flora
This study investigates the effect of skin care,including bathing, on infants’ skin. It focuses onskin barrier function and normal bacterial flora
as a skin condition.

Publications
1.

2.

3.

4.

5.

6.

Yonezawa K, Haruna M, Ohya Y. Impact of skinconditions of infants on their mothers’ quality oflife. Journal of Neonatal Nursing, 2022; 28(3):188-191https://doi.org/10.1016/j.jnn.2021.10.
012
Yonezawa K, Haruna M, Ohya Y, YamamotoHanada K. Exacerbation and severity of allergic
symptoms during pregnancy and their impact onmental health. International Journal of Women's
Dermatology. 2022; 8(1): e002. https://doi:10.
1097/JW9.0000000000000002
Matsubara M, Haruna M, Yonezawa K,
Yokoyama M, Tahara-Sasagawa E, Hikita N,
Nakamura Y, Mizuno Y, Sanada H, Tamai N, Abe
M, Kashiwabara K. Development and validationof an infant facial skin assessment tool: aprospective observational study. BMC pediatrics,
2022; 22(1): 614. https://doi-org.utokyo.idm.oclc.
org/10.1186/s12887-022-03691-7
Yokoyama M, Yonezawa K, Matsubara M, Hikita
N, Sasagawa E, Haruna M. The factors related torecovery time of diaper dermatitis in infants: A
prospective observational study. Japan journal ofnursing science: JJNS, 2022; 19(4): e12492.
https://doi-org.utokyo.idm.oclc.org/10.1111/jjns.
12492
Shiraishi M, Matsuzaki M, Haruna M.
Association between perception of pre-pregnancy
body weight and nutritional status during
pregnancy: A cross-sectional study. Asia Pacificjournal of clinical nutrition, 2022; 31(4):692–700. https://doi-org.utokyo.idm.oclc.org/10.
6133/apjcn.202212_31(4).0012
Inuzuka Y, Yamamoto-Hanada K, Akaishi R,
Haruna M, Matsubara M, Saito-Abe M, Sago H,
Ohya Y. Dissemination of atopic dermatitis andfood allergy information to pregnant women in

an online childbirth preparation class. The journalof allergy and clinical immunology. Global,
2022; 1(1): 24-26. doi.org/10.1016/j.jacig.2021.
12.004.
7. Kelleher MM, Phillips R, Brown SJ, Cro S,
Cornelius V, Carlsen KCL, Skjerven HO,
Rehbinder EM, Lowe AJ, Dissanayake E,
ShimojoN,
YonezawaK,
Ohya
Y,
Yamamoto-Hanada K, Morita K, Axon E, Cork
M, Cooke A, Van Vogt E, Schmitt J, … Boyle RJ.
Skin care interventions in infants for preventing
eczema and food allergy. The Cochrane databaseof systematic reviews, 2022; 11(11): CD013534.
https://doi-org.utokyo.idm.oclc.org/10.1002/1465
1858.CD013534.pub3
8. Shinohara E, Ohashi Y, Hada A, Usui Y. Effects
of 1-day e-learning education on perinatal
psychological support skills among midwives andperinatal healthcare workers in Japan: arandomised controlled study. BMC psychology,
2022; 10(1): 133. https://doi-org.utokyo.idm.oclc.
org/10.1186/s40359-022-00832-6
9. Suzuki D, Ohashi Y, Shinohara E, Usui Y,
Yamada F, Yamaji N, Sasayama K, Suzuki H,
Nieva RF Jr, da Silva Lopes K, Miyazawa J, Hase
M, Kabashima M, Ota E. The Current Concept ofPaternal Bonding: A Systematic Scoping Review.
Healthcare (Basel, Switzerland), 2022; 10(11):2265.
https://doi-org.utokyo.idm.oclc.org/10.
3390/healthcare10112265
10. Sugawara C, Yamana H, Sasagawa E, Yonezawa
K, Hikita N, Morita K, Matsui H, Yasunaga H,
Haruna M. Factors Associated with SurgicalTreatment in Postpartum Women with Mastitis or
Breast Abscess: A Retrospective Cohort Study.
Breastfeed Med. 2022; 17(3): 233-238. doi:10.
1089/bfm.2021.0244.
11. Murakami M, Yonezawa K, Shimizu S, Haruna
M, Sasagawa E, Usui Y. Newborn-oriented andenvironmental factors for newborns' skin barrier
functions. Jpn J Nurs Sci. 2022; 19(2): e12457.
doi: 10.1111/jjns.12457.
12. Kaori Yonezawa, Tomomi Tose, Megumi Haruna,Emi Sasagawa, Yuriko Usui. Impact of the
COVID-19 Pandemic on the Childcare ofMothers with infants under one year old
COVID-19. Japan journal of nursing science:

324

JJNS, 2022; 42: 346-355. https://doi.org/10.5630/
jans.42.346 (in Japanese)
13. Shinohara E, Tahara-Sasagawa E, Chizuko
Ushioda, Kaoru Tsurumi, Yuko Imamura,
Kumiko Adachi. Literature Review on Maternaland Child Health Care for Foreign Residents inJapan. The Journal of Japanese Midwives'
Association, 2022; 76(1): 51-56. (in Japanese)

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Department of Psychiatric Nursing
Professor
Daisuke Nishi, M.D., Ph.D.

Associate Professor
Yuki Miyamoto, R.N., P.H.N., P.S.W., Ph.D.

Project Research Associate
Utako Sawada, R.N., Ph.D.

Homepage

http:// plaza.umin.ac.jp/heart/

Introduction and Organization
Our department was firstly established as Department of Fourth Clinical Medical Nursing in School of
Health Care and Nursing in 1957. When the School of
Health Care and Nursing was reorganized as the
School of Health Sciences in 1965, the department
was renamed Department of Mental Health. In 1992,
as School of Health Sciences became The School of
Health Science and Nursing, Department of Mental
Health became Department of Mental Health andPsychiatric Nursing. As the result of the shift to thechair system of the Graduate School of Medicine in
1996, two departments were established, Departmentof Mental Health and Department of PsychiatricNursing. Faculty, staff, and students of two departments have been working cooperatively ever since.
Our department currently has two faculty
members introduced above, a project research
associate, part-time lecturers, visiting research fellows,
4 doctoral course students, 4 master course students,
and research associates.
Our department’s mission comprises twoelements. One is to provide education and researchtraining in mental health and psychiatric nursing toundergraduate and graduate students in order toprepare students to assume leadership roles in nursing
clinical practice, administration, teaching, andresearch in this field. The other is to conduct clinicalresearch in the fields of psychiatric nursing andadvance knowledge and theory through research.
All activities of our department are conducted incollaboration with staff members in the Department of
Mental Health.

Education
Our department is responsible for giving lectureson psychiatric nursing to undergraduate students.
Other than lectures, our department provides students
opportunities to practice psychiatric nursing activities
in several relevant facilities.
Our department is also obliged to educate
graduate students in master and doctor programs in
psychiatric nursing. To accomplish this objective, ourdepartment has a specialized lecture course on
psychiatric nursing, and seminars on mental healthand psychiatric nursing for graduate students. These
activities are conducted and supervised by the faculty.
In collaboration with the department of mental health,
we also have the department seminar every
Wednesday evening, where members provide theactual plans for their own research and discuss the
topic.
We also have a variety of study clubs. We havepsychiatric nursing study club, study group for
multi-level analysis, qualitative research study group,and so on.

326

Research

Publications

Our research field covers mental health andpsychiatric nursing. Our department has many
research projects across diverse fields as follows:
study of self-management in mental health; recovery
in people with mental health difficulties; community
support system for the people with mental healthneeds; peer support; stigma; social inclusion; mental
health in people with substance use disorder orphysical diseases; mental health in nurses or otherworkers; disaster mental health nursing; traumainformed care, and reducing the use of seclusion andrestraint. We are conducting studies in collaboration
with researchers in other institutions and universities.
One of our research topics is "recovery," aconcept that has proximity and overlap with quality oflife among people who have experienced mental
health difficulties. Recovery is a dynamic concept that
includes restoring life, which means developing theindividuals' aspirations for their life and getting backthe life they want to live. In Japan, mental health careis changing and will increasingly need to emphasize
the quality of life and recovery of those who haveexperienced mental health difficulties.
Some examples of our research work on recovery
include (1) Accumulating the narratives of people whohave experienced mental illness. (2) Developing
patient-reported outcome measures that people withmental disorders feel are relevant to their lives. (3)Developing practices that enhance the well-being ofpeople with and without mental disorders. We are also
involved in a range of other projects.
It is necessary to pursue research involving
people who have experience of mental healthdifficulties. We are co-producing research with people
who have experienced mental health difficulties(patient and public involvement in designing andconducting research). There is a need to share thepremise that any person's thoughts and opinions areimportant and valuable. We aim to improve mental
health and medical welfare and to contribute to therealization of a society in which individuals feel thatthey are respected as they are.

1.

2.

3.

4.

5.

6.

Iiyama S, Izutsu T, Miyamoto Y, Benavidez JRM,
Tsutsumi A. Effectiveness of Psychological FirstAid e-Orientation among the General Populationin Muntinlupa, the Philippines. International
Journal of Environmental Research and Public
Health. 2023;20(2):983. doi:10.3390/ijerph20020983
Yamaguchi S, Abe M,Kawaguchi T, Igarashi M,
Shiozawa T, Ogawa M, Yasuma N, Sato S,
Miyamoto Y,Fujii C. Multiple stakeholders’perspectives on patient and public involvement incommunity mental health services research: aqualitative analysis. HealthExpect. 2022; 25:
1844- 1860. doi:10.1111/hex.13529
Chiba R, Funakoshi A,Miyamoto Y. The
Preliminary Efficacy of a Program to Facilitate
Benefit Findingfor People with Mental Illness: A
Pilot
Randomized
Controlled
TrialinJapan.Healthcare. 2022; 10(8):1491. PMID:
36011148. doi:10.3390/healthcare10081491
Hazumi M, Okazaki E, Usuda K, Kataoka M,
Nishi D. Relationship between attitudes toward
COVID-19 infection, depression and anxiety: across-sectional survey in Japan. BMC Psychiatry.
2022;22(1):798. Published 2022 Dec 19. doi:
10.1186/s12888-022-04474-1
Mascayano F, van der Ven E, Moro MF, Schilling
S, Alarcón S, Barathie JA, Alnasser L, Asaoka H,
Ayinde O, Balalian AA, Basagoitia A, Brittain K,
Dohrenwend B, Durand–Arias S, Eskin M,
Fernández–Jiménez E, Freytes M, Giménez L,
Gisle L, Hoek HW, Jaldo R, Lindert J,
Maldonado H, Martínez -Alés G, Martínez-Viciana C, Mediavilla R, McCormack C, Myer L,
Narvaez J, Nishi D, Ouali U, Puac-Polanco V,
Ramírez J, Restrepo-Henao A, Rivera -Segarra E,
Rodríguez AM, Saab D, Seblova D, Tenorio A,
Valeri L, Alvarado R, Susser E, On behalf of the
HEROES group. The impact of the COVID-19
pandemic on the mental health of healthcare
workers: study protocol for the COVID-19
HEalth caRe wOrkErS (HEROES) study. Social
Psychiatry and Psychiatric Epidemiology. 2022
Mar;57(3):633-645.
Harris MG, Kazdin AE, Munthali RJ, Vigo DV,
Hwang I, Sampson NA, Al-Hamzawi A, Alonso J,

327

Andrade LH, Borges G, Bunting B, Florescu S,
Gureje O, Karam EG, Lee S, Navarro-Mateu F,
Nishi D, Rapsey C, Scott KM, Stagnaro JC,
Viana MC, Wojtyniak B, Xavier M, Kessler RC.
Perceived helpfulness of service sectors used formental and substance use disorders: Findings
from the WHO World Mental Health Surveys. Int
J Ment Health Syst. 29;16(1), 2022
7. Shiba K, Daoud A, Kino S, Nishi D, Kondo K,
Kawachi I. Uncovering heterogeneous associationsof disaster-related traumatic experiences withsubsequent mental health problems: A machinelearning approach. Psychiatry Clin Neurosci.
2022 Apr;76(4):97-105.
8. Kazdin, A. E., Wu, C.-S., Hwang, I.,
Puac-Polanco, V., Sampson, N. A., Al-Hamzawi,
A., Alonso, J., Andrade, L. H., Benjet, C.,
Caldas-de-Almeida, J.-M., de Girolamo, G., deJonge, P., Florescu, S., Gureje, O., Haro, J. M.,
Harris, M. G., Karam, E. G., Karam, G.,
Kovess-Masfety, V., Lee, S., McGrath, J. J.,
Navarro-Mateu, F., Nishi, D., Oladeji, B. D.,
Posada-Villa, J., Stein, D. J., Üstün, T. B., Vigo,
D. V., Zarkov, Z., Zaslavsky, A. M., Kessler, R.
C., and the WHO World Mental Health Survey
collaborators. (2021). “Antidepressant use inlow- middle- and high-income countries: a World
Mental Health Surveys report.” Psychological
Medicine [Epub ahead of print]
9. Tsuno K, Okawa S, Matsushima M, Nishi D,
Arakawa Y, Tabuchi T. The effect of social
restrictions, loss of social support, and loss ofmaternal autonomy on postpartum depression in
1 to 12-months postpartum women during the
COVID-19 pandemic. J Affect Disord. 2022 Jun
15;307:206-214. doi: 10.1016/j.jad.2022.03.056.
10. Kessler, R. C., Kazdin, A. E., Aguilar-Gaxiola, S.,
Al-Hamzawi, A., Alonso, J., Altwaijri, Y. A.,
Andrade, L. H., Benjet, C., Bharat, C., Borges, G.,
Bruffaerts, R., Bunting, B., Caldas de Almeida, J.
M., Cardoso, G., Chiu, W. T., Cía, A., Ciutan, M.,
Degenhardt, L., de Girolamo, G., de Jonge, P., deVries, Y. A., Florescu, S., Gureje, O., Haro, J. M.,
Harris, M. G., Hu, C., Karam, A. N., Karam, E.
G., Karam, G., Kawakami, N., Kiejna, A.,
Kovess-Masfety, V., Lee, S., Makanjuola, V.,
McGrath, J. J., Medina-Mora, M. E.,

11.

12.

13.

14.

15.

Moskalewicz, J., Navarro-Mateu, F., Nierenberg,
A. A., Nishi, D., Ojagbemi, A., Oladeji, B. D.,O’Neill, S., Posada-Villa, J., Puac-Polanco, V.,
Rapsey, C., Ruscio, A. M., Sampson, N. A., Scott,K. M., Slade, T., Stagnaro, J. C., Stein, D. J.,
Tachimori, H., ten Have, M., Torres, Y., Viana, M.
C., Vigo, D. V., Williams, D. R., Wojtyniak, B.,
Xavier, M., Zarkov, Z., Ziobrowski, H. N., and
the WHO WMH survey collaborators. (In Press).
Patterns and correlates of patient-reported
helpfulness of treatment for common mental andsubstance use disorders in the WHO World
Mental Health Surveys.World Psychiatry. 2022
Jun;21(2):272-286.
Nishi D. Desire for Shorter Life Expectancy
From a Mental Health Perspective. J Epidemiol.
2022 Sep 30. doi: 10.2188/jea.JE20220197. Epubahead of print. PMID: 36184557.
Nishi D, Imamura K, Watanabe K, Obikane E,
Sasaki N, Yasuma N, Sekiya Y, Matsuyama Y,
Kawakami N. The preventive effect ofinternet-based cognitive behavioral therapy forprevention of depression during pregnancy and in
the postpartum period (iPDP): a large scalerandomized controlled trial. Psychiatry Clin
Neurosci. 2022 Nov;76(11):570-578. doi:
10.1111/pcn.13458. Epub 2022 Sep16. PMID:
36114656.
Hazumi M, Usuda K, Okazaki E, Kataoka M,
Nishi D. Differences in the Course of Depression
and Anxiety after COVID-19 Infection between
Recovered Patients with and without a
Psychiatric History: A Cross-Sectional Study. Int
J Environ Res Public Health. 2022 Sep 8;19(18):11316. doi: 10.3390/ijerph191811316.
PMID: 36141588; PMCID: PMC9517442.
Obikane E, Watanabe K, Nishi D, Kawakami N.
Adverse childhood experiences and personalvalues in adolescence: a cross-sectional study
using community adult samples in Japan. Pediatr
Int. 2022 Sep 27:e15370. doi: 10.1111/ped.15370.
Epub ahead of print. PMID: 36165851.
Sasaki N, Inoue A, Asaoka H, Sekiya Y, Nishi D,
Tsutsumi A, Imamura K. The Survey Measure of
Psychological Safety and Its Association with
Mental Health and Job Performance: A Validation
Study and Cross-Sectional Analysis. Int J

328

16.

17.

18.

19.

Environ Res Public Health. 2022 Aug 11;19(16):9879. doi: 10.3390/ijerph19169879. PMID:
36011522; PMCID: PMC9407795.
Carrozzino D, Christensen KS, Patierno C,Woźniewicz A, Møller SB, Arendt ITP, Zhang Y,
Yuan Y, Sasaki N, Nishi D, Berrocal Montiel C,
Ceccatelli S, Mansueto G, Cosci F. Cross-culturalvalidity of the WHO-5 Well-Being Index andEuthymia Scale: A clinimetric analysis. J Affect
Disord. 2022 Aug 15;311:276-283. doi: 10.1016/
j.jad.2022.05.111. Epub 2022 May 21. PMID:
35609763.
Sarris J, Ravindran A, Yatham LN, Marx W,
Rucklidge JJ, McIntyre RS, Akhondzadeh S,
Benedetti F, Caneo C, Cramer H, Cribb L, deManincor M, Dean O, Deslandes AC, Freeman
MP, Gangadhar B, Harvey BH, Kasper S, Lake J,
Lopresti A, Lu L, Metri NJ, Mischoulon D, Ng
CH, Nishi D, Rahimi R, Seedat S, Sinclair J, Su
KP, Zhang ZJ, Berk M. Clinician guidelines forthe treatment of psychiatric disorders withnutraceuticals and phytoceuticals: The World
Federation of Societies of Biological Psychiatry(WFSBP) and Canadian Network for Mood andAnxiety Treatments (CANMAT) Taskforce.
World J Biol Psychiatry. 2022 Jul;23(6):424-455.
doi: 10.1080/15622975.2021.2013041. Epub
2022 Mar 21. PMID: 35311615.
Bruffaerts R, Harris MG, Kazdin AE, Vigo DV,
Sampson NA, Chiu WT, Al-Hamzawi A, Alonso J,
Altwaijri YA, Andrade L, Benjet C, de Girolamo
G, Florescu S, Haro JM, Hu CY, Karam A,
Karam EG, Kovess-Masfety V, Lee S, McGrathJJ, Navarro-Mateu F, Nishi D, O’Neill S,
Posada-Villa J, Scott KM, Have MT, Torres Y,
Wojtyniak B, Xavier M, Zarkov Z, Kessler RC;
WHO World Mental Health Survey Collaborators.
Perceived helpfulness of treatment for social
anxiety disorder: findings from the WHO World
Mental Health Surveys. Soc Psychiatry Psychiatr
Epidemiol. 2022 Oct;57(10):2079-2095. doi:
10.1007/s00127-022-02249-3. Epub 2022 Mar 9.
PMID: 35262761; PMCID: PMC9458773.
Kataoka M, Kotake R, Asaoka H, Miyamoto Y,
Nishi D. Reliability and Validity of the Japanese
Versionof
the
Attitudes
RelatedtoTrauma-Informed Care (ARTIC-10) Scale. J

20.

21.

22.

23.

24.

25.

Trauma Nurs. 2022 Nov-Dec 01;29(6):312-318.
doi: 10.1097/JTN.0000000000000684. PMID:
36350170; PMCID: PMC9653105.
Asaoka H, Koido Y, Kawashima Y, Ikeda M,
Miyamoto Y, Nishi D. Association between
clinical decision for patients with COVID-19 andpost-traumatic stress symptoms among healthcare
professionals during the COVID-19 andemic.
Environmental and Occupational Health Practice.
in press. doi:10.1539/eohp.2022-0018-OA
Asaoka H, Sasaki N, Imamura K, Kuroda R,
Tsuno K, Kawakami N. Effects of workplacemeasures against COVID-19 on psychologicaldistress of full-time employees: A 12-monthprospective study in the COVID-19 pandemic.
Scand J Work Environ Health. 2022 May 16:4030.
doi: 10.5271/sjweh.4030.
Nozawa K, Ishii A, Asaoka H, Iwanaga M,
Kumakura Y, Oyabu Y, Shinozaki T, Imamura K,
Kawakami N, Miyamoto Y. Effectiveness of an
Online Peer Gatekeeper Training Program for
Postsecondary Students on Suicide Prevention in
Japan: Protocol for a Randomized Controlled
Trial. JMIR Res Protoc. 2022 Apr 26;11(4):e34832. doi: 10.2196/34832.
Iida M, Sasaki N, Imamura K, Kuroda R, Tsuno
K, Kawakami N. COVID-19-Related Workplace
Bullying and Customer Harassment Among
Healthcare Workers Over the Time of the
COVID-19 Outbreak: A Eight-Month Panel
Study of Full-Time Employees in Japan. J Occup
Environ Med. 2022 May 1;64(5):e300-e305. doi:
10.1097/JOM.0000000000002511. Epub 2022
Feb 9. PMID: 35143454.
Yasuma N, Shiozawa T, Ogawa M, Abe M,
Igarashi M, Kawaguchi T, Sato S, Nishi D,
Kawakami N, Yamaguchi S, Fujii C. Whatoutcomes in community mental health research
are important to caregivers of people withschizophrenia? An exploratory qualitative analysisof an online survey. Neuropsychopharmacol Rep.
2022 Oct 10. doi: 10.1002/npr2.12295. Epubahead of print. PMID: 36217559.
Takano A, Miyamoto Y, Shinozaki T, Matsumoto
T, Kawakami N. Effects of a web-based relapse
prevention program on abstinence: Secondary
subgroup analysis of a pilot randomized

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26.

27.

28.

29.

30.

controlled trial. Neuropsychopharmacol Rep.
2022 Sep;42(3):362-367. doi: 10.1002/npr2.
12272. Epub 2022 Jun 11. PMID: 35689457;
PMCID: PMC9515705.
de Vries YA, Al-Hamzawi A, Alonso J, Andrade
LH, Benjet C, Bruffaerts R, Bunting B, deGirolamo G, Florescu S, Gureje O, Haro JM,
Karam A, Karam EG, Kawakami N, KovessMasfety V, Lee S, Mneimneh Z, Navarro-Mateu F,
Ojagbemi A, Posada-Villa J, Scott K, Stagnaro
JC, Torres Y, Xavier M, Zarkov ZN, Kessler RC,
de Jonge P; WHO World Mental Health Survey
collaborators. Transdiagnostic development ofinternalizing psychopathology throughout the life
course up to age 45: a World Mental Health
Surveys report. Psychol Med. 2022 Aug;52(11):2134-2143. doi: 10.1017/S0033291720004031.
Epub 2020 Nov 10. PMID: 33168122; PMCID:
PMC9367642.
Tsuji R, Nishi D, Sasaki N, Akiyama H, Kuroda
R, Tsuno K, Imamura K, Kawakami N.
Association between meal frequency with others
and psychological distress during the COVID-19
pandemic: A cross-sectional study. Psychiatry
and Clinical Neurosciences Reports. 2022;1(4):e61.
Obikane E(*), Sasaki N(*), Imamura K, Nozawa
K, Vedanthan R, Cuijpers P, Shimazu T, Kamada
M, Kawakami N, Nishi D. Usefulness of
Implementation Outcome Scales for Digital
Mental Health (iOSDMH): Experiences from Six
Randomized Controlled Trials. International
Journal of Environmental Research and Public
Health. 2022; 19(23) doi: https://doi.org/10.3390/
ijerph192315792.
(*) These authors contributed equally to thiswork.
Sasaki N, Ikeda M, Nishi D. Long-term influenceof unintended pregnancy on psychologicaldistress: a large sample retrospective crosssectional study. Archives of women’s mental
health. 2022:1-9. doi: 10.1007/s00737-02201273-1
Sasaki N, Imamura K, Watanabe K, Hidaka Y,
Ando E, Eguchi H, Inoue A, Tsuno K, Komase Y,
Iida M, Otsuka Y, Sakuraya A, Asai Y, Iwanaga
M, Kobayashi Y, Inoue R, Shimazu A, Tsutsumi

31.

32.

33.

34.

A, Kawakami N. The impact of workplace
psychosocial factors on menstrual disorders andinfertility: a protocol for a systematic review andmeta-analysis. Systematic reviews. 2022;11(1):195.
Sasaki N, Tabuchi T, Okubo R, Ishimaru T,
Kataoka M, Nishi D. Temporary employment andsuicidal ideation in COVID-19 pandemic in
Japan: A cross-sectional nationwide survey.
Journal of occupational health. 2022;64(1):e12319.
Hidaka Y, Kawakami N, Watanabe K, and Nishi
D. 2022. The association between premenstrual
syndrome before pregnancy and antenatal
depression: A cross‐sectional study withpre-recorded information. Psychiatry and Clinical
Neurosciences Reports, 1(3), p.e27.
Imamura K, Sasaki N, Sekiya Y, Watanabe K,
Sakuraya A, Matsuyama Y, Nishi D, Kawakami
N. The Effect of the Imacoco Care Psychoeducation Website on Improving PsychologicalDistress Among Workers During the COVID-19
Pandemic: Randomized Controlled Trial.JMIR
Form Res. 2022 Mar 10;6(3):e33883. doi:
10.2196/33883. PMID: 35133972.
Iida M, Watanabe K, Yeo SA, Yasuma N, Nishi D.
& Kawakami N. Association of Personal Values
in Adolescence with Subjective Health Status,
Meaning in Life, and Life Satisfaction in
Adulthood: A Cross‐sectional Study with
Retrospective Recall. Japanese PsychologicalResearch.2022. doi: 10.1111/jpr.12444

330

Department ofGerontological Nursing /Wound Care Management
Professor
Gojiro Nakagami, Ph.D., R.N.

Assistant Professor
Mari Abe, Ph.D., R.N., Toshiaki Takahashi, Ph.D., R.N., Yuko Mugita, Ph.D., R.N.

Homepage

http://www.rounenkango.m.u-tokyo.ac.jp/index-e.html

Introduction and Organization
The Department of Gerontological Nursing wasestablished in June 2003, followed by theestablishment of the Department of Wound CareManagement in April 2006. We have been promoting
the education of undergraduate and graduate students,
clinical activities in hospitals relating to pressure
injuries and diabetic foot, and research activities on
the topics of gerontological nursing, wound caremanagement, and nursing science and engineering.
Our
department
has
establishedseveraldepartments: Department of Life Support Technology(Molten), Department of Advanced Skin Care (MissParis), Department of Advanced Nursing Technology,
Department of Skincare Science, and Department of
Imaging Nursing Science. We have been promoting
collaborative research among government, industry
and academia, as well as integrating multiple
disciplines across campus.
In April 2017, the Global Nursing Research Center(GNRC) was established with the aim to create atransdisciplinary research and educational environment that fosters young researchers in nursing sciencein order to promote care innovation. Professor Sanada,
former head of the department, served as the first
director of the center until March 2022, and faculty
staff members in our department have been involvedin the Division of Care Innovation in GNRC as aconcurrent position.
The former head of the department, Professor
Hiromi Sanada (currently Professor Emerita of the
University of Tokyo) retired in March 2022, andProfessor Gojiro Nakagami took over as the new headof this department in April 2022. GerontologicalNursing and Wound Care Management is currently
headed by one professor and assisted by threeassistant professors, a project academic specialist, anassistant clerk, seven part-time lecturers forundergraduate courses, and seven part-time lecturers
for graduate courses. The student body consists of fivedoctoral course students and five master’s course
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.”

Teaching activities
1. Undergraduate course
For undergraduate education, our department takes
part in lectures of Health Support Practice, Overview
of Clinical Medicine, and Observation of Human
Anatomy, as well as lectures, exercises, and clinicalpractice about gerontological nursing and nursing
science and engineering.
1) Health Support Practicum (W in 2nd yr; 1
credit)331

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 2022, we
conducted an onsite and online practicum and theprogram included themes related to:a) Policy creation for solving problems confronted innursingb) Health support servicec) Nursing-based hospital managementd) Development of medical devices for supporting
patients’ lives.
2) Overview of Clinical Medicine (S1 in 3rd yr; 2credits)
The aim of this series of lectures is to learn the basic
knowledge and thought processes for understanding
clinical medicine, and to learn the pharmaceutics
required for nursing practice. The main content
themes in the 2022 session included:a) Introduction to surgical treatmentb) Introduction to radiologyc) Surgical anesthesiad) Perioperative managemente) Clinical conditionsf) Natural history and treatment of diseasesg) Nursing pharmaceutics
The above lectures were provided through cooperationfrom the departments at The University of Tokyo
Hospital.
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 2022 curriculum included:a) Introduction to anatomical pathologyb) Case studiesc) Introduction to anatomicopathological researchd) Anatomy using ultrasound equipmente) Visit to specimen room4) Gerontological Nursing (A2 in 3rd yr; 2 credits)
A series of lectures with the aim of understanding thephysical, psychological, and social characteristics ofthe elderly population; to learn fundamental theories
of gerontological nursing; and to promote anunderstanding of the ailments and conditions required
to provide proper care to the elderly. The main themes
covered in the 2022 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,
walking disability, pressure injury, incontinence)d) Age-related changes in the physiological systeme) Aging and dementiaf) Aging and osteoporosisg) Aging and renal function, hypertension, and strokeh) Aging and cardiovascular disordersi) Aging and respiratory disordersj) Pharmacological management of the elderlyk) Use of ultrasonography in nursingl) Nutritional management for the elderlym) Relationship-building and communication skills
with the elderly
A portion of the above lectures was provided throughcooperation from the Department of GeriatricMedicine and other departments at The University ofTokyo Hospital.
5) Clinical Practicum in Gerontological Nursing(A1 in 4th yr; 2 credits)
The aim of this practicum is to gain the holistic
understanding of the elderly, learn the perspective androle functions of nursing for the elderly, and be able tothink about the issues and future of gerontologicalnursing. In 2022, the practice was conducted online
and consisted mainly of online interviews andactivities with senior volunteers, case scenario
exercises, lectures on multidisciplinary cooperation ineach geriatric care setting (hospital, geriatric healthcare facility, and home), remote observation of actual
geriatric nursing care, practice ultrasound techniquesthat can be utilized in geriatric nursing, and gathering
information and experience with the latest equipment
and systems in nursing, caregiving, and healthcare.

332

2. Graduate course
1) Gerontological Nursing I (S1; 2 credits)
The main theme of Gerontological Nursing I in 2022
was to understand the latest research related to thecare of elderly persons and to discuss future perspectives in gerontological nursing from three viewpoints:
basic biology, engineering, and clinical nursing
research. Recent research papers were selected fromthese three fields and critically evaluated.
2) Gerontological Nursing II (A1; 2 credits)
Gerontological Nursing II provided lectures regarding
recent topics around gerontological medicine andnursing from broad viewpoints, including biological,
individual, and social aspects, by part-time lecturers
and specialists from each research field. The aim of
this course was to understand and learn scientificways of thinking about gerontological considerationsof the future Japanese community. The main titles in
2022 were as follows:a) Prevention of catheter failure using echob) Nursing care innovationc) Biological nursing: skin blottingd) Nursing science and engineering for innovation ofcare in the super-aging societye) Care of cancer patients undergoing chemotherapy:
Appearance care from the perspective of skin caref) Clinical issues and research findings in thecommunity as a dermatology practitionerg) Clinical issues from a plastic surgery perspectivewith a focus on visiting physicians, and the latest
wound care methods
3) Wound Care Management I (S2; 2 credits)
The main purpose of Wound Care Management I in
2022 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) Prediction and prevention of woundsb) Assessment of woundsc) Treatment and care of woundsd) Institutions and policies related to wound care andmanagement

4) Wound Care Management II (A2; 2 credits)
Wound management includes the prediction andprevention of wound development, wound assessment,
treatment, and care (including excretory care),requiring a wide range of knowledge from nurses
engaged in wound management. Therefore, researchin wound care nursing requires a multidisciplinary
approach that integrates different fields of nursing
science and engineering. In this special lecture,
students will learn the latest knowledge necessary forwound management, including basic research andpractice, and will acquire scientific thinking ability
and skills in wound nursing through discussions andexercises. Lectures, exercises, and discussions were
held on (1) wound and skin assessment using
equipment, and (2) pressure management and pressure
injury prevention utilizing robotics technology.
5) Master’s theses
The following research themes were submitted in2022:
 “Development of e-learning and pelvic floor muscle
contraction automatic evaluation algorithm forpelvic floor muscle training biofeedback using
self-performed ultrasound”
 “Development of a skin temperature estimation
system for a prediction method of pressure injury
occurrence based on continuous body sensor data”
 “Development and evaluation of a rapid skin taurine
measurement device using skin blotting for the early
detection of dehydration”
6) Doctoral theses
The following research themes were submitted in2022:
 “The effectiveness of local low-frequency vibration
on wound healing of full-thickness wounds in a
hyperglycemic rat model”
 “Predictive factors and characteristics of infusionsite induration and subcutaneous edema among of
the patients under outpatient chemotherapy” (inJapanese) “Identification of itch-prone skin in dry skin-derived
pruritus by detection of NGF/SEMA3A ratio”(inJapanese)

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Research activities
1. Activity policy
Our gerontological nursing research focuses on those
suffering from geriatric syndromes, such as pressure
injuries, incontinence, malnutrition, pain, dysphagia
and dementia. Our wound care management research
focuses on pressure injuries, diabetic foot ulcers, andskin tears.
The majority of our clinical research has been
conducted at The University of Tokyo Hospital. We
regularly participate in pressure injury multidisciplinary team rounds.
Regarding international activities, our department
has been promoting collaborative research withresearchers in universities around the world. Our
counterparts include Curtin University (Australia)
UniversityofNottingham,
andUniversitas
Muhammadiyah Pontianak in 2022.
2. Research fields and themes in 2022
1) Basic experimental studies:
・Evaluation of wound condition using exudates
・Skin blotting for analyzing dehydration
・Cutaneous wound healing and diabetes mellitus
・Investigation of the effect of cellular senescence onwound healing
・Development of a novel method for controllingwound infection focusing on gene expression ofbacteria and hosts
2) Nursing engineering:・Sensing of the treatment environment anddevelopment of AI-based prediction models
・ Non-invasive detection of tissue injury andpre-injury status using ultrasonography and thermography
・Development of apps using communication robots
for the elderly
・Development of an absorbent pad for the preventionof incontinence-associated dermatitis
・Development of an educational system for new
visiting nurses using XR technology
3) Clinical studies:
・Novel assessment technologies for pressure injuries
・Establishment of an automated pelvic floor muscle
contraction evaluation method using ultrasonography
・Establishment of a novel assessment method forconstipation using ultrasonography
・Implementation of ultrasonography-based peripheral
venous catheter placement techniques・Survey of the skin condition of wheelchair basketballathletes・Survey on the relationship between the microbiota inthe bed environment and the development ofpressure injury infections
・Survey of the effectiveness of biofilm removal on
wound healing
・ Evaluation of the effectiveness of nurses whocompleted advanced nursing procedure training
・Development of a tele-nursing system and clinicalevaluation of its effectiveness
Several awards were given for our research in 2022, as
follows:
Presentations
・ The 52nd Japanese Society for Wound Healing
Research Encouragement Award (November 2022).
Haba D, Qin Q, Minematsu T, Sanada H, Nakagami
G. Verification of the effect of local low-frequency
vibration stimulation on glucose metabolism andvasodilatation/neogenesis to promote healing offull-thickness wound in diabetic rats. (in Japanese)・ The Japanese Society of Physical Therapy 6th
Symposium of Young Researchers Network Data
Analysis Award (July 2022). Haba D, Qin Q,
Nakagami G. New treatment strategy for diabetic
foot ulcer based on promotion of glucose
metabolism by local low-frequency vibration. (inJapanese)
・31st Annual Meeting of the Japanese Society for
Wound, Ostomy and Incontinence Management,
Best Presentation Award, English Session (June2022). Haba D, Nakagami G, Qin Q, Minematsu T,
Sanada H. Local low-frequency vibration promotes
wound healing of a full-thickness wound in the
diabetic rat.
Papers・42nd Japan Academy of Nursing Science Academic
Paper Award for Excellence (December 2022).
Abe-Doi M, Murayama R, Kawamoto A,
Komiyama C, Doorenbos A, Sanada H. Damage tosubcutaneous tissue at the catheterization site
during chemotherapy: A prospective observational

334

study using ultrasonography. Japan Journal of
Nursing Science. 2021;e12436.
・The 10th Society of Nursing Science and Technology
Conference Award (October 2022). Higashimura S,
Tamai N, Nakagami G, Tobe H, Sanada H. A pilot
epidemiological study on chronic dehydration ofolder adults in a home care setting. Journal of
Nursing Science and Engineering. 2022;9:123-135.
・ The 10th Society of Nursing Science andEngineering Incentive Award (October 2022).
Matsumoto M, Ishibashi K, Kitamura A, Tamai N,
Miura Y, Takahashi T, Higashimura S, Nakagami G,
Sanada H. An AI-based evaluation method of fecal
retention for rectal echocardiographic videos taken
by home care nurses. Journal of the Society of
Nursing Science and Technology. Journal of
Nursing Science and Engineering. 2021;9:34-46.
(in Japanese)
・The 10th Society of Nursing Science and Technology
Incentive Award (October 2022). Koudounas S,
Minematsu T, Mugita Y, Tomida S, Nakai A,
Nakagami G, Sanada H. Inhibiting effect ofsynthetic urine on the growth and mobility of
Pseudomonas aeruginosa, Escherichia coli, Proteus
mirabilis and Klebsiella pneumoniae shifts to apromoting effect during culture. Journal of Nursing
Science and Engineering. 2021;8:220-229.
・ Ohura Award of the Japanese Decubitus Ulcer
Society (August 2022). Takizawa C, Kitamura A,
Nakagami G, Matsumoto M, Hayashi C, Kawasaki
A, Sanada H. The relationship between thetemperature distribution detected by thermography
and suspected deep tissue injuries. Japanese Journalof Pressure Ulcers. 2022;24(1):14-28.
・ Ohura Award of the Japanese Decubitus Ulcer
Society (August 2022). Nakagami G, Yokota S,
Kitamura A, Takahashi T, Morita K, Noguchi H,
Ohe K, Sanada H. Supervised machine learningbased prediction for in-hospital pressure injury
development using electronic health records: A
retrospective observational cohort study in auniversity hospital in Japan. International Journal of
Nursing Studies. 2021;119:103932.

References
Original Papers
1. Higashimura S, Tamai N, Nakagami G, Tobe H,
Sanada H. A pilot epidemiological study on
chronic dehydration of older adults in home caresetting. Journal of Nursing Science andEngineering. 2022;9:123-135.
2. Matsumoto M, Misawa N, Tsuda M, Manabe N,
Kessoku T, Tamai N, Kawamoto A, Sugama J,
Tanaka AH, Haruma K, Sanada H, Nakajima A.
Expert consensus document: diagnosis forchronic constipation with faecal retention in therectum using ultrasonography. Diagnostics. 2022;12(2):300.
3. Takahashi T, Nakagami G, Murayama R,
Abe-Doi M, Matsumoto M, Sanada H. Automaticvein measurement by ultrasonography to prevent
peripheral intravenous catheter failure for clinicalpractice using artificial intelligence: development
and evaluation study of an automatic detection
method based on deep learning. BMJ open. 2022;
12(e051466).
4. Higashimura S, Nakagami G, Sanada H.
Effectiveness of new pelvic floor exercises on
urinary incontinence in older women withcognitive impairment: A pilot study at long-termcare facilities. Journal of Society of Nursing
Practice. 2022;34(1):26-39.
5. Nitta S, Maeda T, Koudounas S, Minematsu T,
Weller C, Sanada H. Which objective itchassessment tools are applicable to patients withcognitive impairments? A scoping review.
International Journal of Older People Nursing.
2022:e12458.
6. Tanabe H, Oosawa K, Miura M, Mizuno S,
Yokota T, Ueda T, Zushi Y, Nagata M, Murayama
R, Abe-Doi M, Sanada H. Effect of a thin-tippedshort bevel needle for peripheral intravenous
access on the compressive deformation anddisplacement of the vein: a preclinical study.
Journalof
Vascular
Access.
2022:
11297298221075169.
7. Shintani Y, Murayama R, Abe-Doi M, Sanada H.
Incidence, causes, and timing of peripheral
intravenous catheter failure related to insertion
timing in the treatment cycle in patients with

335

8.

9.

10.

11.

12.

13.

14.

hematological malignancies: a prospective
descriptive study. Japan Journal of Nursing
Science. 2022:e12484.
Sugama J, Ishibasi M, Ota E, Kamakura Y, Saitoh
E, Sanada H, Nakayama T, Nomura T, Yamada M,
Nakagami G, Sato N, Shibata S, Hase T, Fukada J,
Miki T, Arita M, Urai T, Okawa Y, Kitamura A,
Dai M, Takahashi T, Tamai N, Tobita I, Noguchi
H, Matsumoto M, Miura Y, Mukai K, Mugita Y,
Yoshida M, Kurachi M, Shirasaka T, Yamane Y.
Japanese clinical practice guidelines for
aspiration and pharyngeal residual assessment
during eating and swallowing for nursing care.
Japan Journal of Nursing Science. 2022:e12496.
Murayama R, Oyama H, Abe-Doi M, Masamoto
Y, Kashiwabara K, Tobe H, Komiyama C, Sanada
H, Kurokawa M. Safety verification of a new
peripheral intravenous catheter placed in theupper arm vein for administration of drugs withhigh irritant potential. Drug Discoveries &Therapeutics. 2022;16(3):128-134.
Minematsu T, Tomida S, Tobe H, Koudaunas S,
Nakagami G, Sanada H. Evaluation of liquid-lessbiofilm staining on wound blotting samples.
Journal of Nursing Science and Engineering.
2022;9:222-228.
Shimura T, Nakagami G, Ogawa R, Ono S,
Takahashi T, Nagata M, Kashiwabara K, Sugama
J, Sanada H, Oe M. Incidence of and risk factors
for self-load-related and medical device-relatedpressure injuries in critically ill patients: aprospective observational cohort study. Wound
Repair and Regeneration. 2022;30(4):453-467.
Takizawa C, Kitamura A, Nakagami G,
Matsumoto M, Hayashi C, Kawasaki A, Sanada
H. The relationship between the temperature
distribution detected by thermography andsuspected deep tissue injuries. Japanese Journalof Pressure Ulcers. 2022;24(1):14-28.
Qin Q, Nakagami G, Ohashi Y, Dai M, Sanada H,
Oe M. Development of a self-monitoring tool for
diabetic foot prevention using smartphone-based
thermography: Plantar thermal pattern changes
and usability in the home environment. Drugdiscoveries & therapeutics. 2022;16(4):169-176.
Oe M, Fukuda M, Ohashi Y, Shimojima Y,
Tsuruoka K, Qin Q, Yamauchi T, Sanada H.

15.

16.

17.

18.

Evaluation of foot ulcer incidence in diabetic
patients at a diabetic foot ulcer prevention clinic
over a 10-year period. Wound repair andregeneration. 2022;30(5):546–552.
Astrada A, Nakagami G, Fajrianita I, Matsumoto
M, Kawamoto A, Jais S, Sanada H.
Ultrasonographic features of diabetic footosteomyelitis: a case series. Journal of Wound
Care. 2022;31(9):748-754.
Tsuruoka K, Oe M, Minematsu T, Tomida S,
Ohashi Y, Shimojima Y, Qin Q, Abe M,
Yamauchi T, Sanada H. Association between
elevated skin temperature of the foot callus andinflammatory marker in people with diabetes.
Journal of Japanese Society of Wound, Ostomy
and Continence Management. 2022;23(3):261268.
Iwahira Y, Nakagami G, Sanada H. Risk factors
forcapsularcontracture
after
breastreconstruction with tissue expanders and silicone
implantsinnonirradiatedpatients:
A
retrospective
observational
cohortstudy.
Medicine (Baltimore). 2022;101(48):e31837.
Fact-finding Committee of the Japanese Societyof Pressure Ulcers; Konya C, Takeuchi Y,
Nakagami G, Kitamura A, Morita K, Ishizawa M,
Abe Y, Higuchi H, Mizuki T, Motegi S, Shoju S,
Shimada K, Tanaka K, Kawakami S, Sanada H.
Nationwide time-series surveys of pressure ulcer
prevalence in Japan. Journal of Wound Care.
2022;31(Sup12): S40-S47.

International Health
1. International Social Medicine

337

Department of Global Health
PolicyProfessor
Masahiro Hashizume, MD, PhD

Associate Professor
Chris Fook Sheng Ng, PhD

Assistant Professor
Paul Lester Chua, PhD

Project Assistant Professor
Shuhei Nomura, PhD

Homepage http://www.ghp.m.u-tokyo.ac.jp
Introduction and Organization
As of March 2023 the department, headed by Professor
Masahiro Hashizume, included the following staff
complement; one associate professor (Chris Fook
Sheng Ng); one assistant professor (Paul Lester Chua);
one project assistant professors (Shuhei Nomura); 14
post-doctoral fellows; 9 adjunct lecturers; 9 doctoral
students; and 6 master’s students.
The priority areas of research are:
- Health impacts of climate, climate change and air
pollution.
- Health outcome research (mortality, morbidity anddisability; health service research; health technology
assessment and cost-effectiveness; disease modeling; and comparative risk factor analysis);- Health system performance assessment, including
the analysis of health system inputs, outputs, andimpact;- Health and foreign policy (e.g. global healtharchitecture and governance, the G7 and global
health, donor commitments, and innovations in
global health).

Finally, the fundamental role of the department is to
produce the next generations of leaders in global health.

Education
All lectures in the department are conducted in English,
to ensure that student writing and presentation skills areheld to an international standard.
Master's program
The Master's program is a demanding, interdisciplinary
program emphasizing student-directed learning,problem-solving, and the acquisition of fundamental
public health skills required for global health practices(health policy, statistics, epidemiology, and social
sciences). Students are required to complete aminimum of 30 course credits and a master’s thesis.
Beyond the program and concentration requirements,
students are encouraged to consult with faculty
advisers to choose elective courses best suited to theirneeds.
PhD program
The PhD program is designed to train the next
generation of leaders in global health. PhD students are
required to complete a minimum of 24-course credits

338

and a doctoral thesis which needs to be published in apeer-reviewed journal. PhD students without MPH
degrees should take the lectures to acquire fundamental
public health skills such as health policy, biostatistics
and epidemiology.
Global Health Policy I and IIThis course introduces the principles and theories ofglobal health problems, as well as practical applicationsof quantitative methods (demography, statistics,
epidemiology and econometrics) to analyze andinterpret issues and challenges for policy.
The followings are the topics covered in the academic
year 2022:-

Global environmental change and health
Health impact assessments in environmental
healthEvidence synthesis for global health research
Temperature and mortality
Overview of global burden of disease
Innovations in maternal and child health
Planetary health
Equity in health and universal health coverageassessment
Data and epidemiological methods forenvironmental health research
Air pollution and healthComparative risk assessment
Cancer epidemiology and prevention GHP
Infectious disease surveillance system
Projections of climate change-related healthimpacts
Environment and child healthJapan’s Global Health Diplomacy in the era of
COVID-19 and beyond

GHP seminar
Every Tuesday, 13:00-15:00
1) Journal clubStudents present a summary of research articles fromthe major medical, social science, economics journals,
which are relevant to global health policy. The major
objective is to share knowledge, evoke debates andfacilitate discussions.
2) Research seminar

A guest speaker or a master or doctoral student presents
his/her research. There is a 15-minute presentationfollowed by a 30-minute discussion.

Research
Projections of excess mortality due to climate change- a multi-country environmental epidemiology study.
Grant-in-Aid for Scientific Research (B) (Japan
Society for the Promotion of Science) PI: Masahiro
Hashizume
Climate Change and Human Health in Asia: Current
Impacts, Future Risks, and Health Benefits of
Mitigation Policies. E-Asia as part of Strategic
International Collaborative Research Program (Japan
Science and Technology Agency) PI: Masahiro
Hashizume.
Human resource development and the development of
infectious disease epidemiological methods for the
expansion of infectious disease surveillance systems,
including COVID-19. Health and Labour Science
Research (Ministry of Health, Labour and Welfare) PI:
Masahiro Hashizume.
Analysis of climate influences on medical conditions
and diseases. Bilateral Collaborations (South Africa)(Japan Society for the Promotion of Science) Japanese
PI: Masahiro Hashizume.
Use of burden of disease for health care research in thewith/post-COVID-19 era and empirical analysis.
Grant-in-Aid for Scientific Research (B) (Japan
Society for the Promotion of Science) PI: Shuhei
Nomura.

Selected Publications
1.

2.

Vicedo-Cabrera AM, Tobias A, Jaakkola JJK,
Honda Y, Hashizume M, Guo Y, Schwartz J,
Zanobetti A, Bell ML, Armstrong B, Katsouyanni
K, Haines A, Ebi KL, Gasparrini A. Global
mortality burden attributable to non-optimal
temperatures. Lancet. 2022 Mar 19;399(10330):
1113.
Madaniyazi L, Tobias A, Kim Y, Chung Y,
Armstrong B, Hashizume M. Assessing

339

seasonality and the role of its potential drivers inenvironmental epidemiology: a tutorial. Int J
Epidemiol. 2022 Oct 13;51(5):1677-1686.
3. He C, Kim H, Hashizume M, Lee W, Honda Y,
Kim SE, Kinney PL, Schneider A, Zhang Y, Zhu
Y, Zhou L, Chen R, Kan H. The effects of nighttime warming on mortality burden under futureclimate change scenarios: a modelling study.
Lancet Planet Health. 2022 Aug;6(8):e648-e657.
4. Roy A, Alam MA, Kim Y, Hashizume M.
Association between daily ambient temperatureand drug overdose in Tokyo: a time-series study.
Environ Health Prev Med. 2022;27:36.
5. Nsashiyi RS, Rahman MM, Ndam LM,
Hashizume M. Exploiting the Bayesian approachto derive counts of married women of
reproductive age across Cameroon for healthcare
planning, 2000-2030. Sci Rep. 2022 Oct 27;12(1):18075.
6. Nishikawa H, Seposo XT, Madaniyazi L, Kim Y,
Tobías A, Yamagami M, Kim SE, Takami A,
Sugata S, Honda Y, Ueda K, Hashizume M, Ng
CFS. Long-term trends in mortality risk associatedwith short-term exposure to air pollution in 10
Japanese cities between 1977 and 2015. Environ
Res. 2022 Dec 20;219:115108.
7. Pan R, Honda Y, Minakuchi E, Kim SE,
Hashizume M, Kim Y. Ambient temperature andexternal causes of death in Japan from 1979 to
2015: a time-stratified case-crossover analysis.
Environ Health Perspect. 2022 Apr;130(4):47004.
8. Chua PLC, Ng CFS, Madaniyazi L, Seposo X,
Salazar MA, Huber V, Hashizume M. Projecting
temperature-attributable mortality and hospital
admissions due to enteric infections in thePhilippines. Environ Health Perspect. 2022 Feb;
130(2):27011.
9. Chua PLC, Ng CFS, Tobias A, Seposo XT,
Hashizume M. Associations between ambient
temperature and enteric infections by pathogen: asystematic review and meta-analysis. Lancet
Planetary Health. 2022 Mar;6(3):e202-e218.
10. Madaniyazi L, Jung CR, Ng CFS, Seposo X,
Hashizume M, Nakayama SF, Japan Environment
and Children's Study Group. Early life exposure toindoor air pollutants and the risk of neurodevelopmental delays: The Japan environment and

11.

12.

13.

14.

15.

children's study. Environ Int. 2022 Jan;158:
107004.
Madaniyazi L, Armstrong B, Chung Y, Ng CFS,
Seposo X, Kim Y, Tobias A, Guo Y, Sera F, Honda
Y, Gasparrini A, Hashizume M. Multi-country
Multi-city (MCC) Collaborative Research
Network. Seasonal variation in mortality and therole of temperature: a multi-country multi-citystudy. Int J Epidemiol. 2022 Feb 18;51(1):122-133.
Zhou L, He C, Kim H, Honda Y, Lee W,
Hashizume M, Chen R, Kan H. The burden ofheat-related stroke mortality under climate change
scenarios in 22 East Asian cities. Environ Int. 2022
Dec;170:107602.
Nomura S, Eguchi A, Tanoue Y, Yoneoka D,
Kawashima T, Suzuki M, Hashizume M. Excess
deaths from COVID-19 in Japan and 47
prefectures from January through June 2021.
Public Health. 2022; 203: 15-8.
Nomura S, Eguchi A, Ghaznavi C, Tanoue Y,
Kawashima T, Yoneoka D, Yamasaki L, Suzuki M,
Hashizume M. Excess deaths from non-COVID19-related causes in Japan and 47 prefectures fromJanuary 2020 through May 2021 by place of death.
SSM Popul Health. 2022 Sep;19:101196.
Lwin KS, Ghaznavi C, Win KL, Gilmour S,
Hashizume M, Nomura S. Myanmar's coup risks aflood of vaccine-preventable disease. J Glob
Health. 2022 Sep 3;12:03060.

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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

Website: http://www.ich.m.u-tokyo.ac.jp
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 (19992006), and Masamine Jimba (2006-present).
The mission of the department is to seek equity andsocial 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, in low- andmiddle-income 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 a bottomup approach to national and international policies. Asof March 2023, the members of the department
include the department chair and professor, 1 lecturer,
2 assistant professors, 3 secretaries, 11 visiting
lecturers, 12 doctoral students, 13 master's degree
students, and 43 visiting scientists. More than half ofthe students in this department are international

students.

International Cooperation
Activities
As Regional Vice-President for Northern Part ofWestern Pacific of International Union for Health
Promotion and Education, Professor Jimba
contributed to enhancing health promotion at the
global and regional level. Moreover, as the
Immediate–Past President of Asia-Pacific Academic
Consortium for Public Health, Professor Jimba took aleading role in improving public health research andpractices in the region.

Education
The main objectives of our teaching activities are
the following two: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 technical assistance341

in writing Master’s and doctoral theses. We always
encourage students to publish their theses ininternational journals. In addition, we urge students togain 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.

Research

Publications
1.

2.

3.

The major objectives of our research activities are
the following two: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 forbetter health by making the most of community-based
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 in Japan.
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.

4.

5.

6.

7.

8.

Do AD, Pham TTP, Nguyen CQ, Hoang DV,
Fukunaga A, Stickley A, Yazawa A, Phan DC,
Hachiya M, Jimba M, Huynh DV, Le HX, Do HT,
Mizoue T, Inoue Y. Individual-level social capitalis associated with depressive symptoms among
middle-aged community dwellers in rural
Vietnam: a cross-sectional study. BMJ Open.
2022 Dec 6;12(12):e064998.
Fujii D, Fujimura MS, Ong KIC, Jimba M.
Cutting the Chain of Discrimination during
COVID-19 Pandemic by Health Literacy. JMA J.
2022 Oct 17;5(4):535-538.
Nishikawa M, Yamanaka M, Shibanuma A,
Kiriya J, Jimba M. Cross-Cultural Information
for Japanese Nurses at an International Hospital:
A Controlled Before-After Intervention Study.
Int J Environ Res Public Health. 2022 Oct 7;19(19):12829.
Sarhan MBA, Fujiya R, Shibanuma A, Giacaman
R, Kiriya J, Kitamura A, Jimba M. Health literacy
as a key to improving weight status among
Palestinian adolescents living in chronic conflictconditions: a cross-sectional study. BMJ Open.
2022 Sep 16;12(9):e061169.
Kunieda MK, Manzo ML, Subramanian SV,
Jimba M. Individual- and Neighborhood-Level
Factors of Measles Vaccination Coverage in
Niamey, Niger: A Multilevel Analysis. Vaccines(Basel). 2022 Sep 10;10(9):1513.
Koto-Shimada K, Fujita N, Matsuoka S, Jimba M,
Touch S, Zwi AB. Medium-term outcomes of aprogram to upgrade the nursing faculty in
Cambodia: A qualitative study. Nurse Educ
Today. 2022 Sep;116:105438.
Hartwig L, Namukose V, Kiriya J, Onyancha C,
Shibanuma A, Jimba M. The effectiveness of abehavioral science and design intervention forfamily savings on use of maternal health services
and male involvement: study protocol for arandomized controlled trial. BMC Public Health.
2022 Aug 19;22(1):1579.
Fujimura MS, Conkle J, Van Wyk M, Jimba M.
Nutritional status of children under 5 years old in
Namibia: adjusting for poor quality childanthropometry. J Nutr Sci. 2022 Aug 15;11:e66.

342

9.

10.

11.

12.

13.

14.

15.

16.

17.

Ith S, Yi S, Tuot S, Yem S, Chhoun P, Jimba M,
Shibanuma A. Gender-based violence anddepressive symptoms among female entertainment workers in Cambodia: A cross-sectional
study. PLOS Glob Public Health. 2022 Aug 3;
2(8):e0000873.
Shinejil U, Kiriya J, Shibanuma A, Miller R,
Avirmed D, Jimba M. Association between
Robson classification groups and cesareandelivery: a longitudinal analysis in Mongolia.
AJOG Glob Rep. 2022 Jul 17;2(3):100071.
Carandang RR, Sakamoto JL, Kunieda MK,
Shibanuma A, Yarotskaya E, Basargina M, Jimba
M. Effects of the maternal and child healthhandbook and other home-based records on
mothers' non-health outcomes: a systematic
review. BMJ Open. 2022 Jun 21;12(6):e058155.
Nanishi K, Okawa S, Hongo H, Shibanuma A,
Abe SK, Tabuchi T. Influence of the COVID-19
pandemic on breastfeeding support for healthymothers and the association between compliancewith WHO recommendations for breastfeeding
support and exclusive breastfeeding in Japan.
PeerJ. 2022 May 19;10:e13347.
Choi S, Kiriya J, Shibanuma A, Jimba M.
Mediating role of social capital in the association
between socioeconomic status and childcare
practices in rural Malawi: a cross-sectional study.
BMJ Open. 2022 May 9;12(5):e054134.
Osawa E, Okuda H, Koto-Shimada K, Shibanuma
A, Saito T. The Environment Encouraging
COVID-19 Response at Public Health Centers
and Future Challenges in Japan. Int J Environ
Res Public Health. 2022 Mar 11;19(6):3343.
Arita K, Shibanuma A, Carandang RR, Jimba M.
Competence in Daily Activities and Mental WellBeing among Technical Intern Trainees in Japan:
A Cross-Sectional Study. Int J Environ Res
Public Health. 2022 Mar 8;19(6):3189.
Sakamoto JL, Carandang RR, Kharel M,
Shibanuma A, Yarotskaya E, Basargina M, Jimba
M. Effects of mHealth on the psychosocial healthof pregnant women and mothers: a systematic
review. BMJ Open. 2022 Feb 15;12(2):e056807.
Jimba M, Suzuki M, Kitamura T, Carandang RR,
Sieber NL. Risk of Increasing the Sudden
Diagnosis of AIDS in Japan during and after the

18.

19.

20.

21.

COVID-19 Outbreak. JMA J. 2022 Jan 17;5(1):104-106. doi: 10.31662/jmaj.2021-0174. Epub
2021 Dec 24.
Junaedi A, Ong KIC, Rachmatullah F, Shibanuma
A, Kiriya J, Jimba M. Factors influencing
physical distancing compliance among young
adults during COVID-19 pandemic in Indonesia:
A photovoice mixed methods study. PLOS Glob
Public Health. 2022 Jan 13;2(1):e0000035.
Miller R, Arita K, Igarashi NH, Fujii D, Yumino
A, Jimba M. Social support as a bridge: A rapid
realist review of migrant inclusion in theJapanese response to the COVID-19 pandemic. J
Migr Health. 2022;6:100135.
Takeuchi H, Takanashi S, Hasan SMT, Hore SK,
Yeasmin S, Ahmad SM, Alam MJ, Jimba M,
Khan MA, Iwata T. Anti-Ascaris IgE as a Risk
Factor for Asthma Symptoms among 5-Year-Old
Children in Rural Bangladesh with Even
Decreased Ascaris Infection Prevalence. Int Arch
Allergy Immunol. 2022;183(6):662-672.
Kharel M, Sakamoto JL, Carandang RR,
Ulambayar S, Shibanuma A, Yarotskaya E,
Basargina M, Jimba M. Impact of COVID-19
pandemic lockdown on movement behaviours ofchildren and adolescents: a systematic review.
BMJ Glob Health. 2022 Jan;7(1):e007190.

International Health
2. International Biomedical Sciences

344

Department of Human Genetics
Professor
Akihiro Fujimoto, Ph.D.

Associate Professor
Motoko Unoki, PhD.

Homepage

http://www.humgenet.m.u-tokyo.ac.jp/index.en.html

Introduction and Organization
The Department of Human Genetics wasestablished in 1992. Currently, the department has 1
professor, 5 graduate student, and 1 undergraduate
students. We also accept a few graduate students fromother Universities for their PhD studies.

Teaching activities
For students at the Graduate School of International
Health, courses that cover basic principles as well as
the clinical application of human genetics areprovided.
As to undergraduate students, a series of lectures isgiven to each of the sophomore (Human Genetics I,
compulsory) and junior (Human Genetics II, elective)classes at the School of Health Sciences. A series oflectures is also provided to the first year (M0) students
at the School of Medicine (compulsory).

increasing 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.

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 the3.

4.

Yagasaki K, et al. Practical forensic use ofkinship determination using high-density SNP
profiling based on a microarray platform,
focusing on low-quantity DNA. Forensic Sci Int
Genet. 2022 Nov;61:102752
Kiyose H, et al. Comprehensive analysis offull-length transcripts reveals novel splicing
abnormalities and oncogenic transcripts in livercancer. PLoS Genet. 2022 Aug 4; 18(8):e1010342
Sano Y, et al. Likely pathogenic structuralvariants in genetically unsolved patients withretinitis pigmentosa revealed by long-readsequencing. J Med Genet. 2022 Nov;59(11):1133-1138
Unoki M, Sasaki H: The UHRF protein family inepigenetics, development, and carcinogenesis(Review). Proceedings of the Japanese Academy,Ser. B, Physical and Biological Science 98(8):401-415, 2022

345

Department of Developmental
Medical Sciences
Professor
Meng Ling Moi, Ph.D.

Assistant Professor
Misao Himeno, Ph.D.

Homepage

Ryuji Majima, Ph.D.

http://www.sih.m.u-tokyo.ac.jp/departments-en/

Introduction and Organization
The Department of Maternal and Child Health was
founded in 1966 as the first department that isdedicated to maternal and child health in Japan . With
the subsequent expansion of research activities and thefoundation of the Graduate School of Medicine, thedepartment was renamed in 1998 as the Department ofDevelopmental Medical Sciences. Of date, thedepartment has been involved in basic science researchand studies for the advancement of the physical andmental health of mothers and children. Basic science
research includes those on the infection, immunity andmetabolism, nervous and endocrine systems, whereas
the epidemiologic studies deal with development,
mother-to-child relationship, vaccination and healthpromotion. In 2021, under the new head of department
and new staff members, the department has entered a
new era, with emphasis than on pathogenesis,
prevention and treatment of viral infections, childdevelopment specific conditions (congenital andacquired), from the standpoints of international healthscience, virology, immunology and neuroscience, withresearch and education goals for the development of
measures that contributes to the improvement ofmaternal-child health and public health.
At present, our department consists of one professor,
two assistant professors, two technical specialists, one
secretary, eighteen invited lecturers, ten visiting
researchers, and ten graduate students (including six
overseas student), one undergraduate student and four

research students.
Our department offers courses to both undergraduate
and postgraduate students, have weekly departmental
meetings and individual research groups, communicate
with collaborators inside or outside the University ofTokyo, and have seminars and meetings withresearchers invited from abroad.
Currently, we are collaborating with academia andprivate research institutions from the Asia-Pacificregions, including China, Thailand, Viet Nam,
Malaysia, Myanmar, Indonesia, Bangladesh, Sri Lanka
and Australia, and the United States in research for theadvancement of global maternal and children health.
Our department are actively involved in the education
and research with early and mid-career professionals,
with aims of contributing to the upbringing of global
leaders with competencies and skills to contribute to
the fields of medical research and public health.

Teaching activities
1. Undergraduate course, Faculty of Medicine, Schoolof Integrated Health Sciences
1) Infectious diseases
2) Immunity and defense mechanism3) Human growth and development
4) Topics in life and environmental sciences
5) Maternal and child health6) School health7) International health

3468) Experiments in life sciences
9) Exercises in life sciences
10) 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) Mosquito-borne virus cohort studies in Vietnam,
Thailand, Malaysia, the Philippines, Indonesia
and Myanmar, our department conducts andresearch on viral and host-immunological factorsthat affects outbreaks.
(2) Investigates the immunology and pathogenesis offlaviviral infections by developing biologicalrelevant in-vitro and in-vivo models. In
collaboration with academic and industrial
counterparts, our department also conducts
studies on the development of diagnostics,
vaccines and therapeutics for emerging and reemerging infectious diseases including dengue,
Zika, Chikungunya, Japanese encephalitis viruses.
(3) Determination of the mechanisms of crossreactive immunity during dengue, Zika, Japanese
encephalitis and flavivirus secondary infection,with aims to determine the mechanisms behind
pre-existing immunity in protection orpathogenesis and influences viral evolution
during infection. This knowledge is critical fordeveloping and deploying flavivirus vaccines andanti-viral therapeutics in an increasingly
flavivirus-experienced world.
(4) Clinical, genetic and pathologic studies of acuteencephalopathy: Acute necrotizing encephalopathy, acute encephalopathy with biphasic seizures
and late reduced diffusion, acute encephalitis withrefractory, repetitive partial seizures, andclinically mild encephalitis/encephalopathy with areversible splenial lesion.
(5) Pharmacological studies on the pathogenesis andtreatment of developmental disorders, such as
autism spectrum disorder and attention deficit/
hyperactivity disorder, using genetically engi-

neered animals.
(6) Molecular pathologic and translational studies onchildhood intractable epilepsy and developmental
disorders, such as CDKL5 deficiency disorder,using genetically engineered animals.
(7) Studies on the nutrition, immunity, brain andepigenetics of human fetuses and neonates.
(8) International studies on the maternal and childhealth.
(9) Studies on the virulence, drug resistance andvaccines of herpesviruses and poxviruses.
(10) 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.

Mao ZQ, Minakawa N, Moi ML. Novel Antiviral
Efficacy of Hedyotis diffusa and Artemisia
capillaris Extracts against Dengue Virus, Japanese
Encephalitis Virus, and Zika Virus Infection and
Immunoregulatory Cytokine Signatures. Plants(Basel). 2022 Sep 30;11(19):2589. doi: 10.3390/
plants11192589.
Himeno M, Chen SW, Kido T. Co-culture Modelfor Hepatitis B Virus Infection Using iPSCDerived Liver Progenitor Cells and Liver
Sinusoidal Endothelial Cells. Methods Mol Biol.
2022; 2544:107-117.
Nwe KM, Ngwe Tun MM, Myat TW, Sheng Ng
CF, Htun MM, Lin H, et al. Acute-phase Serum
Cytokine Levels and Correlation with Clinical
Outcomes in Children and Adults with Primaryand Secondary Dengue Virus Infection in
Myanmar between 2017 and 2019. Pathogens,2022; 10.3390/pathogens11050558
Takemura T, Nguyen CT, Pham HC, Nguyen TT,
Hoang VMP, Nguyen LKH, et al. The 2017
Dengue virus 1 outbreak in northern Vietnam wascaused by a locally circulating virus group. Trop
Med Health, 2022; 10.1186/s41182-021-00386-0
Sasaki T, Moi ML, Saito K, Isawa H, Takasaki T,
Sawabe K. Aedes albopictus Strain and Dengue
Virus Serotype in the Dengue Fever Outbreaks in

347

6.

7.

7.

8.

9.

10.

11.

12.

13.

Japan: Implications of Wolbachia Infection. Jpn J
Infect Dis, 2022 ; 10.7883/yoken.JJID.2021.376
Satoh K, Takahashi K, Noguchi K, Kobayashi Y,
Majima R, Iwase Y, et al. Characterization of theSecond Apoptosis Inhibitor Encoded by Guinea
Pig Cytomegalovirus. J Virol. 2022 Dec 21;
96(24):e0162222.
He T, Edwards TC, Majima R, Jung E, KankanalaJ, Xie J et al. Repurposing N-hydroxy
thienopyrimidine-2,4-diones (HtPD) as inhibitorsof human cytomegalovirus pUL89 endonuclease:
Synthesis and biological characterization. Bioorg
Chem. 2022 Dec;129:106198.
Takahashi S, Takeguchi R, Tanaka R, Fukuoka M,
Koike T, Ohtani H, et al. CDKL5 deficiency
causes epileptic seizures independent of cellularmosaicism. J Neurol Sci. 2022 Dec 15;443:
120498.
Moi ML. [Dengue amidst COVID-19: challenges& control measures for the double burden]. Uirusu,
2021; 10.2222/jsv.71.1
Koui Y, Himeno M, Mori Y, Nakano Y, Saijou E,
Tanimizu N et al.Development of human iPSCderived quiescent hepatic stellate cell-like cells for
drug discovery and in vitro disease modeling.
Stem Cell Reports. 2021 Dec 14;16(12):30503063.
Shibata A, Kasai M, Hoshino A, Mizuguchi M.
Association of IL-1B rs16944 Polymorphism
With Acute Encephalopathy With Biphasic
Seizures and Late Reduced Diffusion Is Opposite
to That of Febrile Seizures. Front Neurol. 2022
May 30;13:891721.
Shibamura M, Yamada S, Yoshikawa T, Inagaki T,
Nguyen PHA, Fujii H, et al. Longitudinal Trendsof Prevalence of Neutralizing Antibody against
Human Cytomegalovirus over the Past 30 Years inJapanese Women. Jpn J Infect Dis. 2022 Sep 22;
75(5):496-503.
Kasai M, Omae Y, Khor SS, Shibata A, Hoshino A,
Mizuguchi M et al. Protective association of HLADPB1*04:01:01 with acute encephalopathy withbiphasic seizures and late reduced diffusion
identified by HLA imputation. Genes Immun.
2022 Jun;23(3-4):123-128.
Kasai M, Omae Y, Kawai Y, Shibata A, Hoshino A,
Mizuguchi M, et al. GWAS identifies candidate

susceptibility loci and microRNA biomarkers for
acute encephalopathy with biphasic seizures andlate reduced diffusion. Sci Rep. 2022 Jan 25;
12(1):1332.
14. Nguyen PHA, Yamada S, Harada S, Fukushi S,
Mizuguchi M, Saijo M. Virulence of Herpes
Simplex Virus 1 Harboring a UAG Stop Codon
between the First and Second Initiation Codon in
the Thymidine Kinase Gene. Jpn J Infect Dis.
2022 Jul 22;75(4):368-373.

348

Department of Human Ecology
Professor
Masahiro UMEZAKI, Ph.D.

Associate Professor
Shoko KONISHI, Ph.D.

Research Associates
Lena TAKAYASU, Ph.D.
Yuki MIZUNO, Ph.D.

Homepage: http://www.humeco.m.u-tokyo.ac.jp/en/
Introduction and Organization
The Department of Human Ecology was founded when
Kenji Uraguchi was appointed Professor of the Human
Ecology Department on April 1, 1965. Following
Professor Uraguchi’s retirement on March 31, 1966,
Professor Haruo Katsunuma (also appointed Professor of
the Public Health Department, School of Medicine)
became a joint Professor of the Human Ecology
Department. Tsuguyoshi Suzuki was appointed as an
Associate Professor and worked in the Department until
August 31, 1971, when he was transferred to the Facultyof Medicine, Tohoku University, as a Professor. After
Professor Katsunuma left the Department on March 31,
1972, Professor Akira Koizumi became the head of the
Human Ecology Department on April 1, 1972. Professor
Koizumi was transferred to the Public Health Program,
School of Medicine, on March 31, 1976, and Associate
Professor Shosuke Suzuki served as a department headfrom April 1, 1976, to April 15, 1979.
Tsuguyoshi Suzuki was appointed Professor of the
Human Ecology Program on April 16, 1979. He founded
the theoretical framework of the current human ecology
curriculum, which is based on studying the mechanisms
by which humans adapt to the environment. After
Associate Professor Shosuke Suzuki was transferred to
the Faculty of Medicine, Gunma University, as Professor
on July 31, 1981, Ryutaro Ohtsuka was appointed
Associate Professor on September 1, 1981. Associate

Professor Ohtsuka established a methodology forcollecting quantitative information on demography,
nutrition, and subsistence, targeting small-scale
populations based on extensive fieldwork, themethodology of which continues to be utilized by current
department members. Following the retirement ofProfessor Tsuguyoshi Suzuki on March 31, 1992, Ryutaro
Ohtsuka was appointed professor on April 1, 1992.
Chiho Watanabe was appointed as an Associate
Professor in December 1997. He expanded methodologies
that examine relations between the environment andhealth by utilizing various tools, such as measuringbiomarkers in biological specimens collected in the field
and animal experiments. Professor Ohtsuka retired on
March 31, 2005, and Chiho Watanabe was appointed as a
Professor on April 1, 2005. Masahiro Umezaki was
appointed as an Associate Professor in August 2005.
While relying on quantitative research based onfieldwork, he has also been exploring new research topics,
including the application of spatial information scienceson health sciences, the roles of gut microbiota in humannutrition, mitigation/alleviation strategies of depopulation
and aging in human populations, and medical
anthropology. Professor Chiho Watanabe was transferredfrom the University of Tokyo to the National Institute ofEnvironmental Studies on April 1, 2017. Masahiro
Umezaki was appointed Professor as of January 1, 2018.
Shoko Konishi was appointed Associate Professor as ofJune 1, 2018. Dr. Konishi has been studying the349

associations
betweenfecundity,
fertility,andenvironmental factors from the perspectives of population
studies, environmental sciences, anthropology, andsociology.
In the fiscal year 2022, the Department had four faculty
members: Professor Umezaki and Drs. Konishi,
Takayasu, and Mizuno. The Department also had 14
visiting lecturers for both graduate or undergraduate
courses. Professor Umezaki held additional roles in the
Earth Observation Data Integration and Fusion Research
Initiative (EDITORIA) at the University of Tokyo.
Professor Umezaki and Dr. Konishi joined the UTokyo
Center for Climate Solutions (UTCCS).

Therefore, we must adopt different approaches, including
fieldwork, experimentation, and geographic information
system (GIS)/global positioning system (GPS) analyses.
Our study fields include Asian-Oceanian (including
Japan) rural and urban communities, focusing on
population, nutrition, growth, the environment, andsustainability. Experimental studies have been conductedon the effects of perinatal exposure to heavy metals,
emphasizing the factors that modify these effects. Almost
all our studies require a transdisciplinary approach. We
collaborate with various local and international research
institutes. The following is a list of the major activities
conducted in the past year:

Teaching activities

1. Adaptation to low-protein diet
The inconsistency between the protein-deficient
diets of Papua New Guinea highlanders and theirmuscular physique is well known. Moreover, although
their protein intake is less than biologically adequate,
disorders related to protein deficiency have rarely beenreported. We speculate that the population has adapted
to a low-protein diet by utilizing air nitrogen fixed byintestinal bacteria and/or by intensive “recycling” of theurea that passes into the gastrointestinal tract. Recent
advances in sequencing techniques have enabled us to
examine the adaptation of this population to a lowprotein diet in a more direct way. We evaluated the gut
microbiota of healthy individuals in four Papua New
Guinea communities with varying degrees of protein
deficiency. The association between the gut microbiota
and variations in protein intake and nutritional
biomarkers was investigated. Shotgun metagenomic
analysis further demonstrated that some genes related
to nitrogen fixation and urease were enriched in Papua
New Guinea communities compared with othercountries. Gnotobiotic animal experiments haverevealed different nutritional responses to a low-protein
diet depending on the type of gut microbiotatransplanted.

This Department is one of six in the School ofInternational Health. Human Ecology Special Lecture I
focuses on the basic components of human ecology, suchas demography, nutrition, and environment, andintroduces the notion of human ecosystems and low
fertility in Japan. Human Ecology Special Lecture IIemphasizes recent topics and ongoing research in humanecology and related areas. With these graduate student
classes, we attempt to describe human ecology as a basic
component of international health and providing current
issues and the approaches used in this field. The graduate
course lectures are provided in English.
The Department oversees a part of the School ofIntegrated Health Sciences, providing undergraduate
course lectures on human ecology, environment andhealth, demography, international health, and medical
anthropology. We are also responsible for organizing
pharmacology, toxicology, physiology, and environmental
and human engineering. We focus on introducing globalscale issues, such as population explosion, food security,and environmental issues, regarding problems faced by
the Asia-Pacific region (including Japan). We also
explore the relationship between human activities andenvironmental chemical contamination.

Research activities
Human ecology investigates the human population in
the context of their respective ecologies and the global
context. Mostly, our research tackles tasks in the field of
human environmental health and/or population ecology,
but with a more comprehensive and broader context.

2. Adaptive strategy to aging and depopulation
Japan is experiencing post-demographic transition(i.e., low fertility, aging, and population decrease).
Targeting Japanese rural communities, the frontrunnersof this global issue, we conducted population
projections and studies on their food habits, nutritional
intake, and subjective perceptions of health. We also

350

conducted a study to identify mitigation and alleviation
strategies for aging and depopulation that have beenformulated in local communities.
A case study in Nagasaki city, focusing on theresidential zones on a steep slope and residents’ aging,suggested that older people lived on steep slopes andwithout direct roadway access.
3. Nutrition and eating behaviors
Follow-up surveys have been conducted in a village
in West Java, Indonesia. In the survey in 2022, theimpact of covid-19 epidemics on the survival strategiesof the villagers was investigated.
We also performed animal experiments to elucidate
the determinants of eating behavior. Our experiment
revealed that mice preferred a high-fat diet to a highcarbohydrate diet after the consumption of soluble fiber
for a certain period.
4. Interdisciplinary Investigation on the Technology, theEnvironment, and Fertility (IITEF)
Japan has the highest number of assisted
reproductive technologies in the world. Our ongoingproject is to test the hypothesis that exposure totechnology and environmental chemicals is linked toincreased infertility in the country. A total of 198 maleparticipants were recruited from two hospitals in Tokyoand Tsukuba in 2020 and 2021. We ran preliminary
measurement of urinary isoflavone and paraben
concentrations.
Additionally, the IITEF project administered a largescale online questionnaire survey targeting 8,000 men
living across Japan. The participants were males aged
20 to 54 years who responded to questions onsocioeconomic status and sexual behavior. The findings
have been published as a scientific paper.
5. Iodine intake, thyroid function, and reproductive
healthWe utilized menstrual cycle data and biological
specimens (urine and serum) to analyze theassociations between iodine intake, thyroid function,and menstrual cycle characteristics. As a biomarker ofiodine intake, we measured iodine concentration in
urine using inductively coupled plasma mass
spectrometry (ICP-MS). Serum levels of thyroid
stimulating hormone, thyroxine, triiodothyronine, anti-

thyroglobulin antibody, and anti-TPO antibody were
quantified at a clinical laboratory center. Menstrual
cycle characteristics were obtained from self-recorded
diary of menstrual bleeding for five consecutive
months and self-reported questionnaires. The results
suggest that even within clinical normal range thyroidrelated biomarkers are associated with menstrual cycle
variation.
5. Health transition in Lao People’s Democratic
Republic
The diet in northern Laos has been characterized byconsumption of large amounts of rice with dishes madeof wild plants. Wild plants with bitter taste andastringency, which are supposed to contain more
phytochemicals, are preferred over domesticatedvegetables. Phytochemicals are suspected to play a rolein nutritional adaptation of local people through theirinteractions with intestinal bacteria. As people have
gradually been involved in the market economy, theirdiet has changed toward more consumption of animal
meat and oil, and less consumption of wild plants andconsequently phytochemicals. Our research project
investigated the potential health impacts of such dietarychanges in Oudomxay Province, northern Laos. The
questionnaire survey and biological sample collection
were conducted in three communities with different
degrees of integration into the market economy. By
evaluating oxidative stress, chronic inflammation, andgut microbiota composition in the three communities,
we sought to clarify a biological link between dietarytransition and recent emergence of noncommunicablediseases in rural Laos. To examine phytochemical
intake from wild plants, we have conducted
quantitative dietary surveys, as well as identified
species of wild edible plants and assessed theirphytochemicals.
6. Potential fetal microbiome transfer from intrauterine
exposure
Mounting evidence shows that bacteria in
fertilization products (analyzed using DNA-based
technologies) challenges the sterile womb hypothesis.
We conducted cultivation-based and 16S rRNA
sequence analyses using a mouse model of mid- andlate gestation, which suggested the presence of bacteria
in fetal, placental, and uterine tissues. This low-351

abundance fetal microbiome appears to be volatile andtransient in nature, contrasting the relatively stablebacterial composition that matures during infancy. The
similarity between the bacterial compositions ofmaternal and fetal tissues suggests verticaltransmission, which has also been previously describedin other animals and germ-free animal models. The
existence of this fetal microbiome is hypothesized to be
associated with immunocompetence in mothers and thedevelopment of immunity in fetuses. We havepublished a review article on fetal microbiomes.
7. Mouse gut microbiome transitions
The gut microbiome and aging have been discussed
based on the average flora of people of different ages.
Few studies have been conducted on the microbiome ofthe same individual over a long period of time. We
conducted experiments on mice from shortly after birth
to just before death to determine the changes in the gut
microbiome related to pregnancy and lifespan. Thereare certain phylogenetic trends in bacteria that persist
in the gut for long periods, and these persistentmicrobes are thought to relate strongly to host
homeostasis.

2.

3.

4.

5.

6.

7.

8.

Determinants of chronic inflammation in rural
population in Japan
Chronic inflammation is linked to various
noncommunicable diseases and controlling it can
improve health among older people. Various factors(e.g., age, diet, chemical exposure, etc.) have beenreported as associated with chronic inflammation, but acomplete picture of the determinants of chronic
inflammation has not yet been clarified. We conducteda study to assess chronic inflammation and investigate
its determinants among residents in rural areas in Japan(Ojika city, Nagasaki; Suzu city, Ishikawa), where thepopulation aging rate is high. Nutrient intake wasassessed using a food frequency questionnaire, andseveral biomarkers were measured to assess chronic
inflammation and trace element exposure.

References
1.

Cariño III, R., Takayasu, L., Suda, W., Masuoka, H.,
Hirayama, K., Konishi, S., & Umezaki, M. The
search for aliens within us: a review of evidence and8.

9.

theory regarding the foetal microbiome. Crit Review
Microbiol, 2022;48(5), 611‒623.
Furuhashi, H., Takayasu, L., Isshi, K., Hara, Y., Ono,
S., Kato, M., ... & Suda, W. Effect of storage
temperature and flash-freezing on salivary
microbiota profiles based on 16S rRNA ー targeted
sequencing. European Journal of Oral Sciences,2022;130(2), e12852.
Kibe, M., Tomita, S., & Umezaki, M. Divergence innutritional intake and physical activity patterns
among households in a village of ethnic minorities innorthern Laos at the initial stage of health transition.
Hum Ecol, 2022;50(2), 287‒305.
Konishi, S., & Mizuno, Y. Pre-Conceptional AntiThyroid Antibodies and Thyroid Function in
Association with Natural Conception Rates. IJERPH,
2022;19(20), 13177.
Konishi, S., Moriki, Y., Kariya, F., & Akagawa, M.
Casual sex and sexlessness in Japan: a crosssectional study. Sexes, 2022;3(2), 254‒266.
Konishi, S., Umezaki, M., & Suzuki, S. Perceived
health, fertility, and social network of middle-aged
and older women in Japan. Jpn J Health Hum
Ecology, 2022;88(1), 15‒22.
Kosaka, S., Nakao, R., Goto, C., Umezaki, M., &Ohnishi, M. Food store accessibility affects
nutritional intake through shopping frequency andfood intake in middle-aged to older adults in rural
Nagasaki, Japan. Am J Hum Biol, 2022;34(6),e23725.
Masuda, M., Natsuhara, K., Sueyoshi, S., Odani, S.,
Yagyu, F., Tadokoro, K., ... & Umezaki, M.
Association between the dietary inflammatory index
and disability in Japanese older people. Public
Health Nutr, 2022;25(11), 3137‒3145.
Mizuno, Y., Masuoka, H., Kibe, M., Kosaka, S.,
Natsuhara, K., Hirayama, K., ... & Umezaki, M.
Impact of modernization on urinary concentrationsof arsenic, cadmium, lead, and selenium in rural
residents of Northern Laos. Am J Hum Biol,
2022;34(4), e23685.

352

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.
※The following information is the same as that of the previous year for certain reasons.

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, metabolism, 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

353

 Analysis of vesicular traffic, protein secretion, andphagocytosis/trogocytosis in parasites
 Genome wide analysis and comparison of parasite
strains Drug discovery and development against protozoan
infections such as malaria and amebiasis
 Elucidation of divergence of RNA maturation andtranslation

References
1.

2.

3.

4.

5.

Iwasaki, A., Ohtomo, K., Kurisawa, N., Shiota, I.,
Rahmawati, Y., Jeelani, G., Nozaki, T., Suenaga,
K. Isolation, structure determination and total
synthesis of Hoshinoamide C, an anti-parasitic
lipopeptide from the marine cyanobacterium
Caldora penicillata. J Nat Prod. 84:126-135, 2021.
doi: 10.1021/acs.jnatprod.0c01209.
Pramisandi, A., Kurnia, K., Chrisnayanti, E.,
Bernawati, P., Dobashi, K., Mori, M., Mahsunah,
A. H., Nonaka, K., Matsumoto, A., Kristiningrum,
Hidayati, D. N., Dewi, D., Prabandari, E. E.,
Amalia, E., Nurkanto, A., Inaoka, D. K., Waluyo,D., Kita, K., Nozaki, T., Ōmura, S., Shiomi, K.
Gentisyl alcohol and homogentisic acid:
Plasmodium falciparum dihydroorotate dehydrogenase inhibitors isolated from fungi. J. Gen.
Appl. Microbiol., 67, 114-117, 2021. doi 10.
2323/jgam.2020.08.004
Taku, I., Hirai, T., Makiuchi, T., Shinzawa, N.,
Iwanaga, S., Annoura, T., Nagamune, K., Nozaki,T., Saito-Nakano, Y. Rab5b-associated Arf1
GTPase regulates export of N-myristoylated
adenylate kinase 2 from the endoplasmic
reticulum in Plasmodium falciparum. Front Cell
Inf Microbiol 10:610200, 2021. doi: 10.3389/
fcimb.2020.610200..
Saito-Nakano, Y., Wahyuni, R., Nakada-Tsukui,K., Tomii, K., Mitra, B. N., Nozaki, T. Rab7D
small GTPase is involved in phago-, trogocytosis
and cytoskeletal reorganization in the enteric
protozoan Entamoeba histolytica. Cell. Microbiol.
232, e13267, 2021. doi.org/10.1111/cmi.13267
Jeelani, G., Nozaki, T. Eukaryotic translation
initiation factor 5A and its hypusination play animportant role in proliferation and potentially in
differentiation of the human enteric protozoan

parasite Entamoeba histolytica. PLoS Pathog.,
17(2):e1008909, 2021. doi: 10.1371/journal.ppat.
1008909.
6. Nurkanto, A., Jeelani, G., Santos, H. J., Mori, M.,
Annoura, T., Tozawa, Y., Shiomi, K., Nozaki, T.
Characterization of Plasmodium falciparum
pantothenate kinase and identification of its
inhibitors from microbial natural products. Front
Cell Inf Microbiol. 11:639065, 2021. doi: 10.
3389/fcimb.2021.639065
7. Watanabe, N., Nakada-Tsukui, K., and Nozaki, T.
Diversity of phosphoinositide binding proteins in
Entamoeba histolytica. Parasitol Int (review) 83:
102367, 2021. doi: 10.1016/j.parint.2021.102367.
8. Das, K., Watanabe, N., and Nozaki, T. Two
StAR-related lipid transfer proteins play specificroles in endocytosis, exocytosis, and motility inthe parasitic protist Entamoeba histolytica. PLoS
Pathog, 17(4): e1009551, 2021. doi: 10.1371/
journal.ppat.1009551.
9. Das, K., Sardar, S., Ghosal, A., Saito-Nakano, Y.,
Dutta, S., Nozaki, T., Ganguly, S. Multilocus
sequence typing (MLST) of Entamoeba
histolytica identifies a genetic marker associatedwith disease outcomes. Parasitol Int 83:102370,
2021. doi: 10.1016/j.parint.2021.102370..
10. Santos, H. J. and Nozaki, T. Interorganellar
communication and membrane contact sites inprotozoan parasites. Parasitol Int (review) 83:
102372, 2021. doi: 10.1016/j.parint.2021.102372
11. Hartuti, E. D., Sakura, T., Tagod, M. S. O.,
Yoshida, E., Wang, X., Mochizuki, K., Acharjee,
R., Matsuo, Y., Tokumasu, T., Mori, M., Waluyo,D., Shiomi, K., Nozaki, T., Hamano, S., Shiba, T.,
Kita, K., Inaoka, D., K. Identification of
3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothi
azin-6-imine derivatives as novel selective
inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Int J Mol Sci 22:7236,
2021. doi: 10.3390/ijms22137236.
12. Takahashi, H., Iwasaki, A., Kurisawa, N., Suzuki,
R., Jeelani, G., Matsubara, T., Sato, T., Nozaki,T., Suenaga, K. Motobamide, an antitrypanosomal cyclic peptide from the marine cyanobacterium
Leptolyngbya sp. J Nat Prod. 84:1649-1655,
2021. doi: 10.1021/acs.jnatprod.1c00234.

354

13. Kurisawa, N., Otomo, K., Iwasaki, A., Jeelani, G.,
Nozaki, T., and Suenaga, K. Isolation and total
synthesis of Kinenzoline, an antitrypanosomal
linear depsipeptide isolated from a marine
Salileptolyngbya sp. cyanobacterium. J Org
Chem, 86(18):12528-12536, 2021. doi: 10.1021/
acs.joc.1c00817.
14. Acharjee, R. Talaam, K. K., Hartuti, E. D.,
Matsuo, Y., Sakura, T., Gloria, B. M., Hidano, S.,
Kido, Y., Mori, M., Shiomi, K., Sekijima, M.,
Nozaki, T., Umeda, K., Nishikawa, Y., Hamano,
S., Kita, K., Inaoka, D. K. Biochemical studies of
mitochondrial malate:quinone oxidoreductase
from Toxoplasma gondii. Int J Mol Sci. 22(15):7830, 2021. doi: 10.3390/ijms22157830
15. Waluyo D, Prabandari EE, Pramisandi A,
Hidayati DN, Chrisnayanti E, Puspitasari DJ,
Dewi D, Suryani, Kristiningrum, Oktaviani AN,
Afrianti KR, Nonaka K, Matsumoto A, Tokiwa T,
Adipratiwi N, Ariyani T, Hartuti ED, Putri TZ,
Rahmawati Y, Inaoka DK, Miyazaki Y, Sakura T,
Nurlaila N, Siska E, Kurnia K, Bernawati P,
Melinda M, Mahsunah AH, Nugroho NB, Mori
M, Dobashi K, Yamashita M, Nurkanto A,
Watanabe A, Shiomi K, Wibowo AE, Nozaki T.
Exploring natural microbial resources for the
discovery of anti-malarial compounds. Parasitol
Int. 85:102432. doi: 10.1016/j.parint.2021.
102432.
16. Ebihara, A., Iwasaki, A., Miura, Y., Jeelani, G.,
Nozaki, T., Suenaga, K. Isolation and total
synthesis of Bromoiesol sulfates, antitrypanosomal arylethers from a Salileptolyngbya
sp. marine cyanobacterium. J. Org. Chem.
86(17):11763-11770, 2021. doi: 10.1021/acs.joc.
1c01214.
17. Iwasaki, A., Teranuma, K., Kurisawa, N.,
Rahmawati, Y., Jeelani, G., Nozaki, T., Gerwick,W., Suenaga, K. First total synthesis andstructure activity relationship of Iheyamide A, ananti-trypanosomal linear peptide isolated from a
Dapis sp. marine cyanobacterium. J. Nat. Prod.
84(9):2587-2593, 2021. doi: 10.1021/acs.jnatprod.
1c00792.
18. Nakada-Tsukui, K. and Nozaki, T. Trogocytosis
in unicellular eukaryotes. Special Issue: Newphase of phagocytosis and a bite of trogocytosis.

Cells. 10(11), 2975, 2021. doi.org/10.3390/cells
10112975
19. Bharadwaj, R., Tushar, Ahmad, A., Inampudi, K.,
Nozaki, T.*, Somlata*. An atypical EhGEF
regulates phagocytosis in Entamoeba histolytica
through EhRho1. PLoS Pathog 17(11):e1010030.
(*double correspondence) doi: 10.1371/journal.
ppat.1010030.
20. Peng, R., Yoshinari, S., Kawano-Sugaya, T.,
Jeelani, G., Nozaki, T. tRNA splicing in theunicellular parasitic amoebozoan: identificationand functional characterization of divergent 3'phosphate tRNA ligase from Entamoeba
histolytica. Front Cell Inf Microbiol, section
Parasite and Host, 11:746261, 2021. doi: 10.
3389/fcimb.2021.746261.

School of Public Health
1. Epidemiology and Health Sciences

356

Department of Social andPreventive Epidemiology
Professor
Satoshi Sasaki, M.D., Ph.D.

Associate
Kentaro Murakami, Ph.D.

Homepage

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

Introduction and Organization
The Department of Social and Preventive Epidemiology is a new department which was established at thesame time of the establishment of the School of Public
Health, the University of Tokyo (April 2007).
Epidemiology is a study of quantitatively assessing
health status and disease development in populations
and statistically analyzing the relationship of risk
factors with the development of certain disease. In
addition to traditional risk factors including alcohol
drinking, smoking, nutrition, and physical activity,
gene and factors controlling gene and socioeconomic
factors are also important topics in epidemiologic
research. Epidemiologic data are needed for
conducting the assessment of certain treatment
including medicine and estimating situation of diseasedevelopment.
Epidemiology not only provides research methodology
in the field of public health but also is considered apractical study for public health and thus a central fieldof health science. However, both education andresearch systems have long been insufficient in Japan.
Social and preventive epidemiology is a study of
epidemiologically clarifying the relationship between
various phenomena in human society (including
individual lifestyle) and certain disease.
The Department of Social and Preventive Epidemiology particularly focuses on nutrition, which isessential for individual and population health, as a main
research topic and epidemiologically researches

various issues related to nutrition (nutritional epidemiology), playing a central role in this research field inJapan.
The Department currently consists of one professor andone associate.

Teaching activities
We have the following two lectures in the School of
Public Health.
Epidemiological research and practice
Practice and assessment in public health
Both are strongly associated with practical tasks inpublic health field, aiming at giving students opportunities for acquiring abilities of conducting publichealth activities and tasks based on theory of
epidemiology.
We have also several lectures for students in otherschools.

Research activities
Our main topic is basic research for development andapplication of research methodology in the field of
nutritional epidemiology. Based on this basic research,
we also conduct a wide range of epidemiologic
research for investigating the relationship of nutrition
with health and disease. As a characteristic of thisresearch field, we conduct many multi-center studies
with various kinds of disease.

357

Another characteristic is collection of research findings(scientific papers) derived from epidemiologic research
all over the world on the association of nutrition withhealth and disease, which is applied for health control
through nutrition improvement and disease control.
8.

References
1.

2.

3.

4.

5.

6.

7.

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 2022;
25(3): 689-701.
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 2022;
25(3): 657-69.
Miyake Y, Tanaka K, Okubo H, Sasaki S,
Tokinobu A, Arakawa M. Maternal metal intake
during pregnancy and childhood behavioral
problems in Japan: the Kyushu Okinawa Maternaland Child Health Study. Nutr Neurosci 2022;
25(8): 1641-9.
Murakami K, Livingstone B, Masayasu S, Sasaki
S. Eating patterns in a nationwide sample ofJapanese aged 1-79 years from MINNADE study:
eating frequency, clock time for eating, time spenton eating and variability of eating patterns Public
Health Nutr 2022; 25(6): 1515-27.
Omura Y, Murakami K, Matoba K, Nishimura R,
Sasaki S. Effects of individualized dietary advice
compared with conventional dietary advice for
adults with type 2 diabetes: A randomized
controlled trial. Nutr Metab Cardiovasc Dis 2022;
32(4): 1035-44.
Murakami K, Shinozaki N, Yuan X, Tajima R,
Matsumoto M, Masayasu S, Sasaki S. Food
Choice Values and Food Literacy in a Nationwide
Sample of Japanese Adults: Associations with Sex,
Age, and Body Mass Index. Nutrients 2022; 14(9):1899.
Sugimoto M, Murakami K, Sasaki S. Temporal

9.

10.

11.

12.

13.

14.

patterns of sleep and eating among children during
school closure in Japan due to COVID-19
pandemic: associations with lifestyle behaviours
and dietary intake. Public Health Nutr 2022; :Online ahead of print.
Shinozaki N, Murakami M, Asakura K, Masayasu
S, Sasaki S. Development of a Digital
Photographic Food Atlas as a Portion Size
Estimation Aid in Japan. Nutrients 2022; 14(11):2218.
Fujiwara A, Murakami K, Suga H, Sasaki S,
Three-Generation Study of Women on Diets and
Health Study Group. Cross-Sectional Associationsof Intakes of Starch and Sugars with Depressive
Symptoms in Young and Middle-Aged Japanese
Women: Three-Generation Study of Women on
Diets and Health. Nutrients 2022; 14(12): 2400.
Sugimoto M, Temme EHM, Biesbroek S,
Kanellopoulos A, Okubo H, Fujiwara S, Asakura
K, Masayasu S, Sasaki S, Van't Veer P. Exploring
culturally acceptable, nutritious, affordable, andlow climatic impact diet for Japanese diets: Proofof concept of applying a new modelling approach
using Data Envelopment Analysis. British Journalof Nutrition 2022; 128(12): 2438-52.
Miyake Y, Tanaka K, Okubo H, Sasaki S, Arakawa
M. Tryptophan intake is related to a lower
prevalence of depressive symptoms during
pregnancy in Japan: baseline data from the
Kyushu Okinawa Maternal and Child HealthStudy. Eur J Nutr 2022; 61(8): 4215-22.
Miyake Y, Tanaka K, Okubo H, Sasaki S, Arakawa
M. Maternal calcium intake during pregnancy andchildhood blood pressure: the Kyushu Okinawa
Maternal and Child Health Study. Ann Epidemiol
2022; 73: 17-21.
Murakami K, Shinozaki N, Kimoto N, Masayasu
S, Sasaki S. Relative Validity of Food Intake in
Each Meal Type and Overall Food Intake Derived
Using the Meal-Based Diet History Questionnaire
against the 4-Day Weighed Dietary Record inJapanese Adults. Nutrients 2022; 14(15): 3193.
Sari DW, Noguchi-Watanabe M, Sasaki S,
Yamamoto-Mitani N. Dietary Patterns of 479
Indonesian Adults and Their Associations with
Sodium and Potassium Intakes Estimated by Two
24-h Urine Collections. Nutrients 2022; 14(14):

358

15.

16.

17.

18.

19.

2905.
Fujiwara A, Omura Y, Oono F, Sugimoto M,
Sasaki S, Takimoto H. A Scoping Review of
Epidemiological Studies on Intake of Sugars in
Geographically Dispersed Asian Countries:
Comparison of Dietary Assessment Methodology.
Adv Nutr 2022; 13(5): 1947-73.
Murakami K, Shinozaki N, Kimoto N, Masayasu
S, Sasaki S. Relative Validity of the Meal-Based
Diet History Questionnaire for Estimating
Nutrient Intake among Japanese Women and Men
aged 30-76 Years. Nutrients 2022; 14(20): 4270.
Higashi J, Asakura K, Mori S, Sasaki S, Nishiwaki
Y. Guardianship dietary and other behaviouralfactors associated with skipping breakfast inJapanese primary school children: A childguardian dyad study. Asia Pac J Clin Nutr 2022;
31(4): 701-12.
Nguyen MQ, Miyake Y, Tanaka K, Hasuo S,
Takahashi K, Nakamura Y, Okubo H, Sasaki S,
Arakawa M. Maternal Consumption of Dairy
Products during Pregnancy Is Associated with
Decreased Risk of Emotional Problems in 5-YearOlds: The Kyushu Okinawa Maternal and Child
Health Study. Nutrients 2022; 14(22): 4713.
Shinozaki N, Murakami K. Accuracy of estimatesof serving size using digitally displayed foodphotographs among Japanese adults. J Nutr Sci
2022; 11(24): e105.

359

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.

360

References
1.

2.

3.

4.

5.

6.

7.

8.

Abe H, Sumitani M, Matsui H, Inoue R, Fushimi
K, Uchida K, Yasunaga H. Use of naldemedine isassociated with reduced incidence of hyperactive
delirium in cancer patients with opioid-induced
constipation: a nationwide retrospective cohort
study in Japan. Pharmacotherapy. 2022;42(3):241-249.
Abe H, Sumitani M, Matsui H, Inoue R, Konishi
M, Fushimi K, Uchida K, Yasunaga H..
Gabapentinoid use is associated with reduced
occurrence of hyperactive delirium in older
cancer patients undergoing chemotherapy: anationwide retrospective cohort study in Japan.
Anesthesia & Analgesia. 2022;135(2):362-369.
Aso S, Matsui H, Fushimi K, Yasunaga H. Effectof Dobutamine on Patients with Septic Shock: A
Retrospective Nationwide Study. Annals ofClinical Epidemiology. 2022;4(2): 41-48.
Awano N, Jo T, Izumo T, Inomata M, Morita K,
Matsui H, Fushimi K, Urushiyama H, Nagase T,
Yasunaga H. Recombinant human soluble
thrombomodulin for acute exacerbation of
idiopathic pulmonary fibrosis: A nationwide
observational study. Journal of Intensive Care.
2022;10(1):14.
Chinen T, Sasabuchi Y, Matsui H, Yamaguchi H,
Yasunaga H. Oxaliplatin- versus cisplatin-based
regimens for elderly individuals with advanced
gastric cancer: A retrospective cohort study. BMC
Cancer. 2022;22(1):460.
Fujita A, Hashimoto Y, Matsui H, Yasunaga H,
Aihara M. Recent trends in glaucoma surgery: anationwide database study in Japan, 2011-2019.
Japanese Journal of Ophthalmology. 2022;66(2):183-192.
Fujita A, Hashimoto Y, Okada A, Obata R, Aihara
M, Matsui H, Yasunaga H. Association Between
Proteinuria and Retinal Vein Occlusion in
Individuals with Preserved Renal Function: A
Retrospective
CohortStudy.
Acta
Ophthalmologica. 2022;100(7):e1510-e1517
Fukui R, Kaneko H, Okada A, Yano Y, Itoh H,
Matsuoka S, Morita K, Kiriyama H, Kamon T,
Fujiu K, Michihata N, Jo T, Takeda N, Morita H,
Nakamura S, Nishiyama A, Node K, Yokoo T,

9.

10.

11.

12.

13.

14.

15.

Nangaku M, Yasunaga H, Komuro I.
Semiquantitative assessed proteinuria and risk ofheart failure: Analysis of a nationwide
epidemiological database. Nephrology Dialysis
Transplantation. 2022;37(9):1691-1699.
Furuya H, Nakajima M, Ikeda K, Nakamura K,
Ohbe H, Aso S, Kumazawa R, Iwamoto T, Iwata
A, Furuta S, Matsui H, Fushimi K, Yasunaga H,
Nakajima H. Prognosis and treatment of
myositis-associated severe interstitial lungdisease. Arthritis Care & Research. 2022;74(3):478-483.
Fuseda Y, Michihata N, Kumazawa R, Fushimi K,
Yasunaga H. Annual Trend in Lumbar Puncture
for Infants Younger Than 3 Months Hospitalizedwith Suspected Serious Bacterial Infection: A
Nationwide Inpatient Database Study. Pediatric
Infectious Disease Journal. 2022;41(8):631-635.
Hamada S, Nakajima M, Kaszynski RH, Otaka S,
Goto H, Matui H, Fushimi K, Yamaguchi Y,
Yasunaga H. Association between adjunctclindamycin and in-hospital mortality in patientswith necrotizing soft tissue infection due to group
A Streptococcus: A nationwide cohort study.
European Journal of Clinical Microbiology &Infectious Diseases. 2022;41(2):263-270.
Hashimoto Y, Kaneko H, Okada A, Matsui H,
Yasunaga H, Aihara M, Obata R. Association
between retinal vein occlusion and Life's Simple
7 cardiovascular health metrics: A large claims
database study. Ophthalmology Retina. 2022;
6(8):684-692.
Hashimoto Y, Matsui H, Michihata N, Ishimaru
M, Yasunaga H, Aihara M, Kaburaki T. Incidenceof sympathetic ophthalmia after inciting events: anational database study in Japan. Ophthalmology.
2022;129(3):344-352.
Hashimoto Y, Michihata N, Yamana H, Shigemi
D, Morita K, Matsui H, Yasunaga H, Aihara M.
Safety of topical ophthalmic antibiotics inpregnant women with hordeola, chalazia,
blepharitis, or bacterial conjunctivitis: propensity
score analyses. EYE. 2022 ;36(5):1066-1073.
Hashimoto Y, Yamana H, Michihata N, Shigemi
D, Ishimaru M, Matsui H, Yasunaga H, Aihara M.
Eye drops for dry eye disease during pregnancy
andadverseneonatal
outcomes:
high-

361

16.

17.

18.

19.

20.

21.

22.

dimensional
propensity
score
analyses.
Ophthalmic Epidemiology. 2022;29(4):384-393.
Hirano T, Nakajima M, Ohbe H, Kaszynski RH,
Iwasaki Y, Arakawa Y, Sasabuchi Y, Fushimi K,
Matsui H, Yasunaga H. Corticosteroid use withextracorporeal cardiopulmonary resuscitation forout-of-hospital cardiac arrest: A nationwide
observational study. Resuscitaion Plus. 2022;12:100308.
Hirano Y, Kaneko H, Konishi T, Itoh H, Matsuda
S, Kawakubo H, Uda K, Matsui H, Fushimi K,
Daiko H, Itano O, Yasunaga H, Kitagawa Y.
Short-Term Outcomes of Epidural Analgesia in
Minimally
Invasive
EsophagectomyforEsophageal Cancer: Nationwide Inpatient Data
Study in Japan. Annals of Surgical Oncology.
2022;29(13):8225-8234.
Hirose N, Morita K, Matsui H, Fushimi K,
Yasunaga H. Association between nurse aide
staffing and patient mortality after major cancer
surgeries in acute care settings: A retrospective
cohort study using a national inpatient database.
Nursing and Health Sciences. 2022;24(1):283292.
Hirose N, Morita K, Matsui H, Fushimi K,
Yasunaga H. Dose-response association between
nurse staffing and patient outcomes following
major cancer surgeries using a nationwide
inpatient database in Japan. Journal of ClinicalNursing. 2022;31(17-18):2562-2573.
Honda A, Michihata N, Iizuka Y, Uda K, Morita
K, Mieda T, Takasawa E, Ishiwata S, Tajika T,
Matsui H, Fushimi K, Yasunaga H, Chikuda H.
Risk factors for severe lower extremity ischemia
following venoarterial extracorporeal membrane
oxygenation: An analysis using a nationwide
inpatient database. Trauma Surgery & Acute Care
Open. 2022;7:e000776.
Hosoi T, Yamana H, Tamiya H, Matsui H,
Fushimi K, Akishita M, Yasunaga H, Ogawa S.
Association between comprehensive geriatricassessment and polypharmacy at discharge inpatients with ischaemic stroke: a nationwide
retrospective cohort study. eClinicalMedicine.
2022;50:101528.
Inooka Y, Yamana H, Shinoda Y, Inokuchi H,
Matsui H, Fushimi K, Yasunaga H, Haga N.

23.

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25.

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Predictive factors for oral intake recovery after
acute stroke: analysis of a Japanese nationwide
inpatient database. Dysphagia 2022;37(6):16231632.
Ishimaru M, Ono S, Morita K, Matsui H,
Hagiwara Y, Yasunaga H. Prevalence, incidence
rate and risk factors of medication-related
osteonecrosis of the jaw (MRONJ) in patientswith osteoporosis and cancer: a nationwide
population-based study in Japan. Journal of Oraland Maxillofacial Surgery. 2022;80(4):714-727.
Ishimaru T, Fujiogi M, Michihata N, Konishi T,
Morita K, Matsui H, Uda K, Fushimi K,
Kawashima H, Fujishiro J, Yasunaga H.
Perioperative Outcomes of Laparoscopically
Assisted Anorectoplasty versus Conventional
Procedures for Anorectal Malformation: A
Retrospective Nationwide Database Study.
Pediatric Surgery International. 2022;38(12):1785-1791.
Itoh H, Kaneko H, Okada A, Suzuki Y, Fujiu K,
Matsuoka S, Michihata N, Jo T, Nakanishi K,
Takeda N, Morita H, Node K, Di Tullio MR,
Homma S, Yasunaga H, Komuro I. Age-Specific
Relation of Cardiovascular Health Metrics With
Incident Cardiovascular Disease. American
Journal of Cardiology. 2022;177:34-39.
Iwasaki Y, Ohbe H, Shigemi D, Fushimi K,
Yasunaga H. Effect of antithrombin Ⅲ among
patients
withdisseminatedintravascular
coagulation in obstetrics: a nationwide
observational study in Japan. BJOG: AnInternational Journal of Obstetrics andGynaecology. 2022;129(5):805-811.
Kamijo K, Nakajima M, Shigemi D, Kaszynski
RH, Ohbe H, Goto T, Sasabuchi Y, Fushimi K,
MatsuiH,
Yasunaga
H.
Resuscitative
endovascular balloon occlusion of the aorta forlife-threatening postpartum hemorrhage: A
nationwide observational study in Japan. The
Journal of Trauma and Acute Care Surgery. 2022;
93(3):418-423.
Kamon T, Kaneko H, Itoh H, Okada A, Matsuoka
S, Kiriyama H, Fujiu K, Morita K, Michihata N,
Jo T, Takeda N, Morita H, Nakamura S, Node K,
Yasunaga H, Komuro I. Sex difference in theassociation between lipid profile and incident

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cardiovascular disease among young adults.
Journal of Atherosclerosis and Thrombosis. 2022;
29(10):1475-1486.
Kaneko H, Suzuki Y, Ueno K, Okada A, Fujiu K,
Matsuoka S, Michihata N, Jo T, Takeda N, Morita
H, Kamiya K, Node K, Yasunaga H, Komuro I.
Association of Life's Simple 7 with incident
cardiovascular disease in 53,974 patients withcancer. European Journal of Preventive
Cardiology. 2022;29(18):2324-2332.
Kaneko H, Yano Y, Lee HH, Lee H, Okada A,
Itoh H, Morita K, Fukui A, Fujiu K, Suzuki Y,
Matsuoka S, Nakamura S, Michihata N, Jo T,
Takeda N, Morita H, Yokoo T, Nishiyama A,
Node K, Viera AJ, Muntner P, Oparil S, Kim HC,
Yasunaga H, Komuro I. Medication-Na?ve Blood
Pressure and Incident Cancers: Analysis of Two
Nationwide
Population-Based
Databases.
American Journal of Hypertension. 2022;35(8):731-739.
Kaneko H, Yano Y, Suzuki Y, Okada A, Itoh H,
Matsuoka S, Fujiu K, Michihata N, Jo T, Takeda
N, Morita H, Node K, Viera AJ, Lima JAC,
Oparil S, Lam CSP, Carey RM, Yasunaga H,
Komuro I. Reduction in blood pressure forelevated blood pressure/ stage 1 hypertension
according to the ACC/AHA guideline andcardiovascular outcomes. European Journal ofPreventive Cardiology. 2022;29(14):1921-1929.
Karakawa R, Konishi T, Yoshimatsu H, Fuse Y,
Hashimoto Y, Matsui H, Fushimi K, Yano T,
Yasunaga H. Comparison of short-term outcomes
between pedicled- and free-flap autologous breastreconstruction. Breast Cancer. 2022;29(6):10671075.
Kodama S, Jo T, Yasunaga H, Michihata N,
Matsui H, Kumazawa R, Shirota Y, Fushimi K,
Toda T, Hamada M. Outcomes of gastrointestinal
cancer surgeries in Parkinson's disease patients: anationwide study. Parkinsonism and Related
Disorders. 2022;96:45-49.
Konishi T, Fujiogi M, Michihata N, Kumazawa R,
Ohbe H, Matsui H, Fushimi K, Ogita M, Tanabe
M, Seto Y, Yasunaga H. Interstitial lung disorders
following postoperative radiotherapy withconcurrent or sequential hormonal therapy forbreast cancer: a nationwide database study in

35.

36.

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38.

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Japan. Breast Cancer. 2022;29(4):688-697.
Konishi T, Fujiogi M, Michihata N, Matsui H,
Tanabe M, Seto Y, Yasunaga H. Association
between body mass index and incidence of breast
cancer in premenopausal women: A Japanesenationwide database study. Breast Cancer
Research and Treatment. 2022;194(2):315-325.
Konishi T, Fujiogi M, Michihata N, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Association of operative day of theweek with length of stay and total hospitalization
costs in patients with partial mastectomy: anationwide database study in Japan. JMA Journal.
2022;5(3):319-327.
Konishi T, Fujiogi M, Michihata N, Ohbe H,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Cost-effectiveness analysis of
trastuzumab monotherapy versus adjuvant
chemotherapy plus trastuzumab in elderly
patients with HER2-positive early breast cancer.
Japanese Journal of Clinical Oncology. 2022;
52(10):1115-1123.
Konishi T, Fujiogi M, Sato A, Michihata N,
Kumazawa R, Matsui H, Fushimi K, Tanabe M,
Seto Y, Yasunaga H. Short-term outcomes
following breast cancer surgery with and without
neoadjuvant chemotherapy: a nationwide
administrative database study in Japan. Annals of
Surgical Oncology. 2022;29(5):3000-3010.
Konishi T, Fujiogi M, Shigemi D, Matsui H,
Fushimi K, Tanabe M, Seto Y, Yasunaga H. Risk
factors for postoperative bleeding following
breast cancer surgery: a nationwide databasestudy of 477,108 cases in Japan. World Journal ofSurgery. 2022;46(12):3062-3071.
Konishi T, Fujiogi M, Shigemi D, Nishioka K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Surgical and obstetric outcomes ofbreast cancer surgery during pregnancy: A
nationwide database study in Japan. Breast
Cancer Research and Treatment. 2022;195(3):289-299.
Konishi T, Goto T, Fujiogi M, Michihata N,
Kumazawa R, Matsui H, Fushimi K, Tanabe M,
Seto Y, Yasunaga H. New machine learning
scoring system for predicting postoperative
mortality in gastroduodenal ulcer perforation: A

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43.

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45.

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study using a Japanese nationwide inpatient
database. Surgery. 2022;171(4):1036-1042.
Konishi T, Sakata A, Inokuchi H, Kumazawa R,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Treatments and outcomes of adultparapharyngeal and retropharyngeal abscess:
1,882 cases from a Japanese nationwide
database. ?American Journal of Otolaryngology.
2022;44(2):103770.
Konishi T, Takamoto T, Fujiogi M, Hashimoto Y,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Laparoscopic versus open distal
pancreatectomy with or without splenectomy: Apropensity score analysis in Japan. International
Journal of Surgery. 2022;104:106765.
Konishi T, Yoshimoto T, Fujiogi M, Yamana H,
Tanabe M, Seto Y, Yasunaga H. Validity ofoperative information in Japanese administrative
data: a chart review-based analysis of 1221 cases
at a single institution. Surgery Today. 2022;
52(10):1484-1490.
Kumazawa R, Jo T, Matsui H, Fushimi K,
Yasunaga H. Direct oral anticoagulants versus
warfarin for secondary prevention of cerebral
infarction and bleeding in older adults with atrial
fibrillation. Journal of the American Geriatrics
Society. 2022;70(7):2029-2039.
Kurakawa KI, Okada A, Bessho K, Jo T, Ono S,
Michihata N, Kumazawa R, Matsui H, Fushimi K,
Yamaguchi S, Yamauchi T, Nangaku M,
Kadowaki T, Yasunaga H. Major complications
after percutaneous biopsy of native ortransplanted liver in pediatric patients: A
nationwide inpatient database study in Japan.
BMC Gastroenterology. 2022;22(1):395.
Kutsuna S, Ohbe H, Matsui H, Yasunaga H.
Effectiveness of fluoroquinolone antimicrobials
in addition to tetracyclines for Japanese Spotted
Fever: A retrospective analysis using a national
inpatient database. International Journal of
Infectious Diseases. 2022;123:70-75.
Kutsuna S, Ohbe H, Matsui H, Yasunaga H..
Delayed Tetracycline Initiation Increases
Mortality Risk in Patients With Japanese Spotted
Fever: Retrospective Analysis Using a National
Inpatient Database. Open Forum Infectious
Diseases. 2022;9(11):ofac573.

49. Matsuda K, Jo T, Matsui H, Fushimi K, Yasunaga
H, Sugimoto K. Institutional factors associatedwith early mortality of newly diagnosed acutepromyelocytic leukemia. Blood Cancer Journal.
2022;12(12):167.
50. Matsuda K, Jo T, Shimura A, Honda A, Taoka K,
Masamoto Y, Matsui H, Fushimi K, Yasunaga H,
Kurokawa M. Risk of febrile neutropenia in very
elderly patients aged ?80 years receiving theirfirst cycle of R-CHOP regimen: a nationwide
real-world study in Japan. British Journal of
Haematology. 2022;197(3):e37-e41.
51. Matsui H, Yamana H, Fushimi K, Yasunaga H.
Development of deep learning models forpredicting in-hospital mortality using an
administrative claims database. JMIR Medical
Informatics. 2022;10(2):e27936.
52. Matsuoka S, Kaneko H, Kamon T, Suzuki Y,
Yano Y, Okada A, Itoh H, Morita K, Fukui A,
Fujiu K, Michihata N, Jo T, Takeda N, Morita H,
Nakamura S, Yokoo T, Nishiyama A, Node K,
Yasunaga H, Komuro I. Incorporation of Retinal
Arteriolosclerosis into Risk Stratification of
Blood Pressure Category According to the 2017
ACC/AHA Blood Pressure Guideline. Journal of
Atherosclerosis and Thrombosis. 2022;29(10):1487-1498.
53. Matsuoka S, Kaneko H, Okada A, Fukui A, Yano
Y, Itoh H, Morita K, Fujiu K, Michihata N, Jo T,
Takeda N, Morita H, Yamaguchi S, Nakamura S,
Nishiyama A, Yokoo T, Node K, Yamauchi T,
Nangaku M, Yasunaga H, Komuro I. Association
between Proteinuria and Incident Colorectal
Cancer: Analysis of a Nationwide PopulationBased Database. BMJ Open. 2022;12(4):e056250.
54. Matsuoka S, Kaneko H, Okada A, Itoh H, Suzuki
Y, Fujiu K, Michihata N, Jo T, Takeda N, Morita
H, Nakamura S, Node K, Yasunaga H, Komuro I.
Association of retinal atherosclerosis assessedusing Keith-Wagener-Barker system withincident heart failure and other atherosclerotic
cardiovascular disease: Analysis of 319,501
individuals from the general population.
Atherosclerosis. 2022;348:68-74.
55. Matsuoka S, Kaneko H, Okada A, Morita K, Itoh
H, Michihata N, Jo T, Takeda N, Morita H, Fujiu

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60.

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K, Nakamura S, Node K, Yasunaga H, Komuro I.
Age Modified Relationship between Modifiable
Risk Factors and the Risk of Atrial Fibrillation.
Circulation: Arrhythmia and Electrophysiology.
2022;15(1):e010409.
Michihata N, Shigemi D, Yamana H, Matsui H,
Jo T, Yasunaga H. Safety of Japanese Herbal
Kampo Medicines for the Treatment ofDepression During Pregnancy. International
Journal of Gynecology and Obstetrics. 2022
159(3):865-869.
Michihata N, Suzuki T, Honda A, Oka I,
Yoshikawa T, Saito K, Matsui H, Fushimi K,
Yasunaga H. Clinical features of Kawasaki
disease with atlantoaxial rotatory fixation.
Pediatric Infectious Disease Journal. 2022;41(8):626-630.
Michihata N, Suzuki T, Yoshikawa T, Saito K,
Matsui H, Fushimi K, Yasunaga H. Association
between intravenous immunoglobulin dose andoutcomes in patients with acute Kawasaki disease.
European Journal of Pediatrics. 2022;181(10):3607-3615.
Miyachi H, Konishi T, Kumazawa R, Matsui H,
Shimizu S, Fushimi K, Matsui H, Yasunaga H.
Treatments and outcomes of generalized pustular
psoriasis: a cohort of 1516 patients in anationwide inpatient database in Japan. Journal of
the American Academy of Dermatology. 2022;
86(6):1266-1274.
Miyachi H, Konishi T, Shigemi D, Matsui H,
Shimizu S, Fushimi K, Matsue H, Yasunaga H.
Association between psoriasis and short-term
outcomes of acute myocardial infarction: amatched-pair cohort study using a nationwide
inpatient database in Japan. JAAD International.
2022;8:21-30.
Miyakawa T, Michihata N, Morita K, Matsui H,
Honda M, Yasunaga H. Ambient temperature andhospital admissions for acute cholecystitis: A
nationwide inpatient database study in Japan.
HPB. 2022;24(3):398-403.
Miyamoto Y, Iwagami M, Aso S, Uda K, Fushimi
K, Hamasaki Y, Nangaku M, Yasunaga H, Doi K.
Postoperative outcomes of cancer surgery inpatients with and without kidney failure withdialysis therapy: A matched-pair cohort study.

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Clinical Kidney Journal 2022;15(6):1137-1143.
Miyamoto Y, Matsuyama T, Goto T, Ohbe H,
Kitamura T, Yasunaga H, Ohta B. Association
between age and neurological outcomes in
out-of-hospital cardiac arrest patients resuscitatedwith extracorporeal cardiopulmonary resuscitation: a nationwide multicentre observational
study.
European
Heart
Journal:AcuteCardiovascular Care. 2022;11(1):35-42.
Mizuno S, Ono S, Takano A, Yasunaga H, Iwase
H. Dental characteristics associated withmethamphetamine use: Analysis using forensic
autopsy data. BMC Oral Health. 2022;22(1):141.
Nagata S, Ohbe H, Jo T, Matsui H, Fushimi K,
Yasunaga H. Glucocorticoids and rates ofbiphasic reactions in patients with adrenalinetreated anaphylaxis: A propensity score matching
analysis. International Archives of Allergy and
Immunology. 2022;183(9):939-945.
Nakamura K, Ohbe H, Uda K, Matsui H,
Yasunaga H. Effectiveness of early rehabilitation
following aortic surgery: a nationwide inpatient
database study. Gen Thorac Cardiovasc Surg.
2022;70(8):721-729.
Nishimoto Y, Ohbe H, Matsui H, Nakajima M,
Sasabuchi Y, Goto T, Morita K, Fushimi K, SatoY, Yasunaga H. Predictive ability of thesequential organ failure assessment score forin-hospital mortality in patients with cardiac
critical illness: a nationwide observational study.
EHJ Acute Cardiovasucular Care. 2022;11(4):312-321.
Ogasawara H, Obe H, Yasunaga H. Oral foodchallenge management in Japan: A retrospective
analysis of health insurance claims data. Clinical& Experimental Allergy. 2022;52(7):898-900.
Ogawa Y, Yamana H, Noda T, Kishimoto M,
Yoshihara S, Kanaoka K, Matsui H, Fushimi K,
Yasunaga H, Kawaguchi M, Imamura T. Severe
complications after general anesthesia versus
sedation during pediatric diagnostic cardiac
catheterization for ventricular septal defect.
Journal of Clinical Medicine. 2022;11(17):5165.
Ohbe H, Goto T, Matsui H, Fushimi K, Yasunaga
H. Associations of government-issued ICU
admission criteria with clinical practices,
outcomes, and ICU bed occupancy. Annals of the

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American Thoracic Society. 2022;19(6):10131021.
Ohbe H, Goto T, Nakamura K, Matsui H,
Yasunaga H. Development and validation of early
prediction models for new-onset functional
impairment at hospital discharge of ICU
admission. Intensive Care Medicine. 2022;48(6):679-689.
Ohbe H, Matsui H, Kumazawa R, Yasunaga H.
Intensive care unit versus high dependency careunit admission after emergency surgery: anationwide in-patient registry study. British
Journal of Anaesthesia. 2022;129(4):527-535.
Ohbe H, Matsui H, Kumazawa R, Yasunaga H.
Postoperative intensive care unit admission
following major elective surgery: a nationwide
inpatient database study. European Journal of
Anaesthesiology. 2022;39(5):436-444.
Ohbe H, Matsui H, Yasunaga H. ICU versus
high-dependency care unit for patients with acute
myocardial infarction: a nationwide propensity
score-matched cohort study. Critical Care
Medicine. 2022;50(6):977-985.
Ohbe H, Sasabuchi Y, Kumazawa R, Matsui H,
Yasunaga H. Intensive care unit occupancy inJapan, 2015-2018: a nationwide inpatient
database study. Journal of Epidemiology. 2022;
32(12):535-542.
Ohbe H, Sasabuchi Y, Matsui H, Yasunaga H.
Impact of the COVID-19 pandemic on criticalcare utilization in Japan: a nationwide inpatient
database study. Journal of Intensive Care. 2022;10(1):51.
Ohbe H, Tagami T, Ogura T, Matsui H, Yasunaga
H. Low-flow duration and outcomes ofextracorporeal cardiopulmonary resuscitation in
adults with in-hospital cardiac arrest: anationwide inpatient database study. Ciritcal Care
Medicine. 2022;50(12):1768-1777.
Ohbe H, Tagami T, Uda K, Matsui H, Yasunaga
H. Incidence and outcomes of in-hospital cardiac
arrest in Japan 2011-2017: a nationwide inpatient
database study. Journal of Intensive Care. 2022;10(1):10.
Ohisa K, Yamana H, Morita K, Matsui H,
Fushimi K, Yasunaga H. Association between
subcutaneous steroid injection for extravasation

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of vesicant anticancer drugs and skin ulcers
requiring surgery. European Journal of Oncology
Nursing. 2022;58:102119.
Okada A, Hashimoto Y, Goto T, Yamaguchi S,
Ono S, Ikeda Kurakawa K, Nangaku M,
Yamauchi T, Yasunaga H, Kadowaki T. A
machine learning-based predictive model toidentify patients who failed to attend a follow-up
visit for diabetes care after recommendations
from a national screening program. Diabetes Care.
2022;45(6):1346-1354.
Okada A, Yamana H, Yamaguchi S, Kurakawa K,
Michihata N, Matsui H, Fushimi K, Nangaku M,
Yamauchi T, Yasunaga H, Kadowaki T. Effect ofbranched-chain amino acid infusion on
in-hospital mortality of patients with hepatic
encephalopathy and endstage kidney disease: aretrospective cohort study using a national
inpatient database. Journal of Renal Nutrition.
2022;32(4):432-440.
Okada A, Yasunaga H. Prevalence of
non-communicable diseases in Japan using a
newly developed administrative claims database
covering young, middle-aged, and elderly people.
JMA Journal. 2022;5(2):190-198.
Okubo Y, Nishi A, Uda K, Miyairi I, Michihata N,
Kumazawa R, Matsui H, Fushimi K, Yasunaga H.
Financial Incentives for Infection Prevention andAntimicrobial Stewardship to Reduce Antibiotic
Use: A Japan's Nationwide Observational Study.
Journal of Hospital Infection. 2022;131:89-98.
Ono S, Ishimaru M, Yokota I, Konishi T, Okada
A, Ono Y, Matsui H, Itai S, Yonenaga K,
Tonosaki K, Watanabe R, Hoshi K, Yasunaga H.
Risk of post-extraction bleeding with direct oral
anticoagulant
comparedwithwarfarin:
Retrospective cohort study using large scaleclaims data in Japan. Thrombosis Research.
2022;222:24-30.
Sakakibara K, Shigemi D, Toriumi R, Ota A,
Michihata N, Yasunaga H. Emergency Visits andHospitalization after Message Chat, Voice Call,or Video Call for Telehealth in Obstetrics andGynecology: A Cross-Sectional Study Using
Telehealth Service User Data in Japan. J MedInternet Res. 2022;24(9):e35643.
Sakamoto T, Fujiogi M, Ishimaru M, Matsui H,

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Fushimi K, Yasunaga H. Comparison of
postoperative infection after emergency inguinal
hernia surgery with enterectomy between meshrepair and non-mesh repair: a national database
analysis. Hernia. 2022;26(1):217-223.
Sato M, Yamana H, Ono S, Ishimaru M, Matsui
H, Yasunaga H. Trends in prophylactic antibiotic
use for tooth extraction from 2015 to 2018 in
Japan: an analysis using a health insurance claims
database. Journal of Infection and Chemotherapy.
2022;28(4):504-509.
Seike Y, Matsuda H, Shimizu H, Ishimaru S,
Hoshina K, Michihata N, Yasunaga H, Komori K;
Japanese Committee for Stentgraft Management(JACSM). Nationwide analysis of the association
between persistent type II endoleak and lateoutcomes of endovascular abdominal aortic
aneurysm repair in Japan: Propensity-matchedanalysis. Circulation 2022;145(14):1056-1066.
Shibahashi K, Konishi T, Ohbe H, Yasunaga H.
Cost-effectiveness analysis of termination-ofresuscitation rules for patients with out-ofhospital cardiac arrest. Resuscitation. 2022;180:45-51.
Shibahashi K, Ohbe H, Yasunaga H. Association
between intensive care unit admission practices
and outcomes in patients with isolated traumatic
subarachnoid hemorrhage: A nationwide inpatient
database analysis in Japan. Neurocritical Care.
2022;37(2):497-505.
Shibahashi K, Ohbe H, Yasunaga H. Urban-ruralinequalities in care and outcomes of severe
traumatic brain injury: A nationwide inpatient
database analysis in Japan. World Neurosurgery.
2022;163:e628-e634.
Shibahashi K, Ohbe H, Yasunaga H. Adjuvant
oral tranexamic acid and reoperation afterburr-hole surgery in patients with chronic
subdural hematoma: Propensity score-matchedanalysis using a nationwide inpatient database.
Journal of Neurosurgery. 2022;138(2):430-436.
Shigemi D, Tabuchi T, Okawa S, Yasunaga H.
Association between health literacy and
COVID-19 prevention behaviors among pregnant
and postpartum women. The Journal of MaternalFetal & Neonatal Medicine. 2022;35(25):99719977.

94. Sugawara C, Yamana H, Sasagawa E, Yonezawa
K, Hikita N, Morita K, Matsui H, Yasunaga H,
Haruna M. Factors associated with surgicaltreatment in postpartum women with mastitis orbreast abscess: A retrospective cohort study.
Breastfeeding Medicine. 2022;17(3):233-238.
95. Sugihara T, Kamei J, Yasunaga H, Sasabuchi Y,
Fujimura T. Prescription of Choreito, a Japanese
Kampo medicine, with antimicrobials fortreatment of acute cystitis: a retrospective cohort
study. Antibiotics. 2022;11:1840.
96. Suzuki J, Sasabuchi Y, Hatakeyama S, Matsui H,
Sasahara T, Morisawa Y, Yamada T, Fushimi K,
Yasunaga H. Additional effect of azithromycin
over β-lactam alone for severe communityacquired pneumonia-associated acute respiratory
distress syndrome: a retrospective cohort study.
Pneumonia. 2022 ;14(1):1.
97. Suzuki T, Michihata N, Yoshikawa T, Saito K,
Matsui H, Fushimi K, Yasunaga H. Low- versus
high-concentration intravenous immunoglobulin
for children with Kawasaki disease in the acutephase. International Journal of Rheumatic
Diseases. 2022;25(5):576-583.
98. Suzuki Y, Kaneko H, Okada A, Itoh H, Fujiu K,
Michihata N, Jo T, Takeda N, Morita H,
Yamaguchi S, Kamiya K, Matsunaga A, Ako J,
Node K, Yamauchi T, Nangaku M, Yasunaga H,
Komuro I. Impact of Glucose Tolerance on
Incident Proteinuria in Prediabetes: Analysis of a
Nationwide Population-Based Dataset. American
Journal of Nephrology. 2022;53(4):307-315.
99. Suzuki Y, Kaneko H, Okada A, Itoh H, Fujiu K,
Michihata N, Jo T, Takeda N, Morita H,
Yamaguchi S, Yano Y, Kamiya K, Matsunaga A,
Ako J, Fukui A, Yokoo T, Nishiyama A, Node K,
Yamauchi T, Nangaku M, Yasunaga H, Komuro I.
Risk for Proteinuria in Newly Defined
Hypertensive People Based on the 2017
American College of Cardiology/American Heart
Association Blood Pressure Guideline. American
Journal of Cardiology. 2022;168:83-89.
100. Suzuki Y, Kaneko H, Okada A, Itoh H, Matsuoka
S, Fujiu K, Michihata N, Jo T, Takeda N, Morita
H, Kamiya K, Matsunaga A, Ako J, Node K,
Yasunaga H, Komuro I. Comparison ofcardiovascular outcomes between SGLT2

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inhibitors in diabetes mellitus. CardiovascularDiabetology. 2022;21(1):67.
101. Suzuki Y, Kaneko H, Okada A, Itoh H, Morita K,
Fujiu K, Michihata N, Jo T, Takeda N, Morita H,
Yamaguchi S, Kamiya K, Matsunaga A, Ako J,
Fukui A, Nishiyama A, Yokoo T, Node K,
Yamauchi T, Nangaku M, Yasunaga H, Komuro I.
Change in Cardiovascular Health Metrics andRisk for Proteinuria Development: Analysis of a
Nationwide
Population-Based
Database.
American Journal of Nephrology. 2022;53(2-3):
240-248.
102. Suzuki Y, Kaneko H, Okada A, Matsuoka S, Itoh
H, Fujiu K, Michihata N, Jo T, Takeda N, Morita
H, Yamaguchi S, Node K, Yamauchi T, Yasunaga
H, Komuro I. Prediabetes in Young Adults and Its
Association with Cardiovascular Health Metrics
in the Progression to Diabetes. Journal of Clinical
Endocrinology & Metabolism. 2022;107(7):1843-1853.
103. Suzuki Y, Kaneko H, Okada A, Nangaku M,
Yasunaga H, Komuro I. Kidney outcomes inpatients with diabetes mellitus did not differ
betweenindividual
sodium-glucose
cotransporter-2 inhibitors. Kidney International.
2022;102(5):1147-1153.
104. Suzuki Y, Kaneko H, Yano Y, Okada A, Itoh H,
Matsuoka S, Fujiu K, Michihata N, Jo T, Takeda
N, Morita H, Kamiya K, Matsunaga A, Ako J,
Node K, Yasunaga H, Komuro I. Glycemic status
and the association of change in blood pressure
with incident cardiovascular disease. American
Heart Journal. 2022;254:48-56.
105. Suzuki Y, Kaneko H, Yano Y, Okada A, Itoh H,
Matsuoka S, Fujiu K, Michihata N, Jo T, Takeda
N, Morita H, Matsunaga A, Node K, McEvoy JW,
Lam CSP, Oparil S, Yasunaga H, Komuro I.
Association of Cardiovascular Health Metrics
with Risk of Transition to Hypertension in
Non-Hypertensive Young Adults. American
Journal of Hypertension. 2022;35(10):858-866.
106. Suzuki Y, Kaneko H, Yano Y, Okada A, Itoh H,
Matsuoka S, Fujiu K, Yamaguchi S, Michihata N,
Jo T, Takeda N, Morita H, Node K, Kim HC,
Viera AJ, Oparil S, Yasunaga H, Komuro I.
Age-Dependent Relationship of Hypertension
Subtypes with Incident Heart Failure. JAHA.

2022;11(9):e025406.
107. Suzuki Y, Kaneko H, Yano Y, Okada A, Itoh H,
Ueno K, Matsuoka S, Fujiu K, Michihata N, Jo T,
Takeda N, Morita H, Yokota I, Node K, Yasunaga
H, Komuro I. Dose-dependent relationship ofblood pressure and glycemic status with risk ofaortic dissection and aneurysm. European Journalof Preventive Cardiology. 2022;29(18):23382346.
108. Suzuki Y, Kaneko H, Okada A, Fujiu K,
Michihata N, Jo T, Takeda N, Morita H, Kamiya
K, Matsunaga A, Ako J, Node K, Nangaku M,
Yasunaga H, Komuro I. Proteinuria and Risk forHeart Failure in 55,191 Patients Having Historyof Cancer. American Journal of Nephrology.
2022;53(10):753-760.
109. Tagami T, Yamakawa K, Endo A, Hayakawa M,
Ogura T, Hirayama A, Yasunaga H. JapaneseMulticenter Research of COVID-19 byAssembling Real-world Data: A Study Protocol.
ACE. 2022;4(3): 92-100.
110. Taguchi R, Shigemi D, Yasunaga H. Trends inantihypertensive prescription for pregnant
women with hypertension and their peripartum
outcomes before and after label and guideline
revisions in Japan. Hypertension Research. 2022;
45(11):1823-1831.
111. Tahara S, Hattori Y, Aso S, Uda K, Kumazawa R,
Matsui H, Fushimi K, Yasunaga H, Morita A.
Trends in Surgical Procedures for Spontaneous
Intracerebral Hemorrhage in Japan. Journal of
Stroke and Cerebrovascular Diseases. 2022;
31(9):106664.
112. Takeuchi Y, Iwagami M, Ono S, Michihata N,
Uemura K, Yasunaga H. A post-marketing safetyassessment of COVID-19 mRNA vaccination forserious adverse outcomes using administrative
claims data linked with vaccination registry in acity of Japan. Vaccine. 2022;40(52):7622-7630.
113. Uemura K, et al. Duration of influenza vaccine
effectiveness in the elderly in Japan: A
retrospective cohort study using large-scale
population-based registry data. Vaccine. 2022;
40(52):7622-7630.
114. Ueno K, Kamiya K, Kaneko H, Okada A, Itoh H,
Fujiu K, Takeda N, Morita H, Michihata N, Jo T,
Yasunaga H, Komuro I. Acute-phase initiation of

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cardiac rehabilitation for improvement in
activities of daily living in patients hospitalized
for acute heart failure. Journal of Cardiovascular
Development and Disease. 2022;9(4):97.
115. Ueno K, Kaneko H, Kamiya K, Itoh H, Okada A,
Suzuki Y, Matsuoka S, Fujiu K, Michihata N, Jo
T, Takeda N, Morita H, Ako J, Node K, Yamauchi
T, Yasunaga H, Komuro I. Relationship ofnormal-weight central obesity with the risk forheart failure and atrial fibrillation: Analysis of anationwide health check-up and claims database.
European Heart Journal Open. 2022;2(3):oeac026.
116. Ueno K, Kaneko H, Kamiya K, Itoh H, Okada A,
Suzuki Y, Matsuoka S, Fujiu K, Michihata N, Jo
T, Takeda N, Morita H, Ako J, Yasunaga H,
Komuro I. Clinical utility of simple subjective
gait speed for the risk stratification of heart
failure in a primary prevention setting. Scientific
Reports. 2022;12(1):11641.
117. Urushiyama H, Jo T, Hasegawa W, Yokoyama A,
Ando T, Sakamoto Y, Kumazawa R, Uda K,
Michihata N, Awano N, Hiroki M, Fushimi K,
Yasunaga H, Nagase T. Effect of nintedanib onacute exacerbations of fibrosing interstitial lungdiseases: A national database study in Japan. ERJ
Open Research. 2022;8(4):00209-2022.
118. Wada Y, Takahashi H, Matsui H, Yasunaga H,
Fujiwara H, Sasabuchi Y. Adhesion barriers andintraperitoneal or uterine infections after cesarean
section: A retrospective cohort study. Surgery.
2022;172(6):1722-1727.
119. Yamamoto M, Yasunaga H, Kakinoki R,
Tsubokawa N, Morita A, Tanaka K, Sakai A,
Kurahashi T, Hirata H; CeCORD J study Group.
The CeCORD-J study on collagenase injection
versus aponeurectomy for Dupuytren's contracturecompared by hand function and cost effectiveness.
Scientific Reports. 2022;12(1):9094.
120. Yamamoto R, Kaito D, Homma K, Endo A,
Tagami T, Suzuki M, Umetani N, Yagi M,
Nashiki E, Suhara T, Nagata H, Kabata H,
Fukunaga K, Yamakawa K, Hayakawa M, Ogura
T, Hirayama A, Yasunaga H, Sasaki J;
J-RECOVER study group. Early intubation anddecreased in-hospital mortality in patients withcoronavirus disease 2019. Crit Care. 2022;26(1):124.
121. Yamana H, Sasabuchi Y, Matsui H, Michihata N,
Jo T, Yasunaga H. Maoto plus neuraminidase
inhibitor versus neuraminidase inhibitor alone for
reducing hospitalisation in older adults withseasonal influenza. Annals of Clinical
Epidemiology. 2022;4:120-128122. Yamana H, Tsuchiya A, Horiguchi H, Morita S,
Kuroki T, Nakai K, Nishimura H, Jo T, Fushimi
K, Yasunaga H. Validity of a model using
routinely collected data for identifying infections
following gastric, colorectal, and liver cancer
surgeries. Pharmacoepidemiology and Drug
Safety. 2022;31(4):452-460.
123. Yamazaki R, Ohbe H, Matsuda Y, Kito S, Shigeta
M, Morita K, Matsui H, Fushimi K, Yasunaga H.
Early electroconvulsive therapy in patients withbipolar depression: a propensity score-matchedanalysis using a nationwide inpatient database.
Journal of Affective Disorders. 2022;312:245251.
124. Zhang L, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Tsuda Y, Tanaka S, Kobayashi H.
Preoperative Arterial Embolization and Wound
Complications After Resection of Malignant
Bone Tumor in the Pelvis: A Nationwide
Database Study. Japanese Journal of ClinicalOncology. 2022;52(10):1176-1182.

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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.
■ Research on Health Literacy
The increase in media reports and the rapid expansionof the Internet have rendered various sources of healthinformation more available to the general public. Thus,
skills in understanding and applying information
about health issues may have a substantial impact on
health behaviors and health outcomes. These skills
have recently been conceptualized as health literacy.
We investigate its relationship with patient andprovider communication, and patient health behaviors
and outcomes.

References
1.

2.

3.

4.

5.

Furukawa E, Okuhara T, Okada H, Shirabe R,
Yokota R, Iye R, Kiuchi T. Translation,
cross-cultural adaptation, and validation of theJapanese version of The Patient Education
Materials
Assessment
Tool(PEMAT).
International Journal of Environmental Researchand Public Health 2022;19:15763.
Kato M, Ishikawa H, Kiuchi T, Akiyama M,
Kawamura Y, Okuhara T, Ono N, Miyawaki R.
Patterns of Alcohol and alcohol-flavoured
non-alcoholic beverage advertisements OverJapanese free-to-air television networks. BMC
Public Health 2022; 22:1864.
Yokota R, Okuhara T, Okada H, Goto E,
Sakakibara K, Kiuchi T. Associations between
Stigma, Cognitive Appraisals, Coping Strategies
and Stress Responses among Japanese Women
Undergoing Infertility Treatment. Healthcare2022;10(10):1907.
Yokota R, Okuhara T, Okada H, Goto E,
Sakakibara K, Kiuchi T. Association between
StigmaandAnxiety,
Depression,
andPsychological Distress among Japanese Women
Undergoing Infertility Treatment. Healthcare2022;10:1300.
Goto E, Ishikawa H, Okuhara T, Okada H,
Tsunezumi A, Kagawa Y, Fujino Y, Kiuchi T.
Associations between job and workplace factors,
health and physical factors, personal factors, andpresenteeism among general employees in Japan:
A longitudinal study. Journal of Occupational
Health 2022;e12344.
6. Okuhara T, Okada H, Goto E, Tsunezumi A,
Kagawa Y, Kiuchi T. Encouragement of cervicalcancer screening via an evolutionary theoretical
approach: a randomized controlled study in Japan.
Preventive Medicine Reports. 2022;27:101818.
7. Okuhara T, Okada H, Goto E, Tsunezumi A,
Kagawa Y, Kiuchi T. Encouraging HPVVaccination via an Evolutionary Theoretical
Approach: A Randomized Controlled Study inJapan. Vaccines 2022;10(5):701.
8. Yokota R, Okada H, Okuhara T, Goto E,
Furukawa E, Shirabe R, Sakakibara K, Kiuchi T.
Development of the Japanese version of theInfertility Stigma Scale: Examination of its
reliability and validity. Healthcare 2022;10(3):505.
9. Okuhara T, Okada H, Goto E, Tsunezumi A,
Kagawa Y, Kiuchi T. Encouraging COVID-19
vaccination via an evolutionary theoretical
approach: a randomized controlled study in Japan.
Patient Education and Counseling. 2022;S07383991(22)00085-4.
10. Iye R, Okuhara T, Okada H, Goto E, Furukawa E,
Kiuchi T. The Effect of Exposure to “Exemption”
Video Advertisements for Functional Foods: A
Randomized Control Study in Japan. Healthcare2022;10:2.
11. Miyaji T, Kiuchi T, Yamaguchi T. Institutional
Change in Clinical Trials through the COVID-19
Pandemic. Journal of the Society for Clinical
Trial Management 2022;2(1):1-4.

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.

Lecturer
Daisuke Takagi, Ph. D. (health and social behavior)
Masamitsu Kamada, Ph. D.(health education and health sociology)

Research Associate
Asuka Kato, MPH, Ph.D. (health and social behavior)

Homepage http://webpark1166.sakura.ne.jp/
Introduction and Organization
The department originated as one of the firstdepartments dedicated to health education andbehavioral science in Japan, led by former Prof.
Emeritus Tadao Miyasaka, who had double degrees of
M.D. from the University of Tokyo and MPH in healtheducation from Harvard School of Public Health in1950s. He was succeeded by a sociologist, former
Prof. Kyoichi Sonoda who founded the first healthsociology department affiliated with the medical
school in Japan. Since then, the program has beenleading research focusing on socio-behavioral aspectsof health in this country. The legend was extended byformer Prof. Chieko Kawada who raised academic andpractical attention on the concept of empowerment
and adult pedagogy in health education. Since 1997,
the department was further evolved by Prof. Ichiro
Kai who integrated diverse health and social science
disciplines into social gerontology program, and by
Associate Prof. Yoshihiko Yamazaki who ledsociological research projects on salutogenesis, social
stigma, power, and agency in health settings. The

departments were reorganized under the newly
established School of Public Health since 2007. In
2012, the Department of Social Gerontology has beenrenamed as the Department of Health and Social
Behavior to apply a life-course perspective to a wider
range of social conditions and human well-being.
The new department intends to further integrate
health science (medicine and public health) and social
science (economics, sociology, and psychology) toreveal a causal mechanism linking social structure andindividual health for realizing health equity as afundamental goal to human security.

Teaching activities
The departments offer four courses in the master
degree program for public health, and seven courses
in the undergraduate program for the Integrated
Health Sciences track.
1. Graduate Courses, School of Public Health
1) Health and Society I & II: The course wasconsiderably renewed to focus on inequity,
discrimination,socialexclusion,
and

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sociopolitical activities to overcome thesechallenges through community building. The
renewed course invites adjunctive lecturers
specialized in ageism, gender discrimination,
child poverty, and foreign residents in Japan,
each focusing a specific topic of social
determinants of health. Class II offers morepractical topics to make change in social
problems through advocacy, social business, andcommunity management, through small group
work and student presentation of small projects.
2) Health Education: The course provides basic
knowledge on relevant behavioral theories forhealth promotion and behavioral modification,
followed by case method learning on healtheducational intervention in community, school,
and work places. The case discussion was
facilitated by invited lecturers to reach practicallessons for effective communication.
3) Health Sociology: Sociology in medicine andsociology applied to health issues are treated in
the systemic course of lectures, covering social
model of health, medical gaze and socializationof health professionals, phenomenology ofchronic ills, and culture and health.
4) Comparative health systems in Asia: Started in
2020, jointly offered by Prof. Soonman Kwon in
Seoul National University. The course provides
basic frame/theory for comparative analysis ofhealth systems and offers specific country cases
for in-class discussion.
2. Undergraduate Courses, School of Integrated
Health Sciences
1) Introduction to social survey and practice;
Provides introductory lecture on sampling,
psychometrics, design of social survey andquestionnaires. Students are asked to conduct amini social survey within class on the theme theychoose as relevant in their class experience.
2) Health and Society (former Health sociology);
Lecture series on social model of healthgeneration, social relationship and health,chronic illness experience, and social stigma.
3) Health education
Case scenario based practicum and lectures on
health promotion intervention in clinical, school,

and worksite settings.
4) Social security and welfare program: Lecture
series on the history and the current systems ofhealth care security and welfare policies in thiscountry.
5) Integrated Lectures of Public Health Sciences I(jointly offered by the faculty of Health
Sciences)
6) Scientific writing
7) Critical reading/writing of epidemiologicalstudies8) Integrated Practicum of Public Health Sciences
II (jointly offered with Department of Medical
Ethics).

Research activities
The Department has contributed to an ongoing
research of socioeconomic status and health/functions
among elderly population in the collaboration with the
School of Economics of the University of Tokyo andthe Research Institute of Economic, Industry, andTechnology. The Japanese Study of Ageing andRetirement (J-STAR) is a sister study with the U.S.
Health and Retirement Study, Study of Health,Ageing, and Retirement in Europe (SHARE), EnglandLongitudinal Survey of Ageing (ELSA), and theirglobal sisters in Asian countries. The scope of JSTAR
is diverse; contribution of health for successful ageing,social economic conditions and access to health care,household economy and its impact on life styles suchas eating habits and nutrition, impact of retirement
onto cognitive function, etc..
Since 2010, the Department has launched anotherpanel study of younger generation, the Japanese studyof Stratification, Health, Income, and Neighborhood(J-SHINE) in collaboration with researcher groups on
neuroscience, economics, sociology, and social
psychology. The aim of this comprehensive panel
study is to identify a mechanism how socio-economic
environments get to “under-skin” to cause social
gradient of health across socio-economic positions. In
the year of 2011, the JSHINE conducted a
supplemental survey to respondent’s spouse andchildren. Main and supplement surveys were followedin 2012 and 2013, respectively. Obtained panel data
are made open to a broader range of researchers under

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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.
Dr. Takagi, in collaboration with Niigata University,
is conducting a longitudinal social epidemiologicalsurvey of community-dwelling older adults in
Myanmar and Malaysia. In these countries that havedistinctive stage of economic development, culture,
and ageing rate, this study aims at verifying
applicability of the existing social models of healthand building new theories based on each country’s
context. A probability proportionate sampling of sites
and selection of local investigators have been
completed in 2017, and interview surveys is underway
in 2020 before COVID-19 and political difficulty
started. Dr. Takagi also conducted in collaboration
with a municipal government in Chiba Prefecture asurvey targeting regional crime prevalence and thepreventive effect through social network structure byusing sociometric measurement of social network in acommunity.
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, of which results are to be published. Dr.
Kamada most recently works to develop an
application software to objectively obtain daily step
counts of iPhone users that would make a technicalinnovation to facilitate social epidemiology ofphysical activities in fields.
Prof. Hashimoto has been engaged in a joint projectwith the Tokyo Metropolitan Government on theinformation management in the field of welfare
programs to tackle child maltreatment since 2020. In
the last year, a summary report for standardization

information systems, e-learning system to facilitate
effective case recording, and risk prediction models
for recurrent case of maltreatment were submitted to
the government as project outputs as of March 2023.

Other Social activities
Dr. Kato has been leading the research on social andinternalized stigma among the people living withdiabetes, of which contribution is extended to enhanceadvocacy activities in the related academic andsubspecialty societies.

Publications
Peer reviewed journals
1. Sasaki Y, Shobugawa Y, Nozaki I, Takagi D,
Nagamine Y, Funato M, Chihara Y,Shirakura Y,
Lwin KT, Zin PE, Bo TZ, Sone T, Win HH.
Association between Happiness and Economic
Status among Older Adults in Two Myanmar
Regions. Int J Environ Res Public Health. 2022
Mar 9;19(6):3216. doi: 10.3390/ijerph19063216.
2. Takagi D, Kondo N, Tsuji T, Kondo K.
Parks/sports facilities in local communities andthe onset of functional disability among older
adults in Japan:The J-shaped spatial spillover
effects. Health Place. 2022 May;75:102801.
doi:10.1016/j.healthplace.2022.102801.
3. Haseda M, Takagi D, Stickley A, Kondo K,
Kondo N. Effectiveness of a community
organizing intervention on mortality and its
equity among older residents in Japan: A JAGES
quasi-experimental study. Health Place. 2022
Mar;74:102764.doi:10.1016/j.healthplace.2022.
102764.
4. Kitagishi T, Takagi D. Information and communication technology, educational attainment, anddisparity in health information from one’s
personal social network: The J-SHINE 2017
cross-sectional study. PLoS One. 2022 Sep 28;
17(9):e0275285.doi:10.1371/journal.pone.02752
85.
5. Tsuji T, Takagi D, Kondo N, Maruyama Y, Ide
K, Lingling, Wang H, Kondo K. [Promoting
community gathering places “Kayoinoba” forhealthy aging reduce health inequalities amongcommunities: An eight-year ecological study].

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Nihon Koshu Eisei Zasshi. 2022 May 24;
69(5):383-393. Japanese. doi:10.11236/jph.21120. Epub 2022 Mar 16. PMID: 35296594.
6. Kamada M, Hayashi H, Shiba K, Taguri M,
Kondo N, Lee IM, Kawachi I. Large-Scale
Fandom-based Gamification Intervention to
Increase
Physical
Activity:A
Quasiexperimental Study.Med Sci Sports Exerc. 2022
Jan 1;54(1):181-188.doi: 10.1249/MSS.0000000
000002770.
7. Hatakeyama N, Kamada M, Kondo N. Parental
Working Hours and Children’s Sedentary Time:
A Cross-sectional Analysis of the J-SHINE.J
Epidemiol. 2022 Jan 5;32(1):4-11. doi: 10.2188/
jea.JE20200170. Epub 2021 Mar 4.
8. Gomi T, Kitayuguchi J, Okuyama K, Kamada M,
Inoue S, Kamioka H, Mutoh Y. Relationship
Between Neighborhood Food Environment andDiet Variety in Japanese Rural Communitydwelling Elderly: A Cross-sectional Study.J
Epidemiol. 2022 Jun 5;32(6):290-297.doi: 10.
2188/jea.JE20200415. Epub 2021 Jun 22.
9. Abe T, Kitayuguchi J, Fukushima N, Kamada M,
Okada S, Ueta K, Tanaka C, Mutoh Y.
Fundamental movement skills in preschoolers
before and during the COVID-19 pandemic in
Japan: a serial cross-sectional study.Environ
Health Prev Med. 2022;27(0):26. doi: 10.1265/
ehpm.22-00049.
10. Oba K, Kagiwada Y, Kamada M, Miki R, Kondo
Y, Kamakura T, Yamagami T, Fujita T, Tsuchida
Y. Evaluating the feasibility of a remote-based
training program supported by information andcommunications technology in the older adults
living at home.BMC Geriatr. 2022 Jul 13;
22(1):574.doi: 10.1186/s12877-022-03273-3.
11. Amagasa S, Kamada M, Bauman AE, Miyachi M,
Inoue S. Evaluation of pre-Games effects of theTokyo 2020 Olympic Games on Japanese
population-level physical activity: a time-series
analysis.Int J Behav Nutr Phys Act. 2022 Aug 6;
19(1):96.doi: 10.1186/s12966-022-01332-x.
12. Watanabe H, Anezaki H, Kazawa K, Tamaki Y,
Hashimoto H, Moriyama M. Long-term
effectiveness of a disease management program
to prevent diabetic nephropathy: a propensity
score matching analysis using administrative

13.

14.

15.

16.

17.

18.

data in Japan. BMC Endocr Disord. 2022 May
20;22(1):135.doi: 10.1186/s12902-022-01040-4.
Hashimoto A, Kawaguchi H, Hashimoto H.
Contribution of the Technical Efficiency of
Public Health Programs to National Trends andRegional Disparities in Unintentional Childhood
Injury in Japan. Front Public Health. 2022 Jul
12;10:913875.doi:10.3389/fpubh.2022.913875.
Kasajima M, Eggleston K, Kusaka S, Matsui H,
Tanaka T, Son BK, Iijima K, Goda K,
Kitsuregawa M, Bhattacharya J, Hashimoto H.
Projecting prevalence of frailty and dementia andthe economic cost of care in Japan from 2016 to
2043: a microsimulation modelling study. Lancet
Public Health. 2022 May;7(5):e458-e468. doi:
10.1016/S2468-2667(22)00044-5.
Kim H, Jeon B, Frisina Doetter L, Tamiya N,
Hashimoto H. Same same but different?
Comparing institutional performance in the longterm care systems of Japan and South Korea.
Social Policy & Administration, 2022: 56(1),148-162. https://doi.org/10.1111/spol.12761
Kumamaru H, Kakeji Y, Fushimi K, Ishikawa
KB, Yamamoto H, Hashimoto H, Ono M,
Iwanaka T, Marubashi S, Gotoh M, Seto Y,
Kitagawa Y, Miyata H. Cost of postoperativecomplications of lower anterior resection forrectal cancer: a nationwide registry study of
15,187 patients. Surg Today. 2022 May 24.doi:
10.1007/s00595-022-02523-6.
Nozaki, I., Shobugawa, Y., Sasaki, Y., Takagi, D.,
Nagamine, Y., Zin, P. E., Bo, T. Z., Nyunt, T. W.,
Oo, M. Z., Lwin, K. T., & Win, H. H. Unmet neesfor hypertension diagnosis among older adults in
Myanmar: Secondary analysis of a multistage
sampling study. Health Research Policy and
Systems. 2022 November 29; 20:114. https://doi.
org/10.1186/s12961-022-00918-y.
Obikane E, Sasaki N, Imamura K, Nozawa K,
Vedanthan R, Cuijpers P, Shimazu T, Kamada M,
Kawakami N, Nishi D. Usefulness of
Implementation Outcome Scales for Digital
Mental Health (iOSDMH): experiences from six
randomized controlled trials. Int J Environ Res
Public Health. 19:15792, 2022. https://doi.org/
10.3390/ijerph192315792.

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19. Murphy J, Milton K, Mclaughlin M, Shilton T,
McLoughlin G, Reece LJ, Mair JL, Direito A,
Kariippanon KE, Mackenzie KJ, Mavilidi MF,
Shellington EM, Kamada M, Heron L, Jauregui
E, Abdeta C, Pina I, Pinto R, Sutherland R.
Advocating for implementation of the Global
Action Plan on Physical Activity: challenges andsupport requirements. J Phys Act Health. 20(1):10-19, 2023. https://doi.org/10.1123/jpah.20220357.

Book chapter
1. Takagi, D. (2022). AI-powered recommendations and social relationships. In Y. Sato, Y.
Inaba, & Y. Fujiwara (Eds.), How will AI change
society? (pp. 61-89) The University of Tokyo
Press. (Japanese)School of Public Health
3. Health Services Sciences

379

Department of Clinical
Information Engineering
Professor
Hiroshi Oyama, M.D., Ph.D.

Assistant professor
Kelssy Hitomi dos Santos Kawata, Ph.D.

Homepage: https://webpark1893.sakura.ne.jp/wp/home/cie_en/
Introduction and Organization
Information engineering significantly impacts
computer hardware, software, and data processing. It isa discipline that seeks objective data and emphasizes
the conception of new data transfer methods, 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 appeared in
the 1950s. In the 1960s, computers were used foraccounting and various statistics. The personal
computer appeared in the 1980s and was adopted for
personal use in many professions. The systematizationof large hospitals, such as university hospitals, pushedahead rapidly.
In the 1990s, the computer began to help humanthinking, such as in presentations, design, anddiscovery. When computers became connected throughthe internet, the distribution of information becamevery easy and rapid, both within organizations andinternationally.
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 biochemistry 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 Science andTechnology from Japan's Ministry of Education,
Culture, Sports, Science, and Technology.

Teaching activities
The Department of Clinical Information Engineering
aims to nurture talented people with special knowledge
and skills at an international level to apply advanced
information technologies to 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.
The education of graduate students is based on
weekly conferences at which the students present theirresearch projects' progress and discuss their future
directions.

380

Research activities
Our research covers biomedical computer applications
focusing on data (collection, analysis, andrepresentation). It constitutes a combination of
information science, computer science, and clinicalscience designed to assist in managing and processing
data, information, and knowledge to support thepractice and delivery of clinical care. Our laboratory is
engaged in the following research activities:
A)

Computer Graphics & Virtual Reality (VR) for
Medical Science: Our research has three goals: toimprove the living conditions of in-patients withlimited physical activity by providing virtual
experiences, to develop new diagnostic methods
using medical imaging, and to develop a surgicaledutainment and preoperative surgical planningsupport system in virtual space.
The advantages of simulating surgicalprocedures using VR techniques include (1)practicing the surgical procedure and image-based
training; (2) planning the surgical procedure forindividual patients preoperatively using VR
images modeled from the patient's preoperative
computed tomography (CT) or magnetic
resonance (MR) images, in collaboration with the
Department of Neurosurgery; (3) allowing
supervisors to evaluate a procedure objectively;and (4) helping patients and their families to better
understand the surgical procedure before and after
the operation.
B)
Social Information Engineering for Public
Health (Public Health Informatics): Ourlaboratory
researches
new
tools
and
methodologies
forapplying
information,
computer science, and technology to public healthpractice, research, and learning. We are studying
differences in the computerization of public healthin the US and Japan.

References
1.

Lem, W. G., dos Santos Kawata, K. H., Kobayashi,T., & Oyama, H. (2023). Public Stigma Related to
People With Mental Health Conditions AmongJapanese Company Employees. Journal of
Clinical Medicine Research, 15(3), 139-147.

2.

3.

Koike, T., Tanaka, S., Kin, T., Suzuki, Y.,
Takayanagi, S., Takami, H., ... Oyama, H. & Saito,
N. (2022). Accurate Preoperative Identification ofMotor Speech Area as Termination of Arcuate
Fasciculus Depicted by Q-Ball Imaging
Tractography. World Neurosurgery, 164, e764-e7
Nagayo, Y., Saito, T., & Oyama, H. (2022).
Augmented reality self-training system forsuturing in open surgery: A randomized controlled
trial. International Journal of Surgery, 106650.

381

Department of Global
Environmental Health
Associate Professor
Yoonhee Kim, Ph.D.

Homepage https://sites.google.com/m.u-tokyo.ac.jp/envhealth/Introduction and Organization
The Department of Global Environmental Health(GEH) started under the School of Public Health(SPH), Graduate School of Medicine, in April 2018and has contributed to the master’s program (MPH). It
has been affiliated with the School of International
Health (SIH), Graduate School of Medicine since July
2018 as an Associate Department, accepting master’sand doctoral students.
The GEH aims:
1. To study relationships between environmental
exposure and human health
2. To produce well-educated professionals with theacademic knowledge and ability to undertake
environmental epidemiological research

Education
This department provides two postgraduate courses
at SPH: 1) Environmental Health and 2) Methods forEnvironmental 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 provides state-of-the-art scientific knowledge
and interpretation for health risk/impact assessment inenvironmental health perspectives. The latter is anadvanced course dealing with statistical andepidemiological methodologies in environmental
epidemiology that provides the theory and practice ofa specific method to estimate the short-term effects ofenvironmental risk factors on human health.
Journal ClubGEH has participated in a biweekly conference callwith multiple schools/institutes* to read and discuss
articles in environmental epidemiology.
*

Seoul National University, Korea Advanced Institute of Science &Technology (KAIST), National Institute for Environmental Studies,
University of Tsukuba, Kyoto University, and Nagasaki University

GEH R Seminar
Every other Tuesday, 11:00-12:30
Graduate students present fundamental knowledge andskills of R language and its applications, particularly
for time-series regression analysis and spatial analysis,that they learned from R textbooks and/or research
articles in environmental epidemiology. Sharing thebasic and advanced methodologies and discussion
helps students develop their capacity to implement
research projects.
All course lectures, thesis advising, and discussions inseminars are carried out in English.

Research
Our research interests particularly focus on climatechange and air pollution in human populations in thefield of environmental epidemiology. We address thescientific questions of how they link, quantify thehealth risks of a specific environmental factor, andfurther investigate social determinants that could
potentially modify the exposure-response relationships.

382

Our research collaborations include:
1. Global perspectives of seasonal variability ofsuicide and the short-term associations between
suicide and ambient temperature and air pollution
using a large-scale daily time-series databaseacross 26 countries, as a part of the Multi-Country
Multi-City (MCC) Collaborative Research
Network
2. Health risk assessment of climate change and air
pollution in Asian countries, including Japan,
South Korea, China, Lao PDR, and Thailand.
3. Nationwide studies on the short-term associations
between suicide and ambient temperature and air
pollution in Finland
4. Establishment of an early warning system for
malaria incidence in southern Africa

Publications
1.

2.

3.

4.

5.

Madaniyazi L, Tobias A, Kim Y, Chung Y,
Armstrong B, Hashizume M. Assessing
seasonality and the role of its potential drivers inenvironmental
epidemiology:atutorial.
International Journal of Epidemiology 2022:
51(5):1677-1686.
Roy A, Alam MA, Kim Y, Hashizume M.
Association between daily ambient temperatureand drug overdose in Tokyo: A time-series study.
Environmental Health and Preventive Medicine
2022:27:36.
Pan R, Honda Y, Minakuchi E, Kim SE,
Hashizume M, Kim Y. Ambient temperature andexternal causes of death in Japan from 1979 to
2015: A time-stratified case-crossover analysis.
Environmental Health Perspectives 2022:130(4):047004.
Kawano A, Kim Y, Meas M, Sokal-Gutierrez K.
Association between satellite-detected tropospheric nitrogen dioxide and acute respiratory
infections in children under age five in Senegal:
Spatio-temporal analysis. BMC Public Health2022:22:178.
Mistry MN, Schneider, R, Masselot P, Royé D,
Armstrong B, and MCC Collaborative Research
Network. Comparison of weather station andclimatereanalysis
dataformodelling6.

temperature-related mortality. Scientific Reports
2022:12:5178.
Madaniyazi L, Armstrong B, Chung Y, Ng CFS,
Seposo X, Kim Y et al. Seasonal variation in
mortality and the role of temperature: amulti-country multi-city study. International
Journal of Epidemiology 2022:51(1):122-133.

Endowed Department

384

Department of Artificial
Intelligence in Healthcare
Project Associate Professor
Yoshimasa Kawazoe, M.D., Ph.D.

Project Research Associate
Emiko Shinohara, Ph.D.

Project Research Associate
Mai Hirabayashi, Ph.D.

Project Research Associate
Daisaku Shibata, Ph.D.

Project Researcher
Kiminori Shimamoto, M.E.

Homepage https://ai-health.m.u-tokyo.ac.jp/

Introduction and Organization
Practical applications based on the development of AI
technology call for a fundamental transformation of
the industrial structure. The global spread of
COVID-19 has significantly changed the way medicalcare, economy, and society operate. To maintain andfurther develop the quality of the Japanese society,which some consider to be in decline because of thefalling birth rate, rational and efficient social
management based on information and communications technology (ICT) as well as artificial intelligence(AI), become indispensable. This course wasestablished in 2018 at the University of Tokyo
Hospital Department of Planning, Information andManagement (Graduate School of Medicine
Department of Biomedical Informatics) as acollaborative course, to explore the form of new
medical services while promoting the development ofunderlying technologies, such as, ICT and AI. The
objective has been to contribute to human resource
development by forming a support base forresearchers involved in this field, and to develop joint
research beyond the boundaries of faculties anduniversities to contribute to the development of
medical care.

Teaching activities
We have promoted activities to train researchers aswell as students in this area inside and outside theuniversity. In 2022, we were in charge of the medical
informatics course at the University of Tokyo Facultyof Medicine designed for 4th-year students. We havealso taught courses to Graduate School of Medicine
School of Public Health professional master's degree
students and have contributed to courses on medical
RWD human resources development projects forworking adults. The courses have focused on
AI-related technologies in medical informatics. We
have provided research guidance to doctoral studentsof the Graduate School of Medicine Department of
Biomedical Informatics as well as Reproductive,
Developmental and Aging Sciences; research385

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
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.
Application
technologyofnaturallanguagetechnology, co-developed with our research partners.
Our goal is to further research into unveiling new
therapeutic effects from diverse electronic medical
chart data. Our studies have already demonstrated theability to accurately identify known adverse eventsfrom chemotherapy within these texts. Moving
forward, our research endeavors will focus on
discovering novel therapeutic benefits of combined
drug treatments, striving to enhance the safety ofpatient care.

Social activities
1.
2.

3.

4.

References1.

processing

By analyzing electronic medical chart records using
computers, we anticipate uncovering new insights into
medicine and healthcare. These charts capture avariety of data, of which the freely written text holds
significant information. Nevertheless, this textual data
has historically posed technical challenges forcomputerized analysis. Supported by the Japan
Science and Technology Agency (JST), this course
highlights our use of natural language processing

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.

2.

Kage H, Shinozaki-Ushiku A, Ishigaki K, Sato Y,
Tanabe M, Tanaka S, Tanikawa M, Watanabe K,
Kato S, Akagi K, Uchino K, Mitani K, Takahashi
S, Miura Y, Ikeda S, Kojima Y, Watanabe K,
Mochizuki H, Yamaguchi H, Kawazoe Y,
Kashiwabara K, Kohsaka S, Tatsuno K, Ushiku T,
Ohe K, Yatomi Y, Seto Y, Aburatani H, Mano H,
Miyagawa K, Oda K. Clinical utility of Todai
OncoPanel in the setting of approved comprehensive cancer genomic profiling tests in Japan.
Cancer Sci. 2023 Jan 5. doi: 10.1111/cas.15717.
Kawazoe Y, Shimamoto K, Yamaguchi R,
Nakamura I, Yoneda K, Shinohara E, ShintaniDomoto Y, Ushiku T, Tsukamoto T, Ohe K.

386

3.

4.

5.

6.

Computational
Pipelinefor
Glomerular
Segmentation and Association of the Quantified
Regions with Prognosis of Kidney Function in
IgA Nephropathy. Diagnostics. 2022;12(12):2955.
Shinohara E, Shibata D, Kawazoe Y.
Development of comprehensive annotation
criteria for patients’ states from clinical texts. J
Biomed Inform. 2022 Oct;134:104200.
Kawazoe Y, Shimamoto K, Shibata D, Shinohara
E, Kawaguchi H, Yamamoto T. Impact of a
Clinical Text–Based Fall Prediction Model on
Preventing Extended Hospital Stays for Elderly
Inpatients: Model Development and Performance
Evaluation. JMIR Med Inform. 2022;10(7):e37913.
Hayakawa J, Seki T, Kawazoe Y, Ohe K. Pathway
importance by graph convolutional network andShapley additive explanations in gene expression
phenotype of diffuse large B-cell lymphoma.
PLoS One. 2022 Jun 24;17(6):e0269570.
Nishimura R, Miyabe Hirabayashi M, Yoshino T.
Baseless-Rumor Alert Bot to Promote Reliabilityof Information. IPSJ Journal. 2022;30(1):2-14.

387

Department of medical researchand the management ofmusculoskeletal pain
Professor
Koh Matsudaira, M.D,Ph.D.

Associate Professor
Hiroyuki Oka, M.D,Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/research/center22/contribute/undouki_toutu.html

Introduction and Organization
The department of medical research and the
management of musculoskeletal pain was establishedat the 22nd Century Medical and Research Centre
thanks to donations from ippon Zoki PharmaceuticalCo., Ltd., AYUMI Pharmaceutical Corporation, ONO
PHARMACEUTICAL CO., LTD., Chugai Pharmaceutical Co., Ltd., SOMPO Holdings, Inc., NuVasive
Japan Co., Ltd., Promotion of Practical Use of AI
Medical Diagnosis Support Equipment, MS&AD
InterRisk Research & Consulting, Inc, Inotech Co.,
Ltd., The Association for Preventive Medicine inJapan, DeNA Co., Ltd., Ibuki LLC. The department is
a collaboration among the Department ofOrthopaedics, the Department of Rehabilitation
Medicine. Currently, our aims are to design analgorithm for diagnosing and treating most types ofmusculoskeletal pain that do not have establishedtreatment guidelines and to elucidate evidence for the
possibility of developing causal therapies.
In the “Comprehensive Survey of Living Conditions”
and the “Survey on the Status of Occurrence of
Diseases at Work,” which were published by the
Health, Labour, and Welfare Ministry, the issues
affecting the locomotive apparatus over the years,
particularly low back pain and joint pain, have beenranked as the top complaints among citizens and as acause of absence from work. Musculoskeletal pain,

mainly low back pain and joint pain, is an issue with ahigh complaint rate that causes tremendous social
loss.
The course on medical research and the
management of musculoskeletal pain was madeavailable to provide more knowledge on highly
prevalent musculoskeletal pain and to become a coreprogramme in leading multidisciplinary clinicalresearch.
To achieve these goals, we will closely collaborate
with the Department of Orthopaedics, Department of
Spinal Surgery, Department of Rehabilitation. On thebasis of an extensive epidemiological survey, we will
identify risk factors that contribute to determining thetherapeutic strategy for treating musculoskeletal pain
as well as the prognosis. In addition, on the basis ofthese determined risk factors, we will develop andpropose diagnostic tools/algorithms as well as
prevention and treatment programmes. Then we willcollect and analyse clinical data and systematise thediagnosis, prevention, and treatment of chronic pain –mainly musculoskeletal pain.

Research activities
We will explore the risk factors that contribute todetermining the therapeutic strategy for treatingmusculoskeletal pain and the prognosis.

388

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.

4.

5.

3) Fostering clinicians who are familiar withmusculoskeletal pain assessment and treatment, andenlightening the general public with evidence-basedknowledge about musculoskeletal pain

References
1.

2.

Arita S, Ishimoto Y, Hashizume H, Nagata K,
Muraki S, Oka H, Takami M, Tsutsui S, Iwasaki
H, Yukawa Y, Akune T, Kawaguchi H, Tanaka S,
Nakamura K, Yoshida M, Yoshimura N, Yamada
H; Consortium. Is radiographic lumbar spinal
stenosis associated with the quality of life?: The
Wakayama Spine Study. PLoS One. 2022 Feb 17;
17(2):e0263930. doi: 10.1371/journal.pone.0263930.
PMID: 35176078; PMCID: PMC8853503.
Teraguchi M, Hashizume H, Oka H, Cheung JPY,
Samartzis D, Tamai H, Muraki S, Akune T,
Tanaka S, Yoshida M, Yoshimura N, Yamada H.
Detailed Subphenotyping of Lumbar Modic
Changes and Their Association with Low Back

6.

7.

Pain in a Large Population-Based Study: The
Wakayama Spine Study. Pain Ther. 2022 Mar;11(1):57-71. doi: 10.1007/s40122-021-00337-x.
Epub 2021 Nov 15. PMID: 34782999; PMCID:
PMC8861214.
Nishizawa A, Katsuhira J, Watanabe M, Fujii T,
Yoshimoto T, Oka H, Matsudaira K. Relationshipbetween the locomotive syndrome and kinetic
and kinematic parameters during static standing
and level walking. Gait Posture. 2022 Mar;
93:146-152. doi: 10.1016/j.gaitpost.2022.01.017.
Epub 2022 Jan 22. PMID: 35151196.
Tamai H, Teraguchi M, Hashizume H, Oka H,
Cheung JPY, Samartzis D, Muraki S, Akune T,
Kawaguchi H, Nakamura K, Tanaka S, Yoshida
M, Yoshimura N, Yamada H. A Prospective,
3-year Longitudinal Study of Modic Changes of
the Lumbar Spine in a Population-based Cohort:
The Wakayama Spine Study. Spine (Phila Pa
1976). 2022 Mar 15;47(6):490-497. doi: 10.1097/
BRS.0000000000004301. PMID: 35213525.
Horii C, Iidaka T, Muraki S, Oka H, Asai Y,
Tsutsui S, Hashizume H, Yamada H, Yoshida M,
Kawaguchi H, Nakamura K, Akune T, Oshima Y,
Tanaka S, Yoshimura N. The cumulative
incidence of and risk factors for morphometricsevere vertebral fractures in Japanese men andwomen: the ROAD study third and fourth
surveys. Osteoporos Int. 2022 Apr;33(4):889-899.
doi: 10.1007/s00198-021-06143-7. Epub 2021
Nov 19. PMID: 34797391.
Osuka Y, Okubo Y, Nofuji Y, Sasai H, Seino S,
Maruo K, Fujiwara Y, Oka H, Shinkai S, Lord
SR, Kim H. Modifiable intrinsic factors related tooccupational falls in older workers. Geriatr
Gerontol Int. 2022 Apr;22(4):338-343. doi:
10.1111/ggi.14370. Epub 2022 Mar 9. PMID:
35266260.
Nagata K, Yamada K, Shinozaki T, Miyazaki T,
Tokimura F, Tajiri Y, Matsumoto T, Yamakawa K,
Oka H, Higashikawa A, Sato T, Kawano K,
Karita T, Koyama T, Hozumi T, Abe H, Hodohara
M, Kohata K, Toyonaga M, Oshima Y, Tanaka S,
Okazaki H; OSSI investigators. Effect ofAntimicrobial Prophylaxis Duration on HealthCare-AssociatedInfections
After
Clean
Orthopedic Surgery: A Cluster Randomized Trial.

389

8.

9.

10.

11.

12.

13.

JAMA Netw Open. 2022 Apr 1;5(4):e226095.
doi: 10.1001/jamanetworkopen.2022.6095. PMID:
35412627; PMCID: PMC9006110.
Murata S, Iwasaki H, Oka H, Hashizume H,
Yukawa Y, Minamide A, Tsutsui S, Takami M,
Nagata K, Taiji R, Kozaki T, Yamada H. A novel
technique using ultrasonography in upper airway
management after anterior cervical decompression and fusion. BMC Med Imaging. 2022 Apr
12;22(1):67. doi: 10.1186/s12880-022-00792-8.
PMID: 35413818; PMCID: PMC9004088.
Yamada K, Fujii T, Kubota Y, Wakaizumi K, Oka
H, Matsudaira K. Negative effect of anger onchronic pain intensity is modified by multiple
mood states other than anger: A large
population-based cross-sectional study in Japan.
Mod Rheumatol. 2022 Apr 18;32(3):650-657.
doi: 10.1093/mr/roab035. PMID: 34910207.
Itoh N, Mishima H, Yoshida Y, Yoshida M, Oka
H, Matsudaira K. Evaluation of the Effect ofPatient Education and Strengthening Exercise
Therapy Using a Mobile Messaging App on Work
Productivity in Japanese Patients With Chronic
Low Back Pain: Open-Label, Randomized,
Parallel-Group Trial. JMIR Mhealth Uhealth.
2022 May 16;10(5):e35867. doi: 10.2196/35867.
PMID: 35576560; PMCID: PMC9152720.
Matsudaira K, Oka H, Yoshimoto T. Changing
concepts in approaches to occupational low backpain. Ind Health. 2022 Jun 1;60(3):197-200. doi:
10.2486/indhealth.60_300. Epub 2022 Apr 15.
PMID: 35431293; PMCID: PMC9171122.
Yoshimura N, Iidaka T, Horii C, Mure K, Muraki
S, Oka H, Kawaguchi H, Akune T, Ishibashi H,
Ohe T, Hashizume H, Yamada H, Yoshida M,
Nakamura K, Tanaka S. Epidemiology oflocomotive syndrome using updated clinicaldecision limits: 6-year follow-ups of the ROAD
study. J Bone Miner Metab. 2022 Jul;40(4):623635. doi: 10.1007/s00774-022-01324-8. Epub
2022 May 10. Erratum in: J Bone Miner Metab.
2022 Jun 14;: PMID: 35536512.
Yoshimoto T, Yamada K, Fujii T, Kawamata K,
Kasahara S, Oka H, Matsudaira K. Validity andReliability of the Japanese Version of the Örebro
Musculoskeletal Pain Screening QuestionnaireShort Form for Chronic Low Back Pain. Pain

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Physician. 2022 Jul;25(4):E681-E688. PMID:
35793192.
Harada T, Hashizume H, Taniguchi T, Iidaka T,
Asai Y, Oka H, Muraki S, Akune T, Kawaguchi
H, Nakamura K, Yoshida M, Tanaka S,
Yoshimura N, Yamada H. Association between
acetabular dysplasia and sagittal spino-pelvicalignment in a population-based cohort in Japan.
Sci Rep. 2022 Jul 25;12(1):12686. doi: 10.1038/
s41598-022-16865-1. PMID: 35879394; PMCID:
PMC9314415.
Yoshimura N, Iidaka T, Horii C, Mure K, Muraki
S, Oka H, Kawaguchi H, Akune T, Ishibashi H,
Ohe T, Hashizume H, Yamada H, Yoshida M,
Nakamura K, Tanaka S. Correction to:
Epidemiology of locomotive syndrome using
updated clinical decision limits: 6-year
follow-ups of the ROAD study. J Bone Miner
Metab. 2022 Sep;40(5):872. doi: 10.1007/s00774022-01349-z. Erratum for: J Bone Miner Metab.
2022 Jul;40(4):623-635. PMID: 35699791.
Yoshimura N, Iidaka T, Horii C, Muraki S, Oka
H, Kawaguchi H, Nakamura K, Akune T, Tanaka
S. Trends in osteoporosis prevalence over a
10-year period in Japan: the ROAD study
2005-2015. J Bone Miner Metab. 2022 Sep;
40(5):829-838. doi: 10.1007/s00774-022-013524. Epub 2022 Aug 29. PMID: 36038673.
Tonosu J, Oka H, Watanabe K, Abe H,
Higashikawa A, Kawai T, Yamada K, Nakarai H,
Tanaka S, Matsudaira K. Relationship Between
Sacroiliac Joint-related Pain and Spinopelvic
Mobility. Spine (Phila Pa 1976). 2022 Sep 15;
47(18):E582-E586. doi: 10.1097/BRS.000000000
0004390. Epub 2022 Jun 29. PMID: 35793690.
Kozaki T, Hashizume H, Taniguchi T, Nishiyama
D, Iwasaki H, Tsutsui S, Takami M, Nagata K,
Fukui D, Yamanaka M, Tamai H, Taiji R, Murata
S, Oka H, Yamada H. S2 alar-iliac screw
loosening as a preventive factor for hip joint
osteoarthritis after adult spinal deformity surgery:a case-control study. Eur Spine J. 2022 Nov;
31(11):3081-3088. doi: 10.1007/s00586-02207344-2. Epub 2022 Aug 23. PMID: 35999305.
Matsubara T, Soma K, Yamada I, Fujita H,
Yoshitani J, Oka H, Okada H, Tanaka S. Offset
nail fixation for intertrochanteric fractures390

improves reduction and lag screw position. PLoS
One. 2022 Nov 16;17(11):e0276903. doi: 10.1371/
journal.pone.0276903. PMID: 36383515; PMC
9668128.

391

Department of Osteoimmunology
Project Associate Professor
Kazuo Okamoto, Ph.D.

Project Assistant Professor
Masayuki Tsukasaki, Ph.D.

Homepage

http://www.osteoimmunology.com/kifu/index.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. The second term started in
May 2019, and was temporarily suspended in June
2022. Subsequently, the third phase started in
November 2022, with support from AYUMI
Pharmaceutical
Corporation,
ELECOM,
JCR
Pharmaceuticals,
Kondo
CottonSpinning,
MIKIHOUSE, MITSUI FUDOSAN, Meiji, Noevir,
TAKENAKA,TENNENBUTSUIKAGAKU
KENKYU ZAIDAN and Yakult.
We aim tounderstand 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.

392

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
imbalance of bone resorption and formation is often
central to metabolic bone diseases, including bone
destruction in RA, postmenopausal osteoporosis, bonetumors and osteopetrosis. Osteoclasts are large,
multinucleated cells formed by the fusion of precursor
cells of monocyte/macrophage lineage.
Matureosteoclasts degrade bone matrix proteins by secreting
proteolytic enzymes and decalcify the inorganic
components of bone by releasing hydrochloric acid.
RANKL is an essential cytokine for osteoclastdifferentiation. RANKL, which are produced by the
supporting mesenchymal cells including osteoblasts,
osteocytes and synovial fibroblasts, binds to its
receptor RANK expressed on osteoclast precursor
cells. Mice with a disruption of either Rank or Rankl
exhibit severe osteopetrosis accompanied by a tooth
eruption defect resulting from a complete lack ofosteoclasts. Mutations in the RANK and RANKL
genes have been identified in human patients withbone disorders such as autosomal recessive osteopetrosis. These genetic findings clearly demonstratethat RANK/RANKL signaling is essential for
osteoclastogenesis in vivo. We aim to elucidate themolecular mechanism underlying RANKL-induced
osteoclast differentiation, in order to develop thenovel therapeutic strategies for the treatment ofvarious bone diseases such as RA and osteoporosis(Tsukasaki et al, J Bone Miner Res, 2016; Okamoto etal, Physiol Rev, 2017). Recently, we have elucidated
the mechanism of osteoclastogenesis at the single celllevel by single-cell RNA sequencing analysis.
Osteoclast differentiation pathway can be divided into
multi stages, and we identified a number of genes that
determine each differentiation stage. We found thatthe transcriptional regulator Cited2 regulates theterminal differentiation step by promoting cell cycle
arrest. The single-cell analysis data covering all
pathways of osteoclast differentiation would be auseful resource for the development of therapeutic
treatments targeting osteoclasts (Tsukasaki et al, Nat
Metab, 2020).

RANKL plays crucial roles in not only osteoclastdifferentiation but also the immune system, including
lymph node development, thymic epithelial celldifferentiation and M cell differentiation in gut.
Thus, RANKL is one of the most important factors
explicitly linking the skeletal and immune systems.
RANKL is synthesized as a membrane-boundmolecule, which is cleaved into the soluble form byproteases. Both forms function as agonistic ligands
for RANK.
However, the functional difference
between the membrane-bound and soluble forms of
RANKL had been poorly understood in vivo. Thus,
we tried to elucidate the physiological andpathological significances of soluble RANKL bygenerating mice that selectively lack soluble RANKL.
Soluble RANKL-deficient mice did not show any
discernible osteopetrotic phenotype. In addition,soluble RANKL made no contribution to ovariectomyinduced osteoporosis.
Thus, membrane-boundRANKL mainly functions in osteoclast differentiationin vivo.
Furthermore, unlike RANKL-null mice,soluble RANKL-deficient mice had normal
development of the immune organs, including lymph
node development, thymic medullary epithelial celldifferentiation and M cell differentiation. Collectively,
we demonstrated that soluble RANKL is dispensablefor physiological regulation of bone and immune
systems (Asano et al, Nat Metab, 2019).
RANKL also deeply contributes to the pathogenesisof bone metastasis. In bone, tumor cells induce theRANKL expression in osteoblasts through the
production of PTHrP and IL-6. RANKL promotes
osteoclastic bone resorption, which provides space fortumor expansion and releases certain growth factors
from the degraded bone matrices to stimulate tumor
growth, forming a vicious cycle. In addition, RANK
is expressed at high levels on many different epithelial
tumor cells that preferentially metastasize to bone.
RANKL acts directly on RANK-expressing tumor
cells to increase tumor migration to bone. Notably,soluble RANKL contributes to bone metastasis byexerting a chemotactic activity in tumor cells
expressing RANK. Soluble RANKL deficiency inmice markedly suppressed the metastasis of murine
melanoma cell line B16F10 and breast cancer cell line
EO771, both of which express RANK, to bone
（Asano et al, Nat Metab, 2019; Okamoto, J Bone

393

Miner Metab, 2021）. Interestingly, the recent humanstudy indicates that breast cancer patients with highlevels of serum RANKL had an increased risk ofdeveloping bone metastases. Thus, to measure theserum RANKL level may help identify the patients
who have a high risk of development of bonemetastasis.
In rheumatoid arthritis, synovial fibroblasts act as
the main source of RANKL that induces osteoclastic
bone resorption in joints. Recent single cell analyses
have shown that synovial fibroblasts could beclassified into two subsets, inflammation type andtissue-destructive type. By analyzing the mechanismof transcriptional regulation of RANKL, we revealed
that transcriptional factor ETS1 drives the polarization
toward tissue-destructive fibroblasts in rheumatoid
arthritis (Yan et al, Nat Immunol, 2022).
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394

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
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. Yan M, Komatsu N, Muro R, Huynh NC,
Tomofuji Y, Okada Y, Suzuki HI, Takaba H,
Kitazawa R, Kitazawa S, Pluemsakunthai W,
Mitsui Y, Satoh T, Okamura T, Nitta T, Im SH,
Kim CJ, Kollias G, Tanaka S, Okamoto K,
Tsukasaki M, Takayanagi H. ETS1 governs
pathological tissue-remodeling programs indisease-associated fibroblasts. Nat Immunol.
23:1330-1341, 2022
2. Ono T, Denda R, Tsukahara Y, Nakamura T,
Okamoto K, Takayanagi H, Nakashima T.
Simultaneous augmentation of muscle and boneby locomomimetism through calcium-PGC-1 ﾎｱ
signaling. Bone Res. 10:52, 2022
3. Tsukasaki M, Komatsu N, Negishi-Koga T,
Huynh NC, Muro R, Ando Y, Seki Y, Terashima A,
Pluemsakunthai W, Nitta T, Nakamura T,
Nakashima T, Ohba S, Akiyama H, Okamoto K,
Baron R, Takayanagi H. Periosteal stem cells

control growth plate stem cells during postnatalskeletal growth. Nat Commun. 13: 4166, 2022
4. Tsukasaki M, Takayanagi H. Osteoclast biology inthe single-cell era. Inflamm Regen. 42: 27, 2022

395

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 Research Associate
Kensuke Asaba, M.D.,Ph.D., Katsuhiro Koyama, M.D., Ph.D., Takayuki Fujiwara, M.D.,
Ph.D., Takahiro Nakao, M.D., Ph.D., Kanna Fujita, M.D., Ph.D., Mai Shimbo, M.D., Ph.D.
Saori Koshino, M.D., Ph.D.

Project researcher
Masaya Akiyama, M.S., Alam Md Ashraful, Ph.D., Yukihiro Nomura, Ph.D., R.T.

Homepage

http://www.ut-radiology.umin.jp/division/cdrpm.html

Introduction and Organization

Clinical Activities

The Department of Computational Diagnostic
Radiology and Preventive Medicine (CDRPM) wasestablished in May 2005. It is under the supervision of
the Department of Radiology.
The aim of our research project is as follows: (1)to create a large database of health screening clinicaldata including medical images, (2) to develop methods
to analyze large volumes of medical images and to
search for algorithms to detect subtle abnormal
findings in these images, and (3) to evaluate theclinical usefulness of such image processing methods
and to apply the system in clinical settings.
The department comprises twelve professors andthree project researchers, along with a medical staff ofapproximately 70 employees in the health-screening
center.

CDRPM is responsible for the clinical activities in
the CDRPM Health Screening Center. The following
diagnostic imaging modalities are installed tofacilitate high level of diagnostic accuracy: positronemission computed tomography (PET), 3-teslamagnetic resonance imaging (3T-MRI) system, multidetector CT (MDCT), ultrasound imaging system, anddigital mammography.

Teaching Activities
At present, CDRPM does not accept students.
However, CDRPM participates in the education of
students and residents in the Department of Radiology.
CDRPM endeavors to help students whose research
themes include image analysis such as computerassisted detection, or epidemiologic studies employing
health-screening data.

396

Research Activities
1) Health screening database
We have developed a unique health screening information system to facilitate daily management of thehealth screening activities and to input healthscreening data. This information system is still underconstant revision. The medical images acquired in thehealth screenings are stored in the hospital picturearchiving and communication system (PACS) for
clinical use. Medical images used solely for research
purposes are stored in an independent PACS installedinside the CDRPM department.
2) Image processing software development
We have structured an integrated software developing
system to facilitate the production of image processing
software. The system is divided into the clinical partand the research part, with the data in the latter being
anonymized. The clinical part consists of case entry
for software development, and clinical application of
the developed software. The research part consists ofan interface to obtain images of the representative
cases to develop the software, and an interface to test
the developed software with the accumulated cases.
3) Clinical evaluation, application of software, andepidemiological studies
Researches based on the health-screening database arecarried out in collaboration with other researchers ofvarious specialties. Images are analyzed using thedeveloped software.

References
1)

2)

Takahashi M, Takenaga T, Nomura Y, Hanakoka
S, Hayashi N, Nemoto M, Nakao T, Miki S,
Yoshikawa T, Kobayashi T, Abe S. Automatedvolume measurement of abdominal adipose tissue
from entire abdominal cavity in dixon MR
images using deep learning. Radiol Phys Technol.
2023;16(1):28-38.
doi:10.1007/s12194-022-00
687-x.
Ishii S, Hatano M, Maki H, Minatsuki S, Saito A,
Yagi H, Shimbo M, Soma K, Numata G,
Fujiwara T, Takeda N, Komura I. Prognostic
value of follow-up vasoreactivity test in

pulmonary arterial hypertension. J Cardiol. 2023.
doi: 10.1016/j.jjcc.2023.01.005.
3) Kikuchi T, Hanaoka S, Nakao T, Nomura Y,
Yoshikawa T, Alam A, Mori H, Hayashi N.
Significance of FDG–PET standardized uptake
values in predicting thyroid disease. European
Thyroid Journal. 2023;12(1):e220165. doi: 10.
1530/ETJ-22-0165.
4) Yoshikawa T, Miki S, Nakao T, Koshino S,
Hayashi N, Abe O. Axillary lymphadenopathy
after pfizer-BioNTech and moderna COVID-19
vaccination: MRI evaluation. Radiology. 2023;
306(1):270-278. doi: 10.1148/radiol.220814.
5) Sasako T, Kadowaki H, Fujiwara T, et al. Severe
aortic stenosis during leptin replacement therapy
in a patient with generalized lipodystrophyassociated progeroid syndrome due to an LMNA
variant: A case report. J Diabetes Investig.
2022;13(9):1636-1638. doi: 10.1111/jdi.13827.
6) Shibata H, Hanaoka S, Nomura Y, Nakao
T,Takenaga T, Hayashi N, Abe O. On thesimulation of ultra-sparse-view and ultra-lowdose computed tomography with maximum aposteriori reconstruction using a progressive
flow-based deep generative model. Tomography(Ann Arbor). 2022;8(5):2129-2152. doi: 10.3390/
tomography8050179.
7) Shimbo M, Hatano M, Ishii S, et al. Renal
replacement therapy as a therapeutic option forright heart failure in severe pulmonary arterial
hypertension. ESC Heart Fail. 2022;9(4):27282731. doi: 10.1002/ehf2.13945.
8) Nakao T, Hanaoka S, Nomura Y, Hayashi N, Abe
O. Anomaly detection in chest 18F-FDG PET/CT
by bayesian deep learning. Jpn J Radiol. 2022;
40(7):730-739. doi: 10.1007/s11604-022-01249-2.
9) Hoshiai S, Hanaoka S, Masumoto T, Nomura
Y ,et al. Effectiveness of temporal subtraction
computed tomography images using deeplearning in detecting vertebral bone metastases.
Eur J Radiol. 2022;154:110445. doi: 10.1016/j.
ejrad.2022.110445.
10) Itai S, Tonosaki K, Ono S, Watanabe R, Koshino
S, et al. The inhibitory effect of catechin on thegrowth of oral bacteria in vitro and halitosis in aclinical setting. . 2022:in press.

39711) Nakayama A, Kodera S, Morita H, Fujiwara T,
Takeda N, Komuro I. Cost-effectiveness ofmanagement for hospitalized patients; genderdifference between female and male cardiologists.
International Heart Journal. 2022;63(2):264-270.
doi: 10.1536/ihj.21-451.
12) Yoshikawa M, Asaba K, Nakayama T.
Estimating causal effects of genetically predictedtype 2 diabetes on COVID-19 in the east asian
population. Front Endocrinol. 2022;13. doi:
10.3389/fendo.2022.1014882.
13) Shimbo M, Amiya E, Komuro I. Telemonitoring
duringexercisetraining
incardiactelerehabilitation: A review. Rev. Cardiovasc.
Med. 2023;. ;24(4). doi: 10.31083/j.rcm2404104.

398

Department of Cell Therapy inRegenerative Medicine
Specially Appointed Associate Professor
Dehua Chang, M.D., Ph.D.

Researcher and Associate
Zhu Shuoji (Ph.D. Student), Shentu Yunchao, Tajima Michiko, Kobayashi Masaki,
Katsuhiko Kida

Administrative Assistant
Noriko Kajiwara

Department Outline
The Department of Cell Therapy in Regenerative
Medicine was established in 2021 to promote practicaltechnologies for regenerative medicine, such as
developing the mass culture of 3D mesenchymal stem
cells (MSCs) and diagnostic imaging related to MSCs.
MSCs are stem cells derived from the mesoderm, a typeof somatic stem cell, and can differentiate into bone,cartilage, cardiomyocytes, etc. MSC culture methods
are classified into two types: adhesive cells (2D) andfloating cells (3D). The advancement and applicationof regenerative medicine necessitate a stem cell culture
method that facilitates faster proliferation, enhanced
stemness, and improved functionality. Our department
aims to develop technology for the mass culture ofhigh-quality MSCs using Cellhesion®, a scaffold
material developed by Nissan Chemical Corporation.
Recently, cell quality evaluation has become necessary
to ensure reproducibility, reliability, and accuracy indrug discovery research using cultured cells. MSCs
express marker genes, such as CD105, CD73, CD90,
etc. However, since it is impossible to determine thequality of MSCs, such as whether they are increasing
cells or not, even if these markers are expressed, it isessential to have a method to evaluate the quality of
MSCs. In addition, because MSCs vary among tissuesof origin, donors, and other factors, even MSCs with alow number of passages may not increase and cannot
be passaged. At present, it is left to the operator todecide at what stage to discontinue the culture. Our
department will use Nikon Corporation's cell imaging
technology to evaluate cell quality during MSC 3D
mass culture.

Research Content
Nissan Chemical Corporation has pioneered inregenerative medicine by developing the scaffold
material Cellhesion® for cultivating UCMSCs,
demonstrating approximately seven times the antiinflammatory efficacy compared to traditional 2D
cultivated cells, showcasing substantial potential fortreating various diseases. In this study, we conducted acomprehensive assessment of the proliferative capacityof UCMSCs cultivated in both 2D and 3D
environments, accompanied by an analysis andevaluation of secretion factors related to angiogenic
factors, angiogenesis, cell migration, self-replication
capacity, and multi-differentiation ability of UCMSCs
in vitro study.
The 3D-cultured UCMSCs maintain their inherent
characteristics as mesenchymal stem cells and preserve
their potential to differentiate into bone, cartilage, andadipose tissues. Comparative studies have shown that
3D culture enhances cell proliferation and increases the399

secretion of vascular growth factors like HGF, VEGF,
IL-6, and IL-8 compared to 2D culture. In 3D culture,
there was a considerable increase in angiogenesis, total
extension, and branching points compared to 2D
culture, as shown by in vitro angiogenesis assays.
It has been observed that UCMSCs when cultivated ina 3D environment using Cellhesion® material,
maintain their undifferentiated and migratory
capacities. Additionally, they exhibit noteworthy andenhanced cellular activity, which is not attainablethrough 2D cultivation. Therefore, it is highly likelythat the use of Cellhesion® material can provide
significant
potential
andopportunitiesforadvancements in regenerative medicine and cellulartherapy.

Future Outlook
We aim to evaluate the anti-inflammatory andangiogenic effects of 3D-cultured MSCs optimized forlarge-scale cultivation. In future studies, we plan toassess the effectiveness of administering supernatants
that contain 3D cultured MSCs and angiogenic factors
in vivo models of knee osteoarthritis and lower limb
ischemia. We aim to explore their potential benefits inpromoting vascular regeneration and reducing
inflammation. Our goal is to assess the efficacy of thesetreatments while ensuring that 3D-cultured MSCs aresafe and reliable.

References
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2.

3.

Liu G, David BT, Trawczynski M, Fessler RG.
Advances in Pluripotent Stem Cells: History,
Mechanisms, Technologies, and Applications.
Stem Cell Rev Rep. 2020; 16(1):3-32.
Zucchelli E, Birchall M, Bulstrode NW, Ferretti P.
Modeling Normal and Pathological Ear Cartilage
In vitro Using Somatic Stem Cells in ThreeDimensional Culture. Front Cell Dev Biol. 2020
Jul 28; 8:666. doi: 10.3389/fcell.2020.00666.
PMID: 32850801; PMCID: PMC7402373.
Lechanteur C, Briquet A, Giet O, Delloye O,
Baudoux E, Beguin Y. Clinical-scale expansion ofmesenchymal stromal cells: a large banking
experience. J Transl Med. 2016 May 20;14(1):145.
doi:
10.1186/s12967-016-0892-y.
PMID:27207011; PMCID: PMC4875672.

4.

Eun Seo Kim, Katsuhiko Kida, Jongsoo Mok, et al.
Cellhesion VP enhances the immunomodulating
potential of human mesenchymal stem cellderived extracellular vesicles. Biomaterials, 2021
Volume 271: 120742.DOI: 10.1016/j.biomaterials.
2021.120742.
5. Li-Tzu Wang, Chiao-Hsuan Ting, Men-Luh Yen,
Ko-Jiunn Liu, Huey-Kang Sytwu, Kenneth K Wu,
B Linju Yen. Human mesenchymal stem cells(MSCs) for treatment towards immune- andinflammation-mediated diseases: review ofcurrent clinical trials. J Biomed Sci. 2016 Nov 4;23(1):76.
6. Katsuda T, Kosaka N, Takeshita F, Ochiya T. The
therapeutic potential of mesenchymal stem cellderived extracellular vesecles. Proteomics. 2013
May; 13 (10-11): 1637-1653.
7. Lechanteur C, Briquet A, Giet O, Delloye O,
Baudoux E, Beguin Y. Clinical-scale expansion ofmesenchymal stromal cells: a large banking
experience. J Transl Med. 2016 May 20;14(1):145.
doi:
10.1186/s12967-016-0892-y.
PMID:27207011; PMCID: PMC4875672.
8. Levenberg S, Burdick JA, Kraehenbuehl T, et al.
Neurotrophin-Induced Differentiation of Human
Embryonic Stem Cells on Three-Dimensional
Polymeric Scaffolds. Tissue Eng 2005; 11:506–
512.
9. Dominici M, Blanc KL, Mueller I, et al. Minimal
criteria for defining multipotent mesenchymal
stromal cells. The International Society for
Cellular Therapy position statement. Cytotherapy
2006; 8:315–317.
10. Kida K, Kanaki T, Gao S, et al. A Novel 3D
CultureSystemUsingaChitin-Based
Polysaccharide Material Produces High-Quality
Allogeneic Human UCMSCs with Dispersed
Sphere Morphology. Cells 2022; 11:995.
11. Cesarz Z, Tamama K. Spheroid Culture of
Mesenchymal Stem Cells. Stem Cells Int 2016;
2016:9176357.

400

Department of Home Care
Medicine
Project Associate Professor
Takashi Yamanaka, M.D., Ph.D.

Project Lecturer
Jiro Okochi, M.D., Ph.D.

Project Research Associate
Kiwami Kidana, M.D., Ph.D., Shota Hamada, R.Ph., Dr.P.H.

Project Researcher
Shigemasa Katayama, M.D., Ph.D., Tatsuya Kurokawa, M.D., Ph.D.,
Maiko Mizuki, MPH.

Homepage

http://chcm.umin.jp/

Introduction and Organization
Department of Home Care Medicine was establishedin 2018 at the 22nd Century Medical and ResearchCenter in the University of Tokyo Hospital based upon
contributions by Mr. Kazuteru Noguchi, JSH Co., Ltd.,
Japan Home Medical Care Inc., Towa Pharmaceutical
Co. Ltd., Sawai Pharmaceutical Co. Ltd., and Ain
Pharmaciez. Our department collaborates with
Department of Geriatric Medicine. We have takenover educational activities and research activities fromCenter for Home Care Medicine, Faculty of Medicine.
With the increase in the elderly population, home care
medicine is more needed compared with the past. We
teach home care medicine to medical students andtrainee doctors along with studying the topics of homecare medicine to systematize it.

Education
Clinical education of home care medicine is provided
for fifth and sixth year medical students. We create apersonalized mandatory program of home care
medicine and give an orientation of the program. Then
medical students learn about home care medicine withphysicians, nurses, medical social workers or caremanagers in the community.
We also create a program of home care medicine fortrainee doctors who wish to learn about it.

Research
The main themes of our study were as follows.
1) Educational program development of home care
medicine and studying the educational effectiveness of the program2) Building a case registry system of home medicalcare3) Follow-up study on QOL or prognosis of patients
who receive home medical care and their caregivers4) Drug treatment in home medical care5) Skills of medical therapeutics and care in homecare medicine

Publications
1.

Kuroda N, Iwagami M, Hamada S, Komiyama J,
Mori T, Tamiya N. Associations of polypharmacy
and drugs with sedative or anticholinergic

401

2.

3.

4.

5.

6.

7.

8.

properties with the risk of long-term care needs
certification among older adults in Japan: Apopulation-based, nested case-control study.
Geriatr Gerontol Int. 2022;22(7):497-504.
Hattori Y, Hamada S, Ishizaki T, Sakata N,
Iwagami M, Tamiya N, Akishita M, Yamanaka T.
National trends in gastrostomy in older adults
between 2014 and 2019 in Japan. Geriatr
Gerontol Int. 2022;22(8):648-652.
Yamanaka T, Kidana K, Mizuki M, Hattori Y,
Hamada S, Akishita M. Sex differences in placesof home care. Geriatr Gerontol Int. 2022;22(9):813-814.
Yamanaka T, Kidana K, Yamaguchi Y, Hirahara S,
Hirakawa Y, Mizuki M, Arai H, Akishita M,
Miura H. Palliative home care for older patientswith respiratory disease in Japan: Practices andopinions of physicians. Geriatr Gerontol Int.
2022;22(11):943-949.
Hattori Y, Hamada S, Yamanaka T, Kidana K,
Iwagami M, Sakata N, Tamiya N, Kojima T,
Ogawa S, Akishita M. Drug prescribing changes
in the last year of life among homebound older
adults: national retrospective cohort study. BMJ
Support Palliat Care. 2022:bmjspcare-2022003639.
Yamaguchi Y, Saif-Ur-Rahman KM, Nomura M,
Ohta H, Hirakawa Y, Yamanaka T, Hirahara S,
Miura H. Opioid Prescription Method forBreathlessness Due to Non-Cancer Chronic
Respiratory Diseases: A Systematic Review. Int J
Environ Res Public Health. 2022;19(8):4907.
Sun Y, Iwagami M, Sakata N, Ito T, Inokuchi R,
Uda K, Hamada S, Ishimaru M, Komiyama J,
Kuroda N, Yoshie S, Ishizaki T, Iijima K, Tamiya
N. Development and validation of a risk score to
predict the frequent emergency house calls
among older people who receive regular home
visits. BMC Prim Care. 2022;23(1):132.
Tsuchiya-Ito R, Hamada S, Slaug B, Ninomiya A,
Uda K, Ishibashi T. Implementation and costs ofhousing adaptations among older adults withdifferent functional limitations in Japan. BMC
Geriatr. 2022;22(1):444.

402

Department of
Therapeutic Strategy forHeart Failure
Research Associate Professor
Eisuke Amiya, M.D., Ph.D (2021/11/1-)

Research Assistant Professor
Seitaro Nomura, M.D., Ph.D(-2023/3/31)
Toshiyuki Ko, M.D., Ph.D (2021/11/1-)
Genri Numata, M.D., Ph.D(2023/4/1-)

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
and Jarvik 2000) considering patients’ physics andclinical status). We also started the “Destination

403

therapy”, which means the implantation of VAD
without heart transplantation.
3. Treatment of PH
Although pulmonary arterial hypertension (PAH)
was a disease of poor prognosis, the treatment outcomeof PAH significantly improved in this decade attributed
to a number of newly approved drugs. Now we can use
ten agents for PAH including oral, inhaled, subcutaneous and intravenous drugs. Combination therapyof these drugs is increasingly prevalent for the management of PAH. We join the nationwide PH registry toestablish optimal treatment strategy for PAH .

Teaching Activities
We have the chair of systematic review of cardiovascular surgery in the spring term at the 2nd grade of
medical course. We also take charge in clinical practiceon diagnosis of cardiovascular disease in the autumn
term at the 2nd grade. We expose the students to dailyclinical works as well as research works during thecourse of “Free Quarter” and “Research Lab Visit”,
which are scheduled in the summer and springvacations at 1st and 2nd grade. Joint lectures with the
Cardiology Department are scheduled 3rd through 4th
grades. Each student is assigned one or two
cardiovascular surgical cases in the Bed Side Learning,in which he/she is required to learn preoperative patient
evaluation and management, surgical treatment andpostoperative care, based on participatory practice.
There are also twelve small key-lectures on
cardiovascular surgery. Hands-on practice is provided
during the “Clinical clerkship” one-month course in thelast months of 3rd grade.
We take charge in core surgical curriculum in the“Super-rotation” postgraduate training. We offer a
program in which each resident can learn basic
knowledge of cardiovascular disease and surgery, andhemodynamic and respiratory evaluation as well asbasic surgical techniques and patient management.
Residents who take the course of cardiovascularsurgery are required three-year general surgicaltraining for General Surgery Board certification. We
have well-developed specialty/ subspecialty training
programs to allow the residents to pass Cardiovascular
Board Examination by 10th postgraduate year.

Research Activities
In order to achieve excellent clinical results and toseek for new possibilities of surgical treatments forheart failure, it is essential for our department of the
University to have active research programs in clinicaland basic subjects related to assisted circulations andheart transplantation. We created highly active research
programs in every field of medical and surgical heart
failure treatment, and played an internationally leadingrole and contributed to its development. A researchmeeting is held every Saturday on a research projectwith Department of Cardiothoracic Surgery.
Basic and/or clinical research activities are focusedon 1) development of new driving method of rotary
blood pump, 2) basic and clinical research on
regenerative therapy, 3) establishment of social support
system for patients with implantable LVAD.

References
1:

2:

3:

4:

5:

Gyoten T, Amiya E, Ono M. SurgicalInterventions for Late Aortic Valve Regurgitation
Associatedwith
Continuous
Flow-Left
Ventricular Assist Device Therapy: Experience
Gained and Lessons Learned. Life (Basel). 2022
Dec 29;13(1):94.
Gyoten T, Amiya E, Kinoshita O, Tsuji M,
Kimura M, Hatano M, Ono M. Clinical outcomesof continuous flow left ventricular assist device
therapy as bridge to transplant strategy inmuscular dystrophy: a single-center study. Gen
Thorac Cardiovasc Surg. 2023 Jun;71(6):347-353.
Tsuji M, Kakuda N, Bujo C, Saito A, Ishida J,
Amiya E, Hatano M, Shimada A, Imai H, Kimura
M, Ando M, Kinoshita O, Yamauchi H, Komuro I,
Ono M. Prophylactic negative pressure woundtherapy is not effective for preventing driveline
infection following left ventricular assist device
implantation. Artif Organs. 2023 Mar;47(3):566573.
Isotani Y, Amiya E, Ishida J, Komuro I.
Summation of Precordial R Wave Amplitudes, a
Clinical Parameter for Detecting Early TTR
Amyloidosis Cardiac Involvement. J Cardiovasc
Dev Dis. 2022 Oct 11;9(10):348.
Bujo S, Amiya E, Maeda MH, Ishida J, Hatano M,
Ishizuka M, Uehara M, Oshima T, Kojima T,404

Nakanishi K, Daimon M, Shimizu J, Toda T,
Komuro I. The effect of immunosuppressive
therapy on cardiac involvements in antimitochondrial antibody-positive myositis. ESC
Heart Fail. 2022 Dec;9(6):4112-4119.
6: Ishizuka M, Uehara M, Katagiri M, Ishida J,
Kojima T, Amiya E, Komuro I. Successfultreatment of recurrent cardiac sarcoidosis with the
combination of corticosteroid and methotrexate
monitored by18F-fluoro-2-deoxyglucose positronemission tomography: case series. Eur Heart J
Case Rep. 2022 Aug 12;6(8):ytac334.
7: Amiya E, Morita H. Simple Way of Identifying
High-Risk Group of Heart Failure in Hypertrophic
Cardiomyopathy in the Japanese Population. Circ
J. 2022 Nov 25;86(12):1941-1942.
8: Kakuda N, Amiya E, Hatano M, Tsuji M, Bujo C,
Ishida J, Yagi H, Saito A, Narita K, Isotani Y,
Fujita K, Ando M, Shimada S, Kinoshita O, Ono
M, Komuro I. Residual Pulmonary Vascular
Resistance Increase Under Left Ventricular Assist
Device Support Predicts Long-Term Cardiac
Function After Heart Transplantation. Front
Cardiovasc Med. 2022 Jun 1;9:904350.
9: Ko T, Nomura S, Yamada S, Fujita K, Fujita T,
Satoh M, Oka C, Katoh M, Ito M, Katagiri M,
Sassa T, Zhang B, Hatsuse S, Yamada T, HaradaM, Toko H, Amiya E, Hatano M, Kinoshita O,
Nawata K, Abe H, Ushiku T, Ono M, Ikeuchi M,
Morita H, Aburatani H, Komuro I. Cardiac
fibroblasts regulate the development of heart
failure via Htra3-TGF-β-IGFBP7 axis. Nat
Commun. 2022 Jun 7;13(1):3275.
10: Narita K, Amiya E, Hatano M, Ishida J, Minatsuki
S, Tsuji M, Bujo C, Kakuda N, Isotani Y, Ono M,
Komuro I. Determining the factors forinterhospital transfer in advanced heart failurecases. Int J Cardiol Heart Vasc. 2022 May 14;40:
101035.
11: Yagi H, Takeda N, Amiya E, Akiyama N, Chang
H, Ishiura H, Sato J, Akazawa H, Morita H,
Komuro I. Nonsyndromic arteriopathy andaortopathy and vascular Ehlers-Danlos syndrome
causing COL3A1 variants. Am J Med Genet A.
2022 Sep;188(9):2777-2782.
12: Gyoten T, Amiya E, Kinoshita O, Tsuji M,
Kimura M, Hatano M, Ono M. Myocardial

13:

14:

15:

16:

17:

18:

19:

recovery evaluation from ventricular assist devicein patients with dilated cardiomyopathy. ESC
Heart Fail. 2022 Aug;9(4):2491-2499.
Shimbo M, Hatano M, Ishii S, Saito A, Yagi H,
Minatsuki S, Maki H, Amiya E, Takeda N,
Komuro I. Renal replacement therapy as atherapeutic option for right heart failure in severe
pulmonary arterial hypertension. ESC Heart Fail.
2022 Aug;9(4):2728-2731.
Amiya E. Social Inequalities in Non-ischemic
Cardiomyopathies. Front Cardiovasc Med. 2022
Mar 7;9:831918. doi: 10.3389/fcvm.2022.831918.
Isotani Y, Amiya E, Ishida J, Ishizuka M, Hatano
M, Nakanishi K, Daimon M, Komuro I. Recovery
of sinus rhythm by tafamidis in patients with wildtype transthyretin amyloid cardiomyopathy withatrial arrhythmias. Oxf Med Case Reports. 2022
Feb 19;2022(2):omac007.
Tsuji M, Kakuda N, Bujo C, Ishida J, Amiya E,
Hatano M, Shimada A, Imai H, Shimada S,
Kinoshita O, Yamauchi H, Ono M, Komuro I.
Sarcopenia and risk of infection in adult hearttransplant recipients in Japan. ESC Heart Fail.
2022 Apr;9(2):1413-1423.
Hatano M, Jimba T, Fujiwara T, Tsuji M, Bujo C,
Ishida J, Amiya E, Kinoshita O, Ono M. Lateonset right ventricular failure after continuousflow left ventricular assist device implantation:case presentation and review of the literature. J
Cardiol. 2022 Aug;80(2):110-115.
Shoji S, Kuno T, Kohsaka S, Amiya E, Asleh R,
Alvarez P, Kampaktsis P, Staffa SJ, Zurakowski
D, Doulamis I, Briasoulis A. Incidence and longterm outcome of heart transplantation patients
who develop postoperative renal failure requiring
dialysis. J Heart Lung Transplant. 2022 Mar;41(3):356-364.
Sugihara T, Nakaoka Y, Uchida HA, Yoshifuji H,
Maejima Y, Watanabe Y, Amiya E, Tanemoto K,
Miyata T, Umezawa N, Manabe Y, Ishizaki J,
Shirai T, Nagafuchi H, Hasegawa H, Miyamae T,
Niiro H, Ito S, Ishii T, Isobe M, Harigai M.
Establishing clinical remission criteria and theframework of a treat-to-target algorithm for
Takayasu arteritis: Results of a Delphi exercise
carried out by an expert panel of the Japan
Research Committee of the Ministry of Health,405

Labour and Welfare for intractable vasculitis.
Mod Rheumatol. 2022 Aug 20;32(5):930-937.
20: Narita K, Amiya E. Social and environmental
risks as contributors to the clonal course of heart
failure. Heart Fail Rev. 2022 Jul;27(4):1001-1016.

406

Department of Biostatistics andBioinformatics
Project Professor
Daisuke Koide, R.Ph., HIM, Ph.D.

Project Lecturer
Shogo Nomura, Ph.D.

Project Assistant Professor
Shotaro Aso, MD, Ph.D .

Homepage

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

Introduction and Organization
Biostatistics is an applied statistics in the fields of
medical and health sciences and contributes to thesefields through developments of statistical methodologies for clinical trials and epidemiological researches.
Biostatisticians who work at an organization for
conducting and coordinating clinical researches (e.g.,
academic research organization) in hospitals andinstitutions are few in Japan. To this end, the Japanfunding agency, Agency for Medical Research andDevelopment (AMED), started the Support Programfor Biostatisticians from 2016.
The AMED selected the Graduate School of the
University of Tokyo and the Graduate school of the
Kyoto University, as 2 centers for training biostatisticians, which function as core facilities, respectively.
Each graduate school establishes a new biostatistics
course, forms a training center upon collaboration
with a hospital, and performs on-the-job training.
This program improves the environment that leads
to higher quality in clinical research and trials, withthe collaboration of industry, academia, and thegovernment, based upon the donations from drug
companies and national research funding. Collaborative projects of industry, academia, and the government through the flow of funds in this program, arethe first of their kind in Japan.
On March 1, 2017, the Department of Biostatistics

and Bioinformation was established in the Graduate
School of Medicine. In the Graduate School ofInterdisciplinary Information Studies in the Universityof Tokyo, the Biostatistics and Bioinformatics course
also started on April 1, 2018. This course provides
specialized education to acquire not only statisticalmethodologies, but also practical skills (e.g., design
and analysis of clinical research, programming,
reporting) for conducting clinical research. We train
biostatisticians with high communication skill andethics that can promote high quality research incollaboration with health care professionals byteaching and on-the-job -training (OJT). AMED has
renewed this project for more 5years since FY2021.

Teaching activities
1) Education in the Biostatistics and Bioinformatics
courseIn the Biostatistics and Bioinformatics course,
through the following teachings, we educate a wide
range of knowledge and skills required to biostatisticians. Its curriculum is made up of 28 subjects
including 42 credits. For students who have taken over
38 credits, we issue a certificate along with the Master
degree.
Biostatistics
Statistical inference,

categorical

data

analysis,

407

survival analysis, longitudinal data analysis, Bayesianstatistics, multiple comparison procedure, multivariate
analysis, causal inference, missing data analysis,
stochastic process and time series analysis, pharmacometrics, statistical programming, genomic data
analysis
Clinical research and epidemiology
Clinical trial methodology, design and analysis of
epidemiological research, research ethics andguidelines, medical research and CDISC standards,
general clinical medicine, regulatory science, medical
writing, medical technology evaluation exercises
In addition, the students receive the OJT at
University of Tokyo Hospital and the National Cancer
Center. The OJT programs are developed by thebiostatisticians of each institution. In the first year of
master's program, the students learn the basic practiceof biostatistician through the training at the Universityof Tokyo Hospital. In the second year, at the National
Cancer Research Center, students receive advanced
training in how to plan the design and analysis ofclinical researches.
2) Seminars and symposiums for the healthcare
professionals and biostatisticians
We give seminars about clinical trial methodologies
and biostatistics for physician, nurse, clinical researchcoordinator, monitor, and other healthcare professionals. We also hold symposia for biostatisticians inacademia and pharmaceutical companies in order toshare and discuss the “state-of-the-arts” of statisticalmethodologies.

Research activities
In the department of biostatistics and bioinformatics,
the main research areas are as follows:
1) Statistical methodology and design of clinical trials
and epidemiology
We study on the statistical methodologies and design
for streamlining clinical trial and estimating treatment
effect precisely. The research area includes Bayesian
design in oncology, clinical trial design using
biomarkers, adaptive design, study on the use ofBayesian statistics in clinical trials, causal inference,and multiple comparison method.
2) Epidemiological methodology
Epidemiology deals with health or disease related
incidence quantitatively in large populations,evaluates cause and effective factors, and ultimately
finds the measures of prevention. It starts fromepidemics (such as infectious diseases) and now its
focus is on lifestyle related diseases, such as cardiovascular disorders. Also, several kinds of medical
databases are developed rapidly in Japan. It is
important to conduct epidemiological, pharmacoepidemiological and clinical epidemiological studies
using such databases.
3) Pharmacoepidemiology
Pharmacoepidemiology is a study to investigate drug
use and its effects in a population. We are engaged inresearch on effectiveness, risk, and cost using dataobtained from hospital information system andelectronic medical record.
4) Clinical Epidemiology
Clinical epidemiology is the application of theprinciples and methods of epidemiology to conductclinical research studies focusing on prevention,
diagnosis, prognosis, and treatment of disease. As thebasic science of Evidence-based Medicine, the importance of clinical epidemiology has been increasing.
5) Medical informatics
Medical informatics is a science of studying how to
use data, information and knowledge in the all
medical fields, such as clinical, medical studies,
education and government. Recently, the area of
medical informatics is much expanding because of the
progress of genomic studies or bioinformatics, andintroduction of new technologies, such as virtual
reality and artificial intelligence (AI).
6) Algebraic statistics
The focus of research is on developing and applying
methods of algebraic statistics to specific statisticalproblems. In statistical inference, the computation ofcomplicated integrals or summation sometimes makes
the problem intractable. When a statistical model408

has algebraic structure, techniques from algebraic
statistics are useful. I currently work on the topics
related to Groebner basis theory and the holonomic
gradient method.

References
1.

2.

3.

4.

Facile R, Muhlbradt EE, Gong M, Li Q, Popat V,
P?tavy F, Cornet R, Ruan Y, Koide D, Saito TI,
Hume S, Rockhold F, Bao W, Dubman S,
Jauregui Wurst B. Use of Clinical Data
Interchange Standards Consortium (CDISC)Standards for Real-world Data: Expert
Perspectives From a Qualitative Delphi Survey.
JMIR Med Inform. 2022 Jan 27;10(1):e30363.
doi: 10.2196/30363. PMID: 35084343; PMCID:
PMC8832264.
Nishikawa A, Yoshinaga E, Nakamura M, Suzuki
M, Kido K, Tsujimoto N, Ishii T, Koide D.
Validation Study of Algorithms to Identify
Malignant Tumors and Serious Infections in a
Japanese Administrative Healthcare Database.
Annals of Clinical Epidemiology. 4(1): 20-31.
2022. Doi: https://doi.org/10.37737/ace.22004
Nakachi K, Ikeda M, Konishi M, Nomura S,
Katayama H, Kataoka T, Todaka A, Yanagimoto
H, Morinaga S, Kobayashi S, Shimada K,
Takahashi Y, Nakagohri T, Gotoh K, Kamata K,
Shimizu Y, Ueno M, Ishii H, Okusaka T, Furuse J,
Hepatobiliary and Pancreatic Oncology Group of
the Japan Clinical Oncology G. Adjuvant S-1
compared with observation in resected biliary
tract cancer (JCOG1202, ASCOT): a multicentre,
open-label, randomised, controlled, phase 3 trial.
Lancet. 2023. 401(10372): 195-203.
Nakamura Y, Okamoto W, Denda T, Nishina T,
Komatsu Y, Yuki S, Yasui H, Esaki T, Sunakawa
Y, Ueno M, Shinozaki E, Matsuhashi N, Ohta T,
Kato K, Ohtsubo K, Bando H, Hara H, Satoh T,
Yamazaki K, Yamamoto Y, Okano N, Terazawa T,
Kato T, Oki E, Tsuji A, Horita Y, Hamamoto Y,
Kawazoe A, Nakajima H, Nomura S, Mitani R,
Yuasa M, Akagi K and Yoshino T. Clinical
Validity of Plasma-Based Genotyping forMicrosatellite
Instability
Assessment
in
Advanced GI Cancers: SCRUM-Japan GOZILA
Substudy. JCO Precis Oncol. 2022. 6: e2100383.

5.

Morizane C, Machida N, Honma Y, Okusaka T,
Boku N, Kato K, Nomura S, Hiraoka N, Sekine S,
Taniguchi H, Okano N, Yamaguchi K, Sato T,
Ikeda M, Mizuno N, Ozaka M, Kataoka T, Ueno
M, Kitagawa Y, Terashima M, Furuse J and Japan
Clinical Oncology G. Effectiveness of Etoposide
and Cisplatin vs Irinotecan and Cisplatin Therapy
for Patients With Advanced Neuroendocrine
Carcinoma of the Digestive System: The
TOPIC-NEC Phase 3 Randomized Clinical Trial.
JAMA Oncol. 2022. 8(10): 1447-1455.
6. Terashima T, Morizane C, Ushiama M, Shiba S,
Takahashi H, Ikeda M, Mizuno N, Tsuji K, Yasui
K, Azemoto N, Satake H, Nomura S, Yachida S,
Sugano K and Furuse J. Germline variants incancer-predisposing genes in pancreatic cancer
patients with a family history of cancer. Jpn J
Clin Oncol. 2022. 52(10): 1105-1114.
7. Niguma K, Mamishin K, Naito Y, Nomura S,
Wakabayashi M, Kusuhara S, Funasaka C, Nakao
T, Fukasawa Y, Kondoh C, Harano K, Kogawa T,
Matsubara N, Hosono A, Onishi T, Kawasaki T
and Mukohara T. Impact of Older Age andMedico-social Factors on the Decision to Offer
Adjuvant Chemotherapy to Patients With Breast
Cancer. Anticancer Res. 2022. 42(7): 3743-3751.
8. Hasegawa H, Tsukada Y, Wakabayashi M,
Nomura S, Sasaki T, Nishizawa Y, Ikeda K,
Takeshita N, Teramura K and Ito M. Impact ofnear-infrared
fluorescenceimagingwithindocyanine green on structural sequelae ofanastomotic
leakageafter
laparoscopic
intersphincteric resection of malignant rectal
tumors. Tech Coloproctol. 2022. 26(7): 561-570.
9. Kojima T, Kato K, Hara H, Takahashi S, Muro K,
Nishina T, Wakabayashi M, Nomura S, Sato A,
Ohtsu A and Doi T. Phase II study of BKM120 inpatients with advanced esophageal squamous cell
carcinoma (EPOC1303). Esophagus. 2022. 19(4):702-710.
10. Aso S, Ono S, Michihata N, Uemura K, Yasunaga
H. Effectiveness of vaccination on influenzarelated critical illnesses in the elderly population.
J Infect Chemother. 2023;S1341-321X(23)000375.

409

Department of Advanced
Cardiology
Project Associate Professor
Katsuhito Fujiu, M.D., Ph.D.

Project Lecturer
Hidehiro Kaneko, M.D., Ph.D.

Project Assistant Professor
Ying Chen, M.D., Ph.D.

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

Introduction and Organization

Research activities

This course is an endowed chair established on April 1,
2018, under the donations of Medtronic Japan Co.,
Ltd., St. Jude Medical Co., Ltd., Boston ScientificJapan Co., Ltd., Fukuda Denshi Tokyo Central Sales
Co., Ltd and SIMPLEX QUANTUM Co., Ltd.
In conjunction with the department ofcardiovascular medicine, this course develops leadingedge medical care. It elucidates the pathogenesis ofunresolved heart failure and cardiovascular disease
and analyzes the pathological condition using cultured
cells, experimental animals, and patient specimens. Byclarifying the new disease pathogenesis mechanismand pathogenesis mechanism, it aims at elucidating
the fundamental pathophysiology of cardiovasculardisease and developing development prevention
methods, new diagnostic methods, and newtherapeutic methods.

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 drugthat acts on the whole body, not on the heart alone,
except for cardiac resynchronization therapy andimplantable defibrillator. From this point of view, as a
research to improve the prognosis of cardiovasculardeath, we will proceed with the investigation,
considering that poor coordination among multiple
organs is involved in the onset of heart disease.
Furthermore, about half of the cells that make up theheart are cardiomyocytes. In contrast, the other half
are non-cardiomyocytes. In this study, we focus on
non-cardiomyocytes and how non-cardiomyocytesinteract with cardiomyocytes. The aim is to find newtherapeutic targets for heart disease by clarifying
whether it is acting, maintaining homeostasis of theheart, and elucidating the pathogenesis of heart failurethat is its failure.
Furthermore, the relationship between theheart and the brain has been examined in detail as astudy of inter-organ cooperation.

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.

410

References
1.

2.

3.

4.

5.

6.

Age Modified Relationship Between Modifiable
Risk Factors and the Risk of Atrial Fibrillation.
Matsuoka S, Kaneko H, Okada A, Morita K, Itoh
H, Michihata N, Jo T, Takeda N, Morita H, Fujiu
K, Nakamura S, Node K, Yasunaga H, Komuro I.
Circ Arrhythm Electrophysiol. 2022 Jan;15(1):e010409. doi: 10.1161/CIRCEP.121.010409.
Nerve-macrophage interactions in cardiovasculardisease. Fujiu K, Manabe I. Int Immunol. 2022
Jan 22; 34(2): 81-95. doi: 10.1093/intimm/dxab
036.
Deep learning model to detect significant aortic
regurgitation using electrocardiography. Sawano
S, Kodera S, Katsushika S, Nakamoto M,
Ninomiya K, Shinohara H, Higashikuni Y,
Nakanishi K, Nakao T, Seki T, Takeda N, Fujiu K,
Daimon M, Akazawa H, Morita H, Komuro I. J
Cardiol. 2022 Mar;79(3):334-341. doi: 10.1016/j.
jjcc.2021.08.029.
Acute-Phase Initiation of Cardiac Rehabilitationfor Short-Term Improvement in Activities of
Daily Living in Patients Hospitalized for AcuteHeart Failure. Ueno K, Kamiya K, Kaneko H,
Okada A, Itoh H, Fujiu K, Takeda N, Morita H,
Michihata N, Jo T, Yasunaga H, Komuro I. J
Cardiovasc Dev Dis. 2022 Mar 25;9(4):97. doi:
10.3390/jcdd9040097.
Change in Cardiovascular Health Metrics andRisk for Proteinuria Development: Analysis of a
Nationwide Population-Based Database. Suzuki
Y, Kaneko H, Okada A, Itoh H, Morita K, Fujiu
K, Michihata N, Jo T, Takeda N, Morita H,
Yamaguchi S, Kamiya K, Matsunaga A, Ako J,
Fukui A, Nishiyama A, Yokoo T, Node K,
Yamauchi T, Nangaku M, Yasunaga H, Komuro I.
Am J Nephrol. 2022; 53(2-3): 240-248. doi:
10.1159/000522147. ＜2022.4＞
Risk for Proteinuria in Newly Defined
Hypertensive People Based on the 2017
American College of Cardiology/American Heart
Association Blood Pressure Guideline. Suzuki Y,
Kaneko H, Okada A, Itoh H, Fujiu K, Michihata
N, Jo T, Takeda N, Morita H, Yamaguchi S, Yano
Y, Kamiya K, Matsunaga A, Ako J, Fukui A,
Yokoo T, Nishiyama A, Node K, Yamauchi T,

Nangaku M, Yasunaga H, Komuro I. Am J
Cardiol. 2022 Apr 1;168:83-89. doi: 10.1016/j.
amjcard.2021.12.023.
7. Association between proteinuria and incident
colorectal cancer: analysis of a nationwide
population-based database. Matsuoka S, Kaneko
H, Okada A, Fukui A, Yano Y, Itoh H, Morita K,
Fujiu K, Michihata N, Jo T, Takeda N, Morita H,
Yamaguchi S, Nakamura S, Nishiyama A, Yokoo
T, Node K, Yamauchi T, Nangaku M, Yasunaga H,
Komuro I. BMJ Open. 2022 Apr 4;12(4):e056250.
doi: 10.1136/bmjopen-2021-056250.
8. Relationship of normal-weight central obesitywith the risk for heart failure and atrial
fibrillation: analysis of a nationwide healthcheck-up and claims database. Ueno K, Kaneko
H, Kamiya K, Itoh H, Okada A, Suzuki Y,
Matsuoka S, Fujiu K, Michihata N, Jo T, Takeda
N, Morita H, Ako J, Node K, Yamauchi T,
Yasunaga H, Komuro I. Eur Heart J Open. 2022
Apr 13; 2(3): oeac026. doi: 10.1093/ehjopen/oeac
026.
9. Impact of Glucose Tolerance and Its Change on
Incident Proteinuria: Analysis of a Nationwide
Population-Based Dataset. Suzuki Y, Kaneko H,
Okada A, Itoh H, Fujiu K, Michihata N, Jo T,
Takeda N, Morita H, Yamaguchi S, Kamiya K,
Matsunaga A, Ako J, Node K, Yamauchi T,
Nangaku M, Yasunaga H, Komuro I. Am J
Nephrol. 2022; 53(4): 307-315. doi: 10.1159/
000522280. ＜2022.5＞
10. Prediction of Atrial Fibrillation Being
Asymptomatic at First Onset by Cardiac Pacing.
Matsubara TJ, Fujiu K, Kodera S, Kani K, Goto
K, Shimizu Y, Oguri G, Hasumi E, Kojima T,
Komuro I. Int Heart J. 2022;63(3):486-491. doi:
10.1536/ihj.21-594. ＜2022.5＞
11. Association of retinal atherosclerosis assessedusing Keith-Wagener-Barker system withincident heart failure and other atherosclerotic
cardiovascular disease: Analysis of 319,501
individuals from the general population.
Matsuoka S, Kaneko H, Okada A, Itoh H, Suzuki
Y, Fujiu K, Michihata N, Jo T, Takeda N, Morita
H, Nakamura S, Node K, Yasunaga H, Komuro I.
Atherosclerosis. 2022 May; 348: 68-74. doi:
10.1016/j.atherosclerosis.2022.02.024.

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12. Age-Dependent Relationship of Hypertension
Subtypes With Incident Heart Failure. Suzuki Y,
Kaneko H, Yano Y, Okada A, Itoh H, Matsuoka S,
Fujiu K, Yamaguchi S, Michihata N, Jo T, Takeda
N, Morita H, Node K, Kim HC, Viera AJ, OparilS, Yasunaga H, Komuro I. J Am Heart Assoc.
2022 May 3;11(9):e025406. doi: 10.1161/JAHA.
121.025406.
13. Comparison of cardiovascular outcomes between
SGLT2 inhibitors in diabetes mellitus. Suzuki Y,
Kaneko H, Okada A, Itoh H, Matsuoka S, Fujiu
K, Michihata N, Jo T, Takeda N, Morita H,
Kamiya K, Matsunaga A, Ako J, Node K,
Yasunaga H, Komuro I. Cardiovasc Diabetol.
2022 May 18;21(1):67. doi: 10.1186/s12933-02201508-6.
14. Prediabetes in Young Adults and Its Association
With Cardiovascular Health Metrics in the
Progression to Diabetes. Suzuki Y, Kaneko H,
Okada A, Matsuoka S, Itoh H, Fujiu K, Michihata
N, Jo T, Takeda N, Morita H, Yamaguchi S, NodeK, Yamauchi T, Yasunaga H, Komuro I. J Clin
Endocrinol Metab. 2022 Jun 16;107(7):18431853. doi: 10.1210/clinem/dgac247.
15. Clinical utility of simple subjective gait speed forthe risk stratification of heart failure in a primaryprevention setting. Ueno K, Kaneko H, Kamiya
K, Itoh H, Okada A, Suzuki Y, Matsuoka S, Fujiu
K, Michihata N, Jo T, Takeda N, Morita H, Ako J,
Yasunaga H, Komuro I. Sci Rep. 2022 Jul 8;12(1):11641. doi: 10.1038/s41598-022-13752-7.
16. Medication-Naïve Blood Pressure and Incident
Cancers:
Analysisof2
Nationwide
Population-Based Databases. Kaneko H, Yano Y,
Lee HH, Lee H, Okada A, Itoh H, Morita K,
Fukui A, Fujiu K, Suzuki Y, Matsuoka S,
Nakamura S, Michihata N, Jo T, Takeda N,
Morita H, Yokoo T, Nishiyama A, Node K, Viera
AJ, Muntner P, Oparil S, Kim HC, Yasunaga H,
Komuro I. Am J Hypertens. 2022 Aug 1;35(8):731-739. doi: 10.1093/ajh/hpac054.
17. Rivaroxaban Monotherapy vs Combination
Therapy With Antiplatelets on Total Thrombotic
and Bleeding Events in Atrial Fibrillation With
Stable Coronary Artery Disease: A Post Hoc
Secondary Analysis of the AFIRE Trial. Naito R,
Miyauchi K, Yasuda S, Kaikita K, Akao M, Ako J,

18.

19.

20.

21.

22.
23.
24.

Matoba T, Nakamura M, Hagiwara N, Kimura K,
Hirayama A, Matsui K, Ogawa H; AFIRE
Investigators. JAMA Cardiol. 2022 Aug 1;7(8):787-794. doi: 10.1001/jamacardio.2022.1561.
Effectiveness and Approach of Rehabilitation in
Patients With Acute Heart Failure: A Review.
Ueno K, Kaneko H, Itoh H, Takeda N, Morita H,
Fujiu K, Kamiya K, Komuro I. Korean Circ J.
2022 Aug;52(8):576-592. doi: 10.4070/kcj.2022.
0181.
Cholecystitis and Cholangitis during Continuous
Renal Replacement Therapy in a Patient with
Retroperitoneal Hemorrhage Requiring Large
Amounts of Contrast Medium for the Assessment
and Intervention. Goto K, Shimizu Y, Kojima T,
Takeda N, Fujiu K, Komuro I. Intern Med. 2022
Aug 15; 61(16): 2533-2537. doi: 10.2169/
internalmedicine.8518-21.
Age-Specific Relation of Cardiovascular Health
Metrics With Incident Cardiovascular Disease.
Itoh H, Kaneko H, Okada A, Suzuki Y, Fujiu K,
Matsuoka S, Michihata N, Jo T, Nakanishi K,
Takeda N, Morita H, Node K, Di Tullio MR,
Homma S, Yasunaga H, Komuro I. Am J Cardiol.
2022 Aug 15;177:34-39. doi: 10.1016/j.amjcard.
2022.04.046.
Semiquantitative assessed proteinuria and risk ofheart failure: analysis of a nationwide
epidemiological database. Fukui A, Kaneko H,
Okada A, Yano Y, Itoh H, Matsuoka S, Morita K,
Kiriyama H, Kamon T, Fujiu K, Michihata N, Jo
T, Takeda N, Morita H, Nakamura S, Nishiyama
A, Node K, Yokoo T, Nangaku M, Yasunaga H,
Komuro I. Nephrol Dial Transplant. 2022 Aug
22;37(9):1691-1699. doi: 10.1093/ndt/gfab248.
Non-Cardiac Organs Metamorphose Heart.
Oshima T, Fujiu K. Int Heart J. 2022;63(5):795-797. doi: 10.1536/ihj.22-403. ＜2022.9＞
Automatic Detection of Left Ventricular
Dilatation and Hypertrophy from Electrocardiograms Using Deep Learning. Kokubo T,
Kodera S, Sawano S, Katsushika S, Nakamoto M,
Takeuchi H, Kimura N, Shinohara H, Matsuoka
R, Nakanishi K, Nakao T, Higashikuni Y, Takeda
N, Fujiu K, Daimon M, Akazawa H, Morita H,
Matsuyama Y, Komuro I. Int Heart J. 2022 Sep
30;63(5):939-947. doi: 10.1536/ihj.22-132.

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25. Incorporation of Retinal Arteriolosclerosis into
Risk Stratification of Blood Pressure Category
According to the 2017 ACC/AHA Blood Pressure
Guideline. Matsuoka S, Kaneko H, Kamon T,
Suzuki Y, Yano Y, Okada A, Itoh H, Morita K,
Fukui A, Fujiu K, Michihata N, Jo T, Takeda N,
Morita H, Nakamura S, Yokoo T, Nishiyama A,
Node K, Yasunaga H, Komuro I. J Atheroscler
Thromb. 2022 Oct 1; 29(10):1487-1498. doi:
10.5551/jat.63262.
26. Sex Difference in the Association between Lipid
Profile and Incident Cardiovascular Disease
among Young Adults. Kamon T, Kaneko H, Itoh
H, Okada A, Matsuoka S, Kiriyama H, Fujiu K,
Morita K, Michihata N, Jo T, Takeda N, Morita H,
Nakamura S, Node K, Yasunaga H, Komuro I. J
Atheroscler Thromb. 2022 Oct 1;29(10):14751486. doi: 10.5551/jat.63166.
27. Association of Cardiovascular Health Metrics
With Risk of Transition to Hypertension in
Non-Hypertensive Young Adults. Suzuki Y,
Kaneko H, Yano Y, Okada A, Itoh H, Matsuoka S,
Fujiu K, Michihata N, Jo T, Takeda N, Morita H,
Matsunaga A, Node K, McEvoy JW, Lam CSP,
Oparil S, Yasunaga H, Komuro I. Am J Hypertens.
2022 Oct 3; 35(10):858-866. doi: 10.1093/ajh/
hpac057.
28. Reduction in blood pressure for elevated bloodpressure/stage 1 hypertension according to theAmerican College of Cardiology/American Heart
Association guideline and cardiovascularoutcomes. Kaneko H, Yano Y, Suzuki Y, Okada A,
Itoh H, Matsuoka S, Fujiu K, Michihata N, Jo T,
Takeda N, Morita H, Node K, Viera AJ, Lima
JAC, Oparil S, Lam CSP, Carey RM, Yasunaga H,
Komuro I. Eur J Prev Cardiol. 2022 Oct 20;
29(14):1921-1929. doi: 10.1093/eurjpc/zwac193.
29. Age prediction from coronary angiography using
a deep neural network: Age as a potential label toextract prognosis-related imaging features.
Sawano S, Kodera S, Sato M, Katsushika S,
Sukeda I, Takeuchi H, Shinohara H, Kobayashi A,
Takiguchi H, Hirose K, Kamon T, Saito A,
Kiriyama H, Miura M, Minatsuki S, Kikuchi H,
Higashikuni Y, Takeda N, Fujiu K, Ando J,
Akazawa H, Morita H, Komuro I. PLoS One.
2022 Oct 27; 17(10):e0276928. doi: 10.1371/

30.

31.

32.

33.

34.

35.

36.

journal.pone.0276928. eCollection 2022.
Kidney outcomes in patients with diabetes
mellitus did not differ between individual
sodium-glucose cotransporter-2 inhibitors.
Suzuki Y, Kaneko H, Okada A, Matsuoka S,
Fujiu K, Michihata N, Jo T, Takeda N, Morita H,
Node K, Nangaku M, Yasunaga H, Komuro I.
Kidney Int. 2022 Nov; 102(5):1147-1153. doi:
10.1016/j.kint.2022.05.031. Epub 2022 Aug 9.
Is Continuous Monitoring for Arrhythmia
Advantageous in Low-Risk Groups? Matsubara
TJ, Fujiu K. JACC Asia. 2022 Nov 1;2(6):747749. doi:10.1016/j.jacasi.2022.09.004. eCollection
2022 Nov.
Threshold of BMI for the Development ofHypertension among Japanese Adults. Suzuki Y,
Kaneko H, Yano Y, Okada A, Hashimoto Y, Itoh
H, Matsuoka S, Yokota I, Fujiu K, Michihata N,
Jo T, Takeda N, Morita H, Kamiya K, Matsunaga
A, Ako J, Node K, Yasunaga H, Komuro I. J Nutr.
2022 Nov;152(11):2565-2571. doi: 10.1093/jn/
nxac192. Epub 2022 Aug 30.
Glycemic status and the association of change inblood pressure with incident cardiovasculardisease. Suzuki Y, Kaneko H, Yano Y, Okada A,
Itoh H, Matsuoka S, Fujiu K, Michihata N, Jo T,
Takeda N, Morita H, Kamiya K, Matsunaga A,
Ako J, Node K, Yasunaga H, Komuro I. Am
Heart J. 2022 Dec;254:48-56. doi: 10.1016/j.ahj.
2022.07.005. Epub 2022 Jul 22.
Deep learning-based age estimation from chest
X-rays indicates cardiovascular prognosis. Ieki H,
Ito K, Saji M, Kawakami R, Nagatomo Y, Takada
K, Kariyasu T, Machida H, Koyama S, Yoshida H,
Kurosawa R, Matsunaga H, Miyazawa K, Ozaki
K, Onouchi Y, Katsushika S, Matsuoka R,
Shinohara H, Yamaguchi T, Kodera S,
Higashikuni Y, Fujiu K, Akazawa H, Iguchi N,
Isobe M, Yoshikawa T, Komuro I. Commun Med(Lond). 2022 Dec 9; 2(1):159. doi: 10.1038/
s43856-022-00220-6.
Association of Life's Simple 7 with incident
cardiovascular disease in 53 974 patients withcancer. Kaneko H, Suzuki Y, Ueno K, Okada A,
Fujiu K, Matsuoka S, Michihata N, Jo T, Takeda
N, Morita H, Kamiya K, Node K, Yasunaga H,
Komuro I. Eur J Prev Cardiol. 2022 Dec 21;

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29(18):2324-2332. doi: 10.1093/eurjpc/zwac195.
37. Dose-dependent relationship of blood pressureand glycaemic status with risk of aortic dissection
and aneurysm. Suzuki Y, Kaneko H, Yano Y,
Okada A, Itoh H, Ueno K, Matsuoka S, Fujiu K,
Michihata N, Jo T, Takeda N, Morita H, Yokota I,
Node K, Yasunaga H, Komuro I. Eur J Prev
Cardiol. 2022 Dec 21;29(18):2338-2346. doi:
10.1093/eurjpc/zwac205.
38. Proteinuria and Risk for Heart Failure in 55,191
Patients Having History of Cancer. Suzuki Y,
Kaneko H, Okada A, Fujiu K, Michihata N, Jo T,
Takeda N, Morita H, Kamiya K, Matsunaga A,
Ako J, Node K, Nangaku M, Yasunaga H,
Komuro I. Am J Nephrol. 2022;53(10):753-760.
doi: 10.1159/000527703. Epub 2022 Dec 21. ＜2023.1＞

414

Laboratory for Advanced Researchon Pathophysiology of Metabolic
Diseases
Project Associate Professor
Miki Okada-Iwabu, 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
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

415

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.

Iwabu M, Okada-Iwabu M, Kadowaki T,
Elucidating exercise-induced skeletal muscle
signaling pathways and applying relevant findings
to preemptive therapy for lifestyle-relateddiseases., Endocr J., 69:1-8, 2022

416

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.

References1.

Katagiri M, Yamada S, Katoh M, Ko T, Ito M,
Komuro I. Heart Failure Pathogenesis
Elucidation and New Treatment Method
Development. JMA J. 2022 Oct 17;5(4):399-406.

417

2.

3.

4.

5.

doi:10.31662/jmaj.2022-0106. Epub 2022 Aug 1.
Ko T, Nomura S, Yamada S, Fujita K, Fujita T,
Satoh M, Oka C, Katoh M, Ito M, Katagiri M,
Sassa T, Zhang B, Hatsuse S, Yamada T, HaradaM, Toko H, Amiya E, Hatano M, Kinoshita O,
Nawata K, Abe H, Ushiku T, Ono M, Ikeuchi M,
Morita H, Aburatani H, Komuro I.Cardiac
fibroblasts regulate the development of heart
failure via Htra3-TGF-β-IGFBP7 axis. Nat
Commun. 2022 Jun 7;13(1):3275. doi: 10.1038/
s41467-022-30630-y.
Miura K, Matsuura K, Yamasaki Itoyama Y,
Sasaki D, Takada T, Furutani Y, Hayama E, Ito M,
Nomura S, Morita H, Toyoda M, Umezawa A,
Onoue K, Saito Y, Aburatani H, Nakanishi T,
Hagiwara N, Komuro I, Shimizu T. Functional
Evaluation of Human Bioengineered Cardiac
Tissue Using iPS Cells Derived from a Patientwith Lamin Variant Dilated Cardiomyopathy. Int
Heart J. 2022;63(2):338-346. doi: 10.1536/ihj.21790.
Adachi Y, Ueda K, Nomura S, Ito K, Katoh M,
Katagiri M, Yamada S, Hashimoto M, Zhai B,
Numata G, Otani A, Hinata M, Hiraike Y, Waki H,
Takeda N, Morita H, Ushiku T, Yamauchi T,
Takimoto E, Komuro I. Beiging of perivascularadipose tissue regulates its inflammation andvascular remodeling. Nat Commun. 2022 Sep7;
13(1):5117.doi:10.1038/s41467-022-32658-6.PM
ID: 36071032.
Liu PY, Fukuma N, Hiroi Y, Kunita A, Tokiwa H,
Ueda K, Kariya T, Numata G, Adachi Y, Tajima
M, Toyoda M, Li Y, Noma K, Harada M, Toko H,
Ushiku T, Kanai Y, Takimoto E, Liao JK,
Komuro I. Tie2-Cre-Induced Inactivation of
Non-Nuclear Estrogen Receptor-α Signaling
Abrogates Estrogen Protection Against Vascular
Injury. JACC Basic Transl Sci. 2022 Nov
16;8(1):55-67. doi: 10.1016/j.jacbts.2022.07.001.
eCollection 2023 Jan. PMID: 36777173.

418

Department of Comprehensive
Radiation Oncology
Project Professor
Keiichi Nakagawa, MD, Ph.D

Project Research Associate
Masanari Minamitani, MD, Ph.D

Homepage

http://www.u-tokyo-rad.jp/staff/shuyougakukouza.html

Introduction and Organization
The endowed chair was launched on April 1, 2021. At
the time of its establishment, there were two members:
project professor Nakagawa and project associate
Ozaki. Due to Ozaki's appointment at Hirosaki
University, on April 1 ,2022, Minamitani joined as aproject associate.
The purpose of the establishment of thiscourse is to: From the standpoint of clinical radiation
oncology and medical physics, (1) promote thedevelopment of radiation therapy technology, (2) train
medical physicists with science and engineering
backgrounds and promote the precision of radiation
therapy, (3) improve the public's literacy about cancer
in general with a focus on radiation therapy (including
medical physics and the effects of radiation on thehuman body), and (4) "cancer education" described in
the Course of Study for junior high and high schools inparticular. We are supporting the promotion of the fourof them. We have received support from Elekta K.K.
and Chiyoda Technol Corporation.
Nakagawa is the former head of the
Radiation Therapy Division. While researching thedevelopment of radiation therapy equipment andclinical applications, he felt the importance ofspecialists in medical physics. Currently, medical
physicists are working at relatively large hospitals that
perform radiation therapy, but the development ofbases for medical physicists has not progressed. One ofthe primary goals of this course is to contribute to thefurther development of medical physics through the
improvement of image quality related to radiation
therapy, the analysis of big data in the field of radiation
therapy, and the development of human resources incollaboration with the Radiation Therapy Division.
In addition, Nakagawa was involved in the
launch of the Basic Act on Cancer Control enacted in2006 and served as a member of the Council for the
Promotion of Cancer Control for ten years. It has aimed
to improve public cancer education and Japanesepeople's health literacy by doing so. Improving healthliteracy using cancer teaching materials leads tovarious benefits in society, such as cancer prevention
and early detection, patient-centered decision-making
when selecting treatment methods, balancing cancer
treatment and work, and social understanding of theeffects of radiation on the human body. Our second
goal is to become a base for these issues.

Clinical activities
Two LINACs, one Tomotherapy, one iridium
brachytherapy device, one gamma knife forstereotactic irradiation of the head, one CT imaging
device dedicated to treatment planning, and treatment
planning devices are equipped in the Department ofRadiation Oncology. The primary purpose of thiscourse is not clinical. Still, we assist in medical
treatment while examining cases with doctors in thetreatment department as appropriate.
In addition, feedback on issues recognized in419

clinical practice is received and linked to technologicaldevelopment.

Education
This course provides graduate school education to
students from the Graduate School of Medicine,
Faculty of Medicine, the University of Tokyo. The
Department also collaborates with the Graduate
Schools of Science and Engineering and accepts
students from science and engineering backgrounds
who wish to become medical physicists and research
students conducting medical physics research.
While there were no admissions of students
aspiring to be medical physicists in 2022, we are
expanding the educational structure in preparation for
accepting students from 2023 onwards. Additionally,
six students from the Department of Radiology andBiomedical Engineering are affiliated with theradiation therapy department, and guidance has been
provided for tasks such as thesis writing.

Research
Following the purpose of this course, we conduct
research on medical physics and cancer education. In
medical physics, we are developing new high-precision
radiation therapy technologies by researching "imageguided radiation irradiation methods" using images
related to radiation therapy and research on image
processing utilizing artificial intelligence and analysisof big data related to radiation therapy in collaboration
with related clinical departments.
For example, in the study on image quality
improvement, we presented a survey on improving theimage quality of MVCT using deep learning.
Megavoltage computed tomography (MVCT) is usedin helical Tomotherapy for image-guided radiotherapy(IGRT). For precise registration based on image
guidance, the quality of MVCT images must be
ensured. However, the image quality of MVCT isconsiderably lower than that of kilovoltage CT (kVCT)
and thereby limits the accuracy of IGRT. We developed
a deep-learning based model to improve the image
quality of MVCT. The image quality of the improved
MVCT image was quantitatively evaluated by several
image quality indices. As a clinical benefit, it wasobserved by medical doctors that the improved images

enhanced the precision of contouring. Furthermore, we
found that our deep-learning based model enables the
improvement of the image quality of MVCT while
reducing metal artifacts, which often appear in kVCT
[4].
In school education for cancer, we have been
continuously conducting joint research with the Japan
Cancer Society since last year. Cancer education has
also been implemented in 25 junior high schools in
Shinagawa and Shibuya wards of Tokyo, as well as in
Hachioji and Hino cities, reaching approximately 2,500
participants. We have also contributed articles todomestic journals about the potential of cancer
education in school settings [8,9]. Minamitani has
given presentations about cancer education at healtheducation seminars conducted by the Tokyo
Metropolitan Board of Education.
For adult cancer education, within the
Corporate Action to Promote Cancer Control, acommissioned project by the Ministry of Health,Labour, and Welfare chaired by Nakagawa, both
Nakagawa and Minamiya have provided lectures tocorporations both online and offline. Plans are in place
to investigate whether such adult cancer education
leads to proper preventive actions against cancer andan increase in cancer screening rates. We developed ascale to measure cancer knowledge and literacy inJapanese people, the Japanese Cancer Intelligence
Quotient (JCIQ) [7].
Furthermore, in February 2022, a joint
research project themed "Awareness of cancer in small
and medium-sized enterprises and the employment
status of cancer patients" began in collaboration with
Dai-ichi Life Insurance Company. The research isbased on insurance contract data from Dai-ichi Life,
analyzing trends in "awareness of cancer" and"employment status of cancer patients" in small andmedium-sized enterprises, in collaboration with Tokyo
University Hospital. The results aim to contribute tocreating a work environment where individuals canwork with peace of mind even after being diagnosed
with cancer. As a result, it was reported in aninternational journal that the interest of businessowners in small and medium-sized enterprises incancer measures is related to the implementation ofcancer screenings and support systems in the company
[6].

420

Additionally, in collaboration with MTI Ltd.,a large-scale web survey was conducted using thefemale health management app "LunaLuna" to gather
information from LunaLuna users about radiation
therapy and cervical cancer. The results of this survey
are planned to be submitted to an international journal
in 2023.
As mentioned above, our department
conducts extensive research activities in both medical
physics and cancer education. Coupled with talentdevelopment, we look forward to further progress inthe next fiscal year.

6:

7:

Publications
1:

2:

3:

4:

5:

Enomoto A, Fukasawa T, Terunuma H, Nakagawa
K, Yoshizaki A, Sato S, Miyagawa K. Decrease in
MAP3Ks expression enhances the cell deathcaused by hyperthermia Int J Hyperthermia.
2022;39(1):200-208.
Atsuto Katano, Masanari Minamitani, Keiichi
Nakagawa, Hideomi Yamashita. The Spontaneous
Remission of Recurrent Lymph Node Metastatic
Prostate Cancer With Lowering Serum ProstateSpecific Antigen Level. Cureus 14(5): e25333
Motoyuki Umekawa, Yuki Shinya, Hirotaka
Hasegawa, Mariko Kawashima, Masahiro Shin,
Atsuto Katano, Masanari Minamitani, Akinori
Kashio, Kenji Kondo & Nobuhito Saito.
Stereotactic radiosurgery ensures an effective andsafe long-term control of Koos grade IV vestibular
schwannomas: a single-center, retrospective,
cohort study. Journal of Neuro-Oncology. 2022;
159:201–209
Ozaki S, Kaji S, Nawa K, Imae T, Aoki A,
Nakamoto T, Ohta T, Nozawa Y, Yamashita H,
Haga A, Nakagawa K. Training of deep crossmodality conversion models with a small dataset,and their application in megavoltage CT tokilovoltage
CT
conversionMedPhys2022;49(6):3769-3782.
Katano A, Minamitani M, Yamashita H,
Nakagawa K. Delayed Onset of Pleural Effusion
After Thoracic Radiation Therapy for Hodgkin
Lymphoma: A Case Report With Over 30-Year
Follow-Up. Cureus.14(7):e27138

8:

9:

Masanari Minamitani, Masayuki Tatemichi,
Tomoya Mukai, Atsuto Katano, Keiichi
Nakagawa. Effect of employers’ concerns about
cancer countermeasures on the implementation ofcancer screening and support for balancing cancer
treatment and work in small and medium‐sized
Japaneseenterprises.
J
Occup
Health.
2022;64:e12352.
Masanari Minamitani, Tomoya Mukai, Hideomi
Yamashita, Atsuto Katano, Mitsunori Miyashita,
and Keiichi Nakagawa. Development of JapaneseCancer Intelligence Quotient to Measure Cancer
Literacy and Knowledge among Japanese
Layperson. JMA J. 2022;5(4):446-457.
Masanari Minamitani and Keiichi Nakagawa.
Cancer Education in school. The Animation on
Radiotherapy. School Health, 2022, 353.
Masanari Minamitani and Keiichi Nakagawa.
Cancer Education Possibility performed inscience class. Science Education. 2022; 71:729732.

421

Department of
Immunotherapeutics
Project Professor
Kazuhiro Kakimi, M.D.,Ph.D.

Project Lecturer
Koji Nagaoka, Ph.D.

Project Researcher
Yukari Kobayashi

Technical AssistantYaeko Furuhashi, Yukiko Konakai

Homepagehttps://immunotherapy-uth.jp/

Introduction and Organization

Teaching activities

The Department of Immunotherapeutics is locatedwithin the 22nd Century Medical and Research Center,established in 2004 within the University of Tokyo
Hospital as a base for industry-academia collaboration
and as an organization promoting translational
research. It was established to conduct clinicalresearch and clarify the role of this treatment
technology in cancer treatment.
In May 2019, MEDINET Co., Ltd. completed theendowed courses for three periods of 15 years, andfrom June, Takara Bio Co., Ltd. made a new start asendowed courses. The laboratory location has also
moved from the Central Clinical Building II to theMolecular Life Innovation Building. We conduct
several joint programs with many clinical departments
and engage in research on tumor immunology byanalyzing the obtained clinical specimens with
cutting-edge technology.
Our goal is to build a system that integrates a hugeamount of clinical data and provides optimal treatment
for each patient. In particular, we are focusing on
identifying neoantigens based on patient genome
information and developing TCR-T cell therapy using
neoantigen-specific TCRs.

Graduate students from the department of
Neurosurgery, Gastroesophageal Surgery, Respiratory
Surgery, and Urology joined our team for research. We
collected surgically resected tumors from each clinicaldepartment, cultured tumor-infiltrating lymphocytes,
extracted DNA/RNA from the tumors, and performed
NGS analysis. We are studying the effects of theintratumoral immune environment on anti-tumor
immune responses
In the laboratory, in addition to basic immunoassay
techniques using cell culture and flow cytometry, they
have mastered the handling of bioinformatics tools
necessary for genome analysis.
Graduate students who are actually in charge ofoutpatient care or endoscopies in their respective
clinical departments, or with the help of colleagues,
build cooperation with medical offices and affiliatedhospitals, collect specimens, and conduct research. I
believe that this experience will help them develop
new treatment methods and tackle unknown issues
when they become future clinical practice leaders.
Three graduate students who published papers on
research using valuable specimens before and after
treatment with immune checkpoint inhibitors,

422

searching for biomarkers that predict postoperative
prognosis, and researching neoantigen immunotherapy
using mouse models, successfully obtained a Ph.D.
degree.

Therefore, we constructed an innovative neoantigen
analysis platform that combines a neoantigen
prediction system and immunogenicity verification
using tumor-specific TCR-expressing cells. Our goal
is to realize TCR-T cell therapy targeting neoantigens.

Research activities
Immune checkpoint inhibitors have been approved forvarious cancer types, but many patients still do notrespond to these therapies or become resistant to themafter therapeutic effects have been shown. In order torationally judge the indications of immune checkpoint
inhibitors and clarify the points of resistance totreatment, we will clarify the molecular mechanismsthat determine the responsiveness to immune
checkpoint inhibitors in individual patients.
Accumulated clinical experience defines responsiveness to immune checkpoint inhibitors, including
tumor-specific factors, tumor microenvironment,
host-related factors, and dynamic changes associatedwith treatment. Furthermore, high-dimensional
analysis at the single-cell level becomes possible, and
it is possible and necessary to comprehensively
integrate detailed and enormous information forpredicting efficacy and searching for the key toovercoming treatment resistance.
We have studied current tumor immunology based on
detailed observations, accumulating hypotheses andtheir verification. On the other hand, in genomic
analysis, comprehensive information is searched foranswers without being bound by preconceptions using
bioinformatics and computer science. To haveconfidence in evaluating the anti-tumor immune
response, we should integrate conventional
immunology and genomic immunology. Therefore,
tumor immunology research conducted in our
department focuses on integrative analysis as cancer
immunogenomics.
NGS has allowed it to analyze neoantigens generated
from genomic abnormalities in individual patients,
enabling the development of cancer immunotherapy
targeting neoantigens.
Neoantigens are predicted based on genomic
information of individual patients by the high binding
ability to MHC molecules. Then, they are validated
for their reactivity to tumor-specific T cells.

Publication List
1.

2.

3.

4.

5.

Ishii T, Mimura I, Nagaoka K, Naito A,
Sugasawa T, Kuroda R, Yamada D, Kanki Y,
Kume H, Ushiku T, Kakimi K, Tanaka T,
Nangaku M. Effect of M2-like macrophages of
the injured-kidney cortex on kidney cancer
progression. Cell Death Discov. 2022 Dec
5;8(1):480. doi: 10.1038/s41420-022-01255-3.
PMID: 36470862; PMCID: PMC9722672.
Sun C, Nagaoka K, Kobayashi Y, Maejima K,
Nakagawa H, Nakajima J, Kakimi K.
Immunotherapies targeting neoantigens are
effective in PD-1 blockade-resistant tumors. Int J
Cancer. 2023 Apr 1;152(7):1463-1475. doi:
10.1002/ijc.34382. Epub 2022 Dec 13. PMID:
36451303.
Teshima T, Kobayashi Y, Kawai T, Kushihara Y,
Nagaoka K, Miyakawa J, Akiyama Y, Yamada Y,
Sato Y, Yamada D, Tanaka N, Tsunoda T, Kume
H, Kakimi K. Principal component analysis of
early
immunecelldynamics
duringpembrolizumab treatment of advanced urothelial
carcinoma. Oncol Lett. 2022 Jun 16;24(2):265.
doi: 10.3892/ol.2022.13384. PMID: 35765279;
PMCID: PMC9219027.
Miyamoto A, Honjo T, Masui M, Kinoshita R,
Kumon H, Kakimi K, Futami J. Engineering
Cancer/Testis
Antigens
With
Reversible
S-Cationization to Evaluate Antigen Spreading.
Front Oncol. 2022 May 4;12:869393. doi:
10.3389/fonc.2022.869393. PMID: 35600379;
PMCID: PMC9115381.
Saito N, Sato Y, Abe H, Wada I, Kobayashi Y,
Nagaoka K, Kushihara Y, Ushiku T, Seto Y,
Kakimi K. Selection of RNA-based evaluation
methods for tumor microenvironment bycomparing with histochemical and flow
cytometric analyses in gastric cancer. Sci Rep.
2022 May 20;12(1):8576. doi:10.1038/s41598022-12610-w. PMID: 35595859.

423

6.

Sato S, Matsushita H, Shintani D, Kobayashi Y,
Fujieda N, Yabuno A, Nishikawa T, Fujiwara K,
Kakimi K, Hasegawa K. Association between
effector-type regulatory T cells and immune
checkpoint expression on CD8+ T cells inmalignant ascites from epithelial ovarian cancer.
BMC Cancer. 2022 Apr 21;22(1):437. doi:
10.1186/s12885-022-09534-z. PMID: 35449092;
PMCID: PMC9026673.

Social Cooperation Program425

Department of Medical
Information Engineering
Project Associate Professor
Taichi Kin, M.D.,Ph.D.

Project Research Associate
Toki Saito, Ph.D.

Homepagehttps://medicalinfo-engneering.org

Introduction and Organization
Department of Medical Information Engineering waslaunched on November 2021, through the financial
support of SoftBank corporation, with assistance by
the Department of Neurosurgery. Two faculty staffs,
Taichi Kin as the Specially Appointed Associate
Professor and Toki Saito as the Specially Appointed
Assistant Professor started the research project.
The Department of Medical Information Engineering
aims at research and development of medical dataprocessing such as medical images by making full useof information and communication technology,
artificial intelligence technology, anonymous processing technology, and cloud technology. Specifically,
this includes medical image processing technologies
such as tissue segmentation, annotation, and virtual
reality surgical simulation, and anonymization,
information and communication technologies of
medical image data.

Teaching activities
Department of Medical Information Engineering was
involved in the education through research activities
of graduate students of the Graduate School of
Medicine.

Research activities
Our research covers the biomedical computer
applications that focus on medical data such as

medical imaging. Our laboratory is engaged in thefollowing research activities:
1) medical image processing
3D reconstruction, segmentation, registration,
rendering, fluid dynamics
2) virtual reality surgical simulation
tissue deformation, using surgical instruments3) surgical support system
surgical navigation, XR technology4) information and communication technology
block chain, anonymization, cloud technology

References
1.

2.

Satoshi Kiyofuji, Taichi Kin, Toki Saito, Tsukasa
Koike, Yasuhiro Takeda, Tatsuya Uchida,
Katsuya Sato, Ryoko Niwa, Yasuyuki Furuta,
Nobuhito Saito. Invention of Online Interactive
Three-dimensional Neurosurgery Simulator with
Audiovisual Capture for Tactile Feedback. Oper
Neurosurg. 24(2): 194-200, 2022.
Tsukasa Koike, Shota Tanaka, Taichi Kin, Yuichi
Suzuki, Shunsaku Takayanagi, Hirokazu Takami,
Kazuha Kugasawa, Shohei Nambu, Takaki
Omura Erika Yamazawa Yoshihiro Kushihara,
Yasuyuki Furuta, Ryoko Niwa, Katsuya Sato,
Tatsuya Uchida, Yasuhiro Takeda, Satoshi
Kiyofuji, Toki Saito, Hiroshi Oyama, Nobuhito
Saito. Accurate Preoperative Identification ofMotor Speech Area as Termination of Arcuate
Fasciculus Depicted by Q-Ball Imaging

426

Tractography. World Neurosurg 164: e764-e771,
2022.
3. Yuki Shinya, Masahiro Shin, Hirotaka Hasegawa,
Satoshi Koizumi, Taichi Kin, Kenji Kondo,
Nobuhito
Saito.
Endoscopic
endonasaltranspetroclival approach for recurrent bilateral
petroclival meningioma. Neurosurg Focus Video
6(2): v7, 2022.
4. Hirotaka Hasegawa, Masahiro Shin, Ryoko Niwa,
Satoshi Koizumi, Shoko Yoshimoto, Naoyuki
Shono, Yuki Shinya, Hirokazu Takami, Shota
Tanaka, Umekawa Motoyuki, Shiori Amemiya,Taichi Kin, Nobuhito Saito. Revisitation ofimaging features of skull base chondrosarcoma incomparison to chordoma. J Neurooncol 159(3):581-590, 2022.
5. Takeda Yasuhiro, Hasegawa Hirotaka, Kin Taichi,
Shinya Yuki, Kawashima Mariko, Furuta
Yasuyuki, Suzuki Yuichi, Sekine Tetsuro, Saito
Nobuhito. Hemodynamic changes during theobliteration process for cerebralarteriovenous
malformations after radiosurgery. Neurosurg
Focus 53(1): E7, 2022.
6. Nozomi Otsuka, Hirohisa Yajima, Satoru
Miyawaki, Satoshi Koizumi, Satoshi Kiyofuji,
Hiroki Hongo, Yu Teranishi, Taichi Kin,
Nobuhito Saito. Case Report: "Clipping" anInternal Carotid Artery Aneurysm With a
Duplicated Middle Cerebral Artery and theAnterior Choroidal Artery Arising From theDome. Front Neurol 13: 845296, 2022.
7. Yuki Shinya, Masahiro Shin, Hirotaka Hasegawa,
Satoshi Koizumi, Taichi Kin, Kenji Kondo,
Nobuhito
Saito.
Endoscopic
endonasaltranspetroclival approach for recurrent bilateral
petroclival meningioma. Neurosurg Focus Video
6(2): V7, 2022.
8. Takeo Igarashi, Tsukasa Koike, Taichi Kin.
Interactive Deformable Image Registration with
Dual Cursor. DOI: 10.2312/pg.20221241. PacificGraphics 2022.
9. Shono Naoyuki, Igarashi Takeo, Kin Taichi, Toki
Saito, Nobuhito Saito. Threshold field painting
saves the time for segmentation of minute arteries.
Int J Comput Assist Radiol Surg. 17(11): 21212130, 2022.
10. Ding Xia, Xi Yang, Oliver van Kaick, Taichi Kin,

Takeo Igarashi. Data-driven Multi-Modal Partial
Medical Image Preregistration by Template Space
Patch Mapping. MICCAI 2022, 259-268.
11. Hirohisa Yajima, Satoru Miyawaki, Satoshi
Koizumi, Satoshi Kiyofuji, Hiroki Hongo,
Masafumi Segawa, Taichi Kin, Hirofumi
Nakatomi, Nobuhito Saito. Development of asigmoid sinus dural arteriovenous fistulasecondary to sigmoid sinus thrombosis after
resection of a foramen magnum meningioma:
illustrative case. J Neurosurg Case Lessons 4(5):CASE22253, 2022.
12. Kiyofuji Satoshi, Shin Masahiro, Kondo Kenji,
Kin Taichi, Uchida Tatsuya, Saito Nobuhito.
Endoscopic Transnasal Resection of Trigeminal
Schwannoma. J Neurol Surg B Skull Base
83(Suppl 3): e637-e638, 2022.

427

Health Economy and Society
PolicyProject Professor
Tomoyuki Takura, Ph.D, MEng.

Project Lecturer
Sayaka Horiuchi, MPH, MD

Homepage

http://plaza.umin.ac.jp/hehp/

Introduction and Organization

Education

Health Economy and Society policy is a donatedfund course established in 22nd Century Medical andResearch Center in February 2017, which is donated by
10 companies, Development Bank of Japan Inc.,
Chugai Pharmaceutical Co., Ltd., Baxter Limited,
Nihon Medi-Physics Co., Ltd., Medibrain Corporation,
Asahi Kasei Medical Co., Ltd., NIPRO Corporation,
Toray Medical Co., Ltd., JMS Co., Ltd., and Terumo
Corporation, and is cooperating with Department of
Cardiac Surgery, Division of Nephrology and Endocrinology, and Department of Clinical Epidemiology &Health Economics as cooperating course.
The social structure has been changing over recent
years and it can be assumed that policies related to the
medical system and medical industry are at a
crossroads in Japan and may undergo dramatic changes
in the future. Our department was established to discuss
future healthcare systems (medical practices andsystems, economy and industry), particularly in termsof theory construction and validation studies pertaining
to the "evaluation of the value of the healthcare field"
and other topics. Concretely, we promote theoreticaland methodological research on health technology
assessment, cost effectiveness analysis, and thehealthcare industry structure, and aim to evaluate thevalue of healthcare technologies and healthcare
systems.

We also promote manpower training programs(Program for “The movements of medical value“: 18times in total) in health technology assessment withcollaboration departments, which is an extension
course. This program includes healthcare economics(pharmaceutical affairs system, financial and insurance
system, hospital accounting, cost-effectivenessevaluation, microeconomics) and data science (medical
big data, bayesian statistics, markov chain monte carlo
method, software analysis) and research ethics.

Research activities
We are engaging in the following research in orderto promote rational and evidence-based medical
resource investment, to support medical practice, andto promote advances in medical technology.
1) The evaluation of the cost effectiveness of various
therapies, including (but not limited to) VAD therapy
for severe heart failure, hemodialysis therapy forend-stage renal failure and radiological diagnostics.
2) A study of the socioeconomic impact of chronic pain
and health behavior (adherence) on the disease
burden and the financial burden (includinginternational comparison).
3) Testing and developing methods for evaluating laborproductivity (e.g., the productivity of cardiology
doctors) by applying data envelopment analysis(DEA) techniques.

428

Moreover, we are also working on a project todevelop a forecasting model for health technology
assessment (HTA) and disease prevention that makes
use of big data and AI as data science. We have also
started a study that applies computational finance toforecast the market value of research and development
projects.

References
1.

2.

3.

4.

5.

6.

Tomoyuki Takura, Kosaku Nitta, Ken Tsuchiya,
Hideki Kawanishi. Long-Term Effects of Contrast
Media Exposure on Renal Failure Progression: A
Retrospective Cohort Study. BMC Nephrology. 24,
135. 2023.
Tomoyuki Takura, Minoru Ono, Junya Ako, Yuji
Ikari, Koichi Toda, Yoshiki Sawa; ETICA Study
Investigators. Clinical and Economic Evaluationof Impella Treatment for Fulminant Myocarditis A Preliminary Retrospective Cohort Study inJapan. Circ J. 2022; 87(5):610-618. doi:
10.1253/circj.CJ-22-0439.
Hiroki Sugimori, Maki Hirao, Ataru Igarashi,
Hiroshi Yatsuhashi, Shunya Ikeda, Naohiko
Masaki, Hiroshi Yotsuyanagi, Takeshi Yoda,
Takeshi Odajima, Tomoyuki Takura, Tomohiro
Hirao. Health state utilities of patients with
hepatitis B and C and hepatitis-related conditionsin Japan. Sci Rep. 12(1):17139. 2022. doi:
10.1038/s41598-022-21470-3.
Tetsuya Shiina, Keiko Goto-Hirano, Tomoyuki
Takura, Hiroyuki Daida. Cost-effectiveness offollow-up invasive coronary angiography after
percutaneous coronary stenting: a real-world
observational cohort study in Japan. BMJ Open.
12(8):e061617. 2022. doi: 10.1136/bmjopen2022-061617.
Tomoyuki Takura, Sayaka Horiuchi. Costeffectiveness analysis of infliximab for thetreatment of Kawasaki disease refractory to theinitial treatment: A retrospective cohort study.
Journal of Cardiology. 80(2):172-178. doi:
10.1016/j.jjcc.2022.03.005. 2022.
Tomoyuki Takura, Hiroko Miura. Socioeconomic
Determinants of Universal Health Coverage in the
Asian Region. Int. J. Environ. Res. Public Health.

2022; 19(4):2376. https://doi.org/10.3390/ijerph
19042376.
7. Tomoyuki Takura, Tomoko Koike, Yoko Matsuo,
Asuko Sekimoto, Masami Mutou. Proxy
Responses Regarding Quality of Life of Terminal
Lung Cancer Patients: preliminary results from aprospective observational study. BMJ Open.
12(2):e048232. doi: 10.1136/bmjopen-2020-048232.
2022.
8. Kazuhiko Ikeuchi, Kazuya Okushin, Makoto
Saito1, Eisuke Adachi1, Takeya Tsutsumi,
Tomoyuki
Takura,HiroshiYotsuyanagi.
Prevalence of HIV infection among non-elderly
individuals with hepatitis C in Japan: Apopulation-based cohort study using a healthinsurance claim data. BMC Infectious Diseases.
22(1):167. doi: 10.1186/s12879-022-07152-5.2022.
9. Yasunori Suematsu, Shin-ichiro Miura, Akira
Minei, Yoko Sumita, Koshiro Kanaoka,
Michikazu Nakai, Hisatomi Arima, Koshi
Nakamura, Tomoyuki Takura, Kazunori Shimada,
Hirokazu Shiraishi, Nagaharu Fukuma, Yusuke
Ohya, Shigeru Makita. Study Protocol of Cardiac
Rehabilitation for Acute Myocardial Infarction
From the JROAD/JROAD-DPC Database ―JROAD-CR ―. The JROAD-CR Investigators.
Circulation Reports. 5 (2): 62-65. 2023.
10. JCS/JACR 2021 Guideline on Rehabilitation in
Patients With Cardiovascular Disease. Shigeru
Makita, Takanori Yasu, Yoshihiro J Akashi,
Hitoshi Adachi, Hideo Izawa, Shunichi Ishihara,
Yoshitaka Iso, Hideo Ohuchi, Kazuto Omiya,
Yusuke Ohya 0, Koichi Okita, Yutaka Kimura,
Akira Koike, Masahiro Kohzuki, Shinji Koba,
Masataka Sata, Kazunori Shimada, Tomoki
Shimokawa, Hirokazu Shiraishi, Naokata
Sumitomo 0, Tetsuya Takahashi, Tomoyuki
Takura, Hiroyuki Tsutsui, Masatoshi Nagayama,
Emiko Hasegawa, Yoshihiro Fukumoto, Yutaka
Furukawa, Shin-Ichiro Miura, Satoshi Yasuda,
Sumio Yamada 0, Yuichiro Yamada, Dai Yumino,
Toshiko Yoshida, Takuji Adachi, Toshimi Ikegame,
Kazuhiro P Izawa, Takeshi Ishida, Neiko Ozasa,
Naohiko Osada, Hiroaki Obata 0, Naoya Kakutani,
Yusuke Kasahara, Masaaki Kato, Kentaro Kamiya,
Shintaro Kinugawa, Yuji Kono, Yasuyuki
Kobayashi, Teruyuki Koyama, Kazuhiro Sase,429

Shinji Sato 0, Tatsuhiro Shibata, Norio Suzuki,
Daisuke Tamaki, Minako Yamaoka-Tojo, Michio
Nakanishi, Eisaku Nakane, Mari Nishizaki, Taiki
Higo, Kanta Fujimi, Tasuku Honda, Yasuharu
Matsumoto, Noriko Matsumoto, Ikuko Miyawaki,
Makoto Murata, Shusuke Yagi, Masanobu Yanase0, Midori Yamada, Miho Yokoyama, Noboru
Watanabe, Haruki Ito, Takeshi Kimura, Syunei
Kyo, Yoichi Goto, Ryuji Nohara, Ken-Ichi Hirata ;Japanese Circulation Society/the Japanese
Association of Cardiac Rehabilitation Joint
Working Group. Circ J. 2022 Dec 9. doi:
10.1253/circj.CJ-22-0234. Online ahead of print.
11. Tomoyuki Takura, Issei Komuro, Minoru Ono.
Trends in the cost-effectiveness level of
percutaneous coronary intervention: Macrosocioeconomic analysis and health technology
assessment. J Cardiol. 2022;81(4):356-363. Sep
28;S0914-5087(22)00243-X. doi: 10.1016/j.jjcc.
2022.09.011. Online ahead of print.
12. Tomoyuki Takura. "Socio-Economic Considerationsof Universal Health Coverage: Focus on theConcept of Health Care Value and Medical
Treatment Price". Health Insurance. London,
IntechOpen; 1-34. 2022 (DOI: 10.5772/
intechopen.104798)

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Department of Healthcare Quality
Assessment
Project Professor
Hiroaki Miyata, PhD

Project Associate Professor
Hiraku Kumamaru, MD, ScD, Hiroyuki Yamamoto, MD, PhD, MPH

Project Assistant Professor
Naoaki Ichihara, MD, PhD, MPH

Project Researcher
Shun Kosaka, MD, PhD, Shiori Nishimura, PhD, Hisateru Tachimori, PhD,
Ryo Nakamaru, MD, PhD, Shiyori Usune

Visiting Researcher
Arata Takahashi, HIM, PhD, Hideki Endo, MD, Chieko Fujimura, Satoshi Shoji, MD, PhD
Shinya Hirakawa, PhD, Naoko Kinukawa, PhD, Daisuke Shinjo, PhD

Clerical Staff (Secretary)
Takayo Nakamura, Yuko Miyashiro

Website http://hqa.umin.jp/
Introduction and Organization

Research

The Department of Healthcare Quality Assessment(HQA) was established in 2006, and now work incollaboration
withtheDepartmentsofCardiovascular Surgery, Health and Social Behavior,
and Pediatric Surgery. It conducts collaborative
research with National Clinical Database (NCD),
Nipro Corporation, Johnson and Johnson K.K, andIntuitive Surgical Sàrl.
The objective of providing healthcare is to provide
high quality healthcare services to all patients.
Institute of Medicine states that health care reform
should focus on improving the patients’ health aswell as health care values that they think areimportant.
“Quality
improvement
initiative,”
therefore, needs to adjust the healthcare systems toaccommodate the fee-for-service perspectives while
improving the clinical environment for both patientsand providers.

Department of Healthcare Quality Assessment(HQA) has been actively collaborating withhealthcare professionals and various clinicalcommittees as they play key roles in the quality
improvement initiatives in the field. In such positiveenvironment driven by the patient-centeredphilosophy, the patients receive more satisfying care,
physicians are rewarded for their excellence, andhealthcare costs are sustained. To accomplish thesegoals, there are 3 principles that navigate us throughthe journey: (a) the topmost value should always beon 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 and medical costs spent--must be scientifically measured and evaluated.
In April 2010, the Japan Society of Surgery and 10
related surgical societies founded the National

431

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
advance surgical sciences in Japan. HQA has beenplaying 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
data on more than 95% of all surgical operations
across Japan in collaboration with the clinicalsocieties. NCD is also connected with theparticipating societies’ board of certification systems,
which makes it unique among other large-scaleclinical registries in the world. Today, more than
5,400 hospitals and clinics are participating in NCD
with the accumulated data of 20 million cases(approximately 2 million each year).
HQA has developed risk models for different
groups of surgical procedures that help us develop
several practical tools aimed for medical
professionals in the joint research activity with Japan
Cardiovascular Surgery Database (JCVSD). One ofthose tools is JapanSCORE, which allows users to
calculate a patient’s post-operative risk of mortality
and morbidities. 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 surgical areas including thegastroenterological surgery and thoracic surgery. Allof these activities help Japan’s healthcare quality
initiatives in various places, and HQA is proud takepart in it.
Since 2014, HQA has been participating in thepost marketing surveillance studies based on NCD,
in collaboration with PMDA (Pharmaceuticals andMedical Devices Agency), Academic societies anddevice manufacturers. Also, starting in 2017, HQA
has led a new initiative at NCD of collecting
diagnosis procedure combination data and insurance
claims data from participating facilities. Data on theuse of medical products as well as on billings fromthese data are being used to supplement the clinicalinformation collected in the registries for conducting
clinical and health services research.
Future Directions
Clinical databases like NCD are the corecomponents of quality improvement initiatives
across the multiple subspecialties. HQA supports
NCD’s systematic data collection, data management,
practical analyses, and the development of usefulfeedback systems. Recently, non-surgical fields suchas clinical oncology are also joining NCD and thistrend has become stronger.
Our benchmarking
projects backed up by NCD’s big data will keep
driving the quality improvement activities in many
healthcare fields.
Increasing numbers of clinical research output has
been coming out of the detailed analyses on NCD
data in collaboration with each specialty field.
Besides professional societies, medical device firms
have started the operation of their post-marketingsurveillance studies in collaboration with NCD.
Working with NCD, the industry, PMDA, and therelated medical societies, HQA helps the project
move
forwardthroughacademic
support.
Furthermore, HQA has been involved in international
collaborative research work with database activities
such as American College of Surgeon’s NSQIP and
Asian Cardiac Database while contributing to thequality improvement activities in different regions of
the world.

Publications
1.

2.

Kumamaru H, Kakeji Y, Fushimi K, Ishikawa
KB, Yamamoto H, Hashimoto H, Ono M,
Iwanaka T, Marubashi S, Gotoh M, Seto Y,
Kitagawa Y, Miyata H. Cost of postoperativecomplications of lower anterior resection forrectal cancer: a nationwide registry study of
15,187 patients. Surg Today. 2022; 52 (12):1766–74.
Shoji S, Kohsaka S, Kumamaru H, Yamaji K,
Nishimura S, Ishii H, Amano T, Fushimi K,
Miyata H, Ikari Y. Cost reduction associatedwith transradial access in percutaneous coronary
intervention: A report from a Japanese

432

3.

4.

5.

6.

7.

8.

9.

nationwide registry. Lancet Reg Heal - West
Pacific. 2022; 28: 100555.
Higuchi R, Kumamaru H, Kohsaka S, Saji M,
Takamisawa I, Nanasato M, Shimokawa T,
Shimizu H, Takayama M. Outcome of
Nonagenarians
UndergoingTransfemoral
Transcatheter Aortic Valve Replacement: A
Nationwide Registry Analysis From Japan.
JACC Asia. 2022; 2 (7): 856–64.
Hoshino N, Endo H, Hida K, Kumamaru H,
Hasegawa H, Ishigame T, Kitagawa Y, Kakeji Y,
Miyata H, Sakai Y. Laparoscopic Surgery for
Acute
Diffuse
Peritonitis
Dueto
Gastrointestinal Perforation: A Nationwide
Epidemiologic Study Using the National
Clinical Database. Ann Gastroenterol Surg.
20211213th ed. 2022; 6 (3): 430–44.
Ichinose J, Yamamoto H, Aokage K, Kondo H,
Sato Y, Suzuki K, Chida M. Real-world
perioperative outcomes of segmentectomy
versus lobectomy for early-stage lung cancer: apropensity score-matched analysis. Eur J cardiothoracic Surg Off J Eur Assoc Cardio-thoracic
Surg. 2022; 63 (1).
Kaibori M, Ichihara N, Miyata H, Kakeji Y,
Nanashima A, Kitagawa Y, Yamaue H,
Yamamoto M, Endo I. Surgical outcomes oflaparoscopic versus open repeat liver resection
for liver cancers: A report from a nationwide
surgical database in Japan. J Hepatobiliary
Pancreat Sci. 2022; 29 (8): 833–42.
Kofunato Y, Takahashi A, Gotoh M, Kakeji Y,
Seto Y, Konno H, Kumamaru H, Miyata H,
Marubashi S. Geriatric Risk Prediction Models
for Major Gastroenterological Surgery Using the
National Clinical Database in Japan: A
Multicenter Prospective Cohort Study. Ann
Surg. 20201015th ed. 2022; 275 (6): 1112–20.
Kono E, Isozumi U, Nomura S, Okoshi K,
Yamamoto H, Miyata H, Yasufuku I, Maeda H,
Sakamoto J, Uchiyama K, Kakeji Y, Yoshida K,
Kitagawa Y. Surgical Experience Disparity
Between Male and Female Surgeons in Japan.
JAMA Surg. 2022; 157 (9): e222938.
Okamura A, Yamamoto H, Watanabe M, Miyata
H, Kanaji S, Kamiya K, Kakeji Y, Doki Y,
Kitagawa Y. Association Between Preoperative

10.

11.

12.

13.

HbA1c Levels and Complications after
Esophagectomy:
Analysisof
15,801
Esophagectomies From the National Clinical
Database in Japan. Ann Surg. 2022; 276 (5):e393–9.
Nishimura S, Kumamaru H, Shoji S, Nakatani E,
Yamamoto H, Ichihara N, Miyachi Y, Sandhu
AT, Heidenreich PA, Yamauchi K, Watanabe M,
Miyata H, Kohsaka S. Assessment of codingbased frailty algorithms for long-term outcome
prediction among older people in community
settings: A cohort study from the Shizuoka
Kokuho Database. Age and Ageing, 2020;
51(3): 1–9.
Ikeda N, Yamamoto H, Taketomi A, Hibi T,
Ono M, Niikura N, Sugitani I, Isozumi U,
Miyata H, Nagano H, Unno M, Kitagawa Y,
Mori M. The impact of COVID-19 on surgicalprocedures in Japan: analysis of data from the
National Clinical Database. Surg Today. 2022;
52 (1): 22-35.
Sato Y, Yamamoto H, Ikeda N, Konishi H,
Endo S, Okada Y, Kondo H, Shintani Y,
Toyooka S, Nakamura H, Hoshikawa Y, ChenYoshikawa TF, Yoshino I, Kakizoe T, Chida M.
The impact of COVID-19 on thoracic surgicalprocedures in Japan: Analysis of data from the
National Clinical Database. Lung Cancer. 2022;
172: 127-35.
Okoshi K, Endo H, Nomura S, Kono E, Fujita Y,
Yasufuku I, Hida K, Yamamoto H, Miyata H,
Yoshida K, Kakeji Y, Kitagawa Y. Comparisonof short term surgical outcomes of male andfemale gastrointestinal surgeons in Japan:
retrospective cohort study. BMJ. 2022; 378:
e070568.

433

Laboratory for Cryo-Electron
Microscopy
Project Associate Professor
Chieko Saito, Ph.D.

Project Assistant Professor
Fabian Eisenstein, Ph.D.

Homepage
Introduction and Organization

Clinical activities

The Laboratory of Cryo-Electron Microscopy was established in April 2022 to promote theanalysis of biological specimens using cryo-electron
microscopy in cooperation with JEOL Ltd. The
duration of the laboratory is four years (April 1, 2022
- March 31, 2026).
This laboratory aims to promote the use ofcryo-electron microscopy in society and to advancecryo-electron microscopy as a research platform, andto foster human resources who will play a role in thiseffort. We will conduct research on sample preparation methods, high-speed imaging methods, and threedimensional structural analysis methods to obtainhigh-resolution images for single-particle analysis andtomographic analysis. In addition, by providing
educational support for lectures on the principles ofcryo-electron microscopy and practical training,
sample preparation, and three-dimensional structural
analysis methods, we aim to develop human resources
capable of promoting structural analysis of biological
specimens through cryo-electron microscopy.
The current members of the labotatory for
Cryo-Electron Microscopy are: Project Associate
Professor (Chieko Saito, appointed in November2022), Project Assistant Professor (Fabian Eisenstein,appointed in January 2023), and Technical Assistant(Toshie Furuya, appointed in August 2022).

No special note.

Teaching activities
To solve technical problems necessary toapply cryo-electron microscopy to life science
research, drug discovery, etc., and to conduct joint
research with various researchers who need thistechnique. We will also develop human resources
capable of promoting such research.
In FY2022, we cooperated in the planningand implementation of a technical course on
cryo-electron microscopy, which was conductedjointly with Structural Biology Laboratory (Kikkawa
Lab.), Laboratory of Advanced Structure Laboratory(Danev Lab.), and other laboratories in UTokyo(Kurumizaka Lab and Nureki Lab). In addition,
students from the World INovative Graduate Study
Program for Life Science and Technology(WINGS-LST) program were accepted to the above
training sessions, which were conducted as anexperimental training course.

Research activities
In FY2022, we conducted collaborative
research with WINGS-LST program students(Graduate School of Engineering), with the Universityof Tokyo Hospital (Department of Cardiovascular
Medicine), and with the Department of Molecular434

Biology, Division of Molecular Cell Biology,
Graduate School of Medicine.
With the start of the second phase of theJapan Agency for Medical Research andDevelopment's Platform for Advanced Technology
Basis for Supporting Innovative Drug Discovery andLife Science Research (AMED BINDS) in April 2022,
we supported in the consulting and the management ofthese facilities. In addition, we supported the start-up
of two cryo-EM facilities (CRYO ARM™ 300 II(JEM-3300) and CRYO ARM™ 200 (JEM-Z200),
manufactured by JEOL) installed at the Kashiwa 2
campus.

References
1. Tomoko Ohshima, Hayashi Yamamoto, Yuriko
Sakamaki, Chieko Saito, Noboru Mizushima.
NCOA4 drives ferritin phase separation tofacilitate
macroferritinophagy
andmicroferritinophagy. Journal of Cell Biology, 221(10)e202203102 (2022).
2. Satoru Takahashi, Chieko Saito, Ikuko KoyamaHonda, Noboru Mizushima. Quantitative 3D
correlative light and electron microscopy oforganelle association during autophagy. Cell
Structure and Function, v47(2) 89-99 (2022)

435

Department of Cellular and Tissue
Communications
Project Professor
Jun K. YAMASHITA, M.D.,Ph.D.

Project Assistant Professor
Tomohiro Minakawa, Ph.D.

Homepagehttps://www.m.u-tokyo.ac.jp/english/departments/units.html

Introduction and Organization
The
Department
of
CellularandTissueCommunications was established on July 1, 2022, withTakara Bio Inc. as the investor and the Department of
Cardiac Surgery (Prof. Minoru Ono) as thecollaborating department. The main purpose of thisdepartment is to elucidate new actions and roles ofextracellular vesicles (EVs) in diseases, which havebeen recently highlighted as a new type of intercellularcommunication, and to develop new next-generation
therapies using EVs. One Project Professor and one
Project assistant professor have been appointed, and Dr.
Yamashita and Dr. Minagawa have been appointed tothese positions respectively.
The details of the reason for the establishment,
significance, and research content are as follows.
The purpose of this department is to develop research
on novel cellular and tissue communications focusing
on a new biological phenomenon called “phenotypicsynchronization of cells (PSyC)” via extracellular
vesicles (EVs), which has recently been discovered andreported in Japan, to elucidate new pathologicalconditions and to develop new therapeutic methods
using EVs. EVs are considered to be involved invarious biological phenomena and pathologicalconditions by delivering various molecules in various
forms, and are an important new research target inmedical biology. Entering this research field based on
the world's first discovery of the unique function ofEVs (PSyC) would contribute to the University forsecuring its leading position in EV research and EV

treatment. The establishment of this department will
benefit for academic, research, and social activities.
The focus of this course is to explore the possibility ofpathological analysis and therapeutic application basedon basic research on the PSyC phenomenon. We also
aim to develop human resources who will pioneer anddevelop new research areas based on the researchcontent of this course.
[Research Contents]
1) Phenotypic Synchronization of Cells (PSyC): Usingcells that can mark EVs, we would like to conducting
real-time monitoring with high spatial-temporal
resolution to elucidate the actual mode of EV exchange,
the signaling molecules in EVs and their mechanismsof action.
(2) Significance of PSyC and EVs in pathologicalconditions: PSyC is considered to be involved not only
in synchronization of differentiation, but also broadly
in homeostasis, aging, and regeneration processes. The
physiological and pathophysiological significance of
PSyC will be clarified.
3) Therapeutic application of PSyC and EVs:
Development of next-generation novel therapies
utilizing cellar and tissue communications and PSyC
with EVs. Explore the possibilities of anti-aging andrejuvenation therapies through cardiac regeneration,
anti-atherosclerosis, and improvement of vascularfunction.
The following are assumed to be possible,
・EV is an area that has recently been highlighted andthe research is progressing rapidly, but the"synchronization of cellular phenotypes" is a unique436

discovery that was reported for the first time.
Furthermore, the new roles and significance of EVs
will be clarified by analysis of the latest technologies
such as real-time monitoring, opening up a newacademic field centered on cellar and tissuecommunications.
・ The analysis of pathological conditions from adifferent perspective, including communication withEVs, will lead to a new understanding of diseases andthe development of new treatment methods.
・By being the first to launch EV therapies supported
by scientific findings, we can lead the development of
new EV therapies worldwide.
・The potential for the development of completely new
therapies such as anti-aging and rejuvenation therapies
can also be expected.
・ The company can expect to commercialize EVs
through its investors and develop the application oftherapeutics and other industrialization.
The research targets of cellar and tissuecommunications and cell differentiation are related tostem cell biology and developmental biology. And
those of heart failure, atherosclerosis, tissue aging, arerelated to cardiovascular medicine and surgery, which
may be the initial therapeutic targets for heart andblood vessels. The research targets centered on EVmediated PSyC are highly unique, but the results canbe linked to various related fields and have highpotential for development. Thus, this course is a newresearch field that has not existed at the University ofTokyo before, and it can lead to new interactions,researchlinkages,andindustry-academia
collaborations.

Research activities
The following is an overview of our research to date.
Drs. Yamashita and Minagawa, members of our faculty,
discovered and reported the PSyC phenomenon(Minakawa, J Extracell Vesicles, 2021). Yamashita andcolleagues have been conducting basic research on
cardiovascular cell differentiation using pluripotent
stem cells and its application to regenerative medicine
and other fields. With the differentiation of pluripotent
stem cells into cardiovascular cells as the basis and coreof their research, they have conducted a series of wideranging research activities, including basic research on

various types of differentiation, induction ofcardiovascular cells from human pluripotent stem cells,
application of 3D organization to cardiac regeneration
therapy and creation of new disease models, andcommercialization of these products.
(1) Cardiovascular cell differentiation of pluripotent
stem cells and application to regenerative medicine: We
have conducted original and advanced research on
cardiovascular cell differentiation and regeneration
using pluripotent stem cells (ES cells and iPS cells).
Using Flk1-positive cells as common progenitors inmouse ES cells, we have established a newexperimental system that allows us to investigate thedifferentiation mechanism of cardiovascular cells
systematically (Nature, 2000). We are the first to
identify cardiac progenitor cells (FCV cells) thatdifferentiate into cardiomyocytes at high rates (FASEB
J, 2005) and to successfully differentiate iPS cells into
cardiovascular cells (Circulation, 2008; Best Paper
Award in the Basic Science category of the samejournal). Based on these achievements, we haveanalyzed the vascular differentiation mechanism ofstem cells (Blood, 2009; J Cell Biol, 2010; Blood, 2011
(front cover); Stem Cells, 2012a), developed celltherapy using cardiac tissue sheets (Stem Cells, 2012b).
We have developed novel methods for induction ofcardiac/endothelial cell differentiation and purificationof human iPS cells (PLoS One, 2011a, 2011b, 2017,2020), and technologies for cardiac tissue formationfrom iPS cells, including simple multiple layering ofcell sheets using gelatin hydrogel (Sci Rep, 2014, 2015,2016). The application of these technologies to cardiac
regenerative medicine is underway (in collaboration
with the Department of Cardiac Surgery of Universityof Tokyo and Kyoto University, and iHeart Japan, Inc.)(2) Development and application of novel pathologicalmodels: We developed the world's first model for alethal arrhythmia, Torsade de Pointes (TdP), using iPS
cell-derived mini 3D tissue (Kawatou, Nat Commun,2017). The model will be further developed for
application to drug safety studies and in vitro disease
reproduction and therapeutic research.
(3) Pioneering new EV biology & medicine: The
discovery of EV-induced cellular phenotypicsynchronization (Minakawa, J Extracell Vesicles,2021) will bring a new research field to the EV world.
EVs, together with real-time monitoring, will elucidate

437

a variety of new functions of EVs. We will also
investigate the application of EVs to novel cardiac
regeneration therapies based on their currently
discovered ability to induce myocardial differentiation.
(4) Regeneration of human hearts: We would like tomaking it possible to regenerate human hearts byenabling the proliferation of human cardiomyocytes
and the conversion of cardiac progenitor cells into stem
cells. We are currently analyzing the regulatory
mechanism of human cardiomyocyte proliferation
using various bioinformatics methods and ouruniversity's supercomputer.
(5) AMPK-based anti-aging and rejuvenation
strategies: Metformin, an AMPK activator, is apotential longevity drug that can extend lifespan, andundifferentiated transcription factors used to induce
iPS cells have also been suggested to have lifespanextending effects. AMPK activation, which serves as alink between these factors, has been shown to inducenaïve conversion of pluripotent stem cells (Liu,
iScience, 2021). A similar mechanism has been found
to operate in human cells (Yang, BioRxiv, 2022).
(6) Applications of Bioinformatics to pluripotent stem
cells. Development of a new cytotoxicity detection
system: We are developing a new cytotoxicity detection
system using the pluripotent stem cells with their broad
gene expression potential due to their pluripotency andlow genomic modification (Yamane, iScience, 2022;
Mori, BMC Bioinformatics, 2023). (in collaboration
with Dr. Wataru Fujibuchi).
With these studies as a background, we have beenworking mainly on (3), (4), (5), and (6) since our
appointment in FY2022.

References[Papers]
1. Yamane J, Wada T, Otsuki H, Inomata K, Suzuki
M, Hisaki T, Sekine S, Kouzuki H, Kobayashi K,
Sone H, Yamashita JK, Osawa M, Saito MK,
Fujibuchi W. StemPanTox: A fast and wide-target
drug assessment system for tailor-made safety
evaluations using personalized iPS cells. iScience.
6;25:104538, 2022.
2. 大塚 悟史、中尾 洋一: 春ウコンに含まれるアストロサイト分化誘導促進物質の同定,
化学と生物, 61:6-8, 2023

[Awards]
皆川朋皓, 第 28 回（令和 4 年度）日本炎症・再生医学会奨励賞 2022.7.7[Lectures]
1. 山下潤. 幹細胞と組織工学による組織機能の構成的再現. 第 43 回日本炎症再生医学会シンポジウム, 2022.7.6.
2. 皆川朋皓, 山下潤. 近接する細胞へのエクソ
ソーム・細胞外小胞送達による細胞形質同調.
第 43 回 日本炎症・再生医学会, 2022.7.7
3. 山下潤. 細胞外小胞の新しい機能と可能性－細胞形質を制御する－. 第 81 回日本癌学会
学術集会・共催セミナー, 2022.9.30.
4. Yamashita JK. Cardiovascular regeneration withhuman iPS cell-derived heart tissue. Symposium
on Medical Exchange of Shanghai University andthe University of Tokyo, 2022.11.17.
5. Kawatou M, Minatoya K, Ashihara T, Yamashita
JK. Human iPS cell-engineered heart tissue toreproduce ventricular fibrillation in vitro. 第 87回日本循環器学会学術集会, 2023.3.11.
6. 山下潤. 再生医療への幹細胞/ティッシュエン
ジニアリング融合技術の役割と新展開. 第 22回日本再生医療学会総会シンポジウム,
2023.3.24.
7. 山下潤. 血管内塞栓を形成しない安全な基材による新しい効率的心筋前駆細胞移植法の開発. 第 22 回日本再生医療学会総会, 2023.3.25.
8. 皆川朋皓, 山下潤. 隣接細胞間における小胞動態のライブイメージング. 生物物理学会中部支部講演会, 2023.3.31.

438

Department of Next Generation
Locomotive Imaging System
Project Associate Professor
Toru Doi, M.D., Ph.D.

Project Assistant Professor
Nozomu Ohtomo, M.D.

Introduction and Organization
The Department of Next Generation Locomotive
Imaging System is established to develop new imaging
system for scoliosis deformity in April 2020, which is
fully funded by ZOZO Corporation. Screening
examinations of scoliosis include the forward bending
test and Moiré tomography. However, screening tests
such as the forward bending test are not considered
accurate enough to detect scoliosis and Moiré
tomography is no longer manufactured and cannot be
used for school screening examinations. Moreover,radiographic examinations for diagnosing scoliosis
requires radiation exposure. Therefore, it is necessary
to develop a new screening tool for detecting scoliosis.
We aimed to develop a new screening tool for detecting
scoliosis using a 3-dimension (3D) measurement
bodysuit (ZOZOSUIT®).

Research activities
Our research aim is to develop a new screening imaging
system for detecting scoliosis, using a unique 3D bodymeasurement suit (ZOZOSUIT®), which wasdeveloped by ZOZO Co.. The development of this newgeneration imaging system may detect scoliosis
deformity without radiation exposure.
Patients with scoliosis or suspected scoliosis, nonscoliosis patients, and healthy volunteers wereenrolled. They were divided into Non-Scoliosis andScoliosis groups. The Scoliosis group was further
subdivided into Mild-, Moderate-, and SevereScoliosis groups. Patients’ characteristics and Z

values, which were calculated by a 3D virtual humanbody model created by ZOZOSUIT® to evaluate
trunk asymmetry caused by scoliosis, werecompared between the Non-Scoliosis and Scoliosis
groups or among the Non-, Mild-, Moderate- andSevere-Scoliosis groups. Finally, the optimal cutoffof the Z value was determined to detect moderate tosevere scoliosis using receiver operating
characteristics (ROC) curve analysis. A total of 101
patients were included in this study. The NonScoliosis group included 47 patients, and theScoliosis group included 54 patients, with 11, 31,
and 12 patients in the Mild-, Moderate-, and SevereScoliosis groups, respectively. The Scoliosis group
showed a significantly higher Z value than the NonScoliosis group. The Moderate- or Severe-Scoliosis
group had a significantly higher Z value than theNon- or Mild-Scoliosis group. The ROC curve
analysis revealed that the optimal cutoff of the Zvalue was 19.9 mm (sensitivity, 95.3%; specificity,
58.6%). A novel scoliosis screening method using
ZOZOSUIT® may be useful for detecting moderate
to severe scoliosis.

References
1. Treatmentofrestenosis
after
lumbardecompression surgery: decompression versus
decompression and fusion.
Junya Miyahara, Yuichi Yoshida, Mitsuhiro
Nishizawa, Hiroyuki Nakarai, Yudai Kumanomido,
Keiichiro Tozawa, Yukimasa Yamato, Masaaki

439

Iizuka, Jim Yu, Katsuyuki Sasaki, Masahito Oshina,
So Kato, Toru Doi, Yuki Taniguchi, Yoshitaka
Matsubayashi, Akiro Higashikawa, Yujiro
Takeshita, Takashi Ono, Nobuhiro Hara, Seiichi
Azuma, Naohiro Kawamura, Sakae Tanaka,
Yasushi Oshima.
Journal of Neurosurgery Spine 2022 Jan 7:1-8.
2. Evaluation of bone strength using finite-element
analysis in patients with ossification of theposterior longitudinal ligament.
Toru Doi, Satoru Ohashi, Nozomu Ohtomo,
Keiichiro Tozawa, Hiroyuki Nakarai, Yuichi
Yoshida, Yusuke Ito, Ryuji Sakamoto, Koji
Nakajima, Kosei Nagata, Naoki Okamoto, Hideki
Nakamoto, So Kato, Yuki Taniguchi, Yoshitaka
Matsubayashi, Sakae Tanaka, Yasushi Oshima.
Spine Journal 2022 Mar 4:S1529-9430(22)000948.
3. Dose surgical treatment affect the degree ofanxiety or depression in patients with degenerative
cervical myelopathy?
Naohiro Tachibana, Toru Doi, Koji Nakajima,
Hideki Nakamoto, Junya Mihayahra, Kosei Nagata,
Hiroyuki Nakarai, Keiichiro Tozawa, Nozomu
Ohtomo, Ryuji Sakamoto, So Kato, Yuki Taniguchi,
Yoshitaka Matsubayashi, Sakae Tanaka, Yasushi
OshimaGlobal Spine Journal. 2022 Mar 29;21925682
221088549.

440

Department of Next-Generation
Endoscopic Computer Vision
Project Associate Professor
Yosuke Tsuji, M.D., Ph.D.

Project Research Associate
Hiroya Mizutani, M.D., Ph.D., Tomonori Aoki, M.D., Ph.D.

Introduction and Organization
This Social Cooperative Chair was launched in
January 2023 with the investment of AI Medical
Services, Inc. As an affiliated chair of the Universityof Tokyo Graduate School of Medicine, it is also
supported by the Department of Gastroenterology(Prof. Mitsuhiro Fujishiro).
The main research project of the department is the useof AI in gastrointestinal endoscopy. As a result of theintroduction of the option of endoscopy in
population-based gastric cancer screening (a public
medical service aiming at reducing mortality fromgastric cancer) from 2016, the number of endoscopic
examinations has dramatically increased, and theincreased workload on physicians and the risk of
missing gastric cancer have become major issues. At
the same time, since endoscopy is an examination
method that depends on the skill of the physician, thedifference in skill is also an issue. Recently, many
attempts to apply the latest AI technologies such as
Deep Learning to the medical field have been reported,and there are high expectations for the application of
AI in the field of endoscopy. The purpose of ourdepartment is to conduct research and development
for the utilization of AI in endoscopy and evaluate theresults in clinical practice.

Clinical activities
Our department is not directly involved in the clinicalpractice. Dr. Tsuji (Project Associate Professor) is thehead of the Gastrointestinal Tract Group in the
Department of Gastroenterology at the University ofTokyo Hospital, where he manages the treatment of
the gastrointestinal tract. Together with Drs. Hiroya
Mizutani, and Tomonori Aoki (Project Research
Associate), who also belong to the Gastrointestinal
Tract Group of the Department of Gastroenterology at
the University of Tokyo Hospital, he is involved inmany diagnoses and treatments using gastrointestinalendoscopy.

Teaching activities
Our department is not directly involved in education.
Dr. Tsuji (Project Associate Professor) is in charge ofa lecture on "Non-neoplastic Bowel Disease" in theorganized course "Gastroenterology" for thesecond-year medical students in the Department ofInternal Medicine, School of Medicine, the Universityof Tokyo.

Research activities
Our department will conduct research, development,
and clinical evaluation of software programs thatassist physicians in diagnosis using the latest image
analysis technology. Specifically, the following two
points will be the main focus of the research:(1) We will develop AI equipped with endoscopists'knowledge to improve the quality of endoscopic
diagnosis by equalizing the endoscopic diagnosis andreducing missed diagnoses.
(2) To establish next-generation endoscopic diagnosis
and treatment methods using AI, we will acquire,process, and classify data based on actual clinical441

experience. We will resolve issues related to the small
number of data on rare cases, annotation cost, etc.,
which are challenges in the social implementation ofendoscopic AI, from the perspective of image analysis
technology.
To develop an endoscopic diagnosis support AI, alarge amount of high-quality "training data," i.e., alarge number of high-quality endoscopic images andvideos of diseases, is first required. In addition,
information such as the location of the disease, theextent of the disease, and the final diagnosis must be
linked to the image data. For this reason, we arebuilding a system for training AI by accumulating alarge number of endoscopic images as high-quality
video data in collaboration with the University ofTokyo and other facilities. After accumulating acertain number of data, we will develop an AI to
support disease detection and differential diagnosis
and conduct necessary trials to verify the effectivenessof the AI and to introduce it into actual clinicalpractice in the future.

References
1.

2.

3.

4.

Nagao S, Tani Y, Shibata J, Tsuji Y, Tada T,
Ishihara R, Fujishiro M. Implementation of
artificial intelligence in upper gastrointestinalendoscopy. DEN Open. 2022 Mar 15;2(1):e72.
Ochiai K, Tada T, Shibata J, Nagao S, Tsuji Y,
Fujishiro M, Ishihara S. Artificial Intelligence inColonoscopy:
ExploringComputer-aided
Detection Systems Stomach and Intestine 2022,
57(10) :1298-1304
Kubota D, Tsuji Y, Mizutani H, Nagao S,
Fujishiro M. An unexpected adverse event ofendoscopic ultrasonography: acute aortic
dissection. Gastrointest Endosc. 2022 Nov;96(5):866-867.
Hisada H, Tsuji Y, Obata M, Cho R, Nagao S,
Miura Y, Mizutani H, Ohki D, Yakabi S,
Takahashi Y, Sakaguchi Y, Kakushima N,
Yamamichi N, Fujishiro M. The impact ofsarcopenia on short- and long-term outcomes ofendoscopic submucosal dissection for earlygastric cancer. J Gastroenterol. 2022 Dec;57(12):952-961442

Next-Generation Precision
Medicine Development
Laboratory
Project Associate Professor
Hidenori Kage, M.D., Ph.D.

Project Lecturer
Akiko Kunita, Ph.D.

Introduction and Organization
In June 2019, The University of Tokyo, National
Cancer Center Japan, and Konica Minolta, Inc. agreed
to develop Todai OncoPanel (TOP), a next-generation
comprehensive cancer genomic panel (CGP). TOP was
initially developed by Professor Aburatani, The
University Tokyo Research Center for Advanced
Science and Technology and Hiroyuki Mano, former
professor at The University of Tokyo and current Headof Cell Informatics, at National Cancer Center Japan.
The research collaboration combines the knowledge ofAmbry Genetics Corporation, a Konica Minolta
company, and its global gene diagnostic technology,
with the TOP technology to reinforce the informatics
foundation technology of the TOP and develop a nextgeneration CGP. The Department of Next-Generation
Precision Medicine Development Laboratory wasestablished in April 2021 as a Social Collaboration
Department within 22nd Century Medical andResearch Center of The University of Tokyo Hospital,collaborating with Konica Minolta, Inc.

Clinical activities
As a Social Collaboration Department within 22nd
Century Medical and Research Center, we do notdirectly engage in clinical activities. Dr. Kage isinvolved in cancer genomic medicine at The Universityof Tokyo Hospital through oversight of the Expert

Panel.

Teaching activities
As a Social Collaboration Department within 22nd
Century Medical and Research Center, we do notdirectly engage in teaching activities. When M4
medical students came to the Department of Clinical
Genomics for a one-month rotation in fiscal year 2022,
Dr. Kage gave lectures and participated in Expert
Panels with the students.

Research activities
TOP can detect a large number of gene mutations with
its DNA panel and gene fusions with its RNA panel. At
the Department of Next-Generation Precision Medicine
Development Laboratory, we focus on (1) optimizationof pathological specimens for CGP tests and (2)evaluation of TOP through Advance Medicare Care B.
(1) Best tissue processing practices for CGP tests with
RNA panel
Background: Formalin-fixed, paraffin-embedded(FFPE) samples are valuable resources routinely used
for pathology and clinical CGP tests. However, theyalso represent a multistage process that is notstandardized, especially for RNA sequencing. Because
pre-analytical sample processing ultimately affects thesequencing accuracy, its optimization is essential.

443

Therefore, we evaluated the effects of fixative
concentrations, fixation time, and tissue size on
DNA/RNA quality.
Methods: Pig livers were removed within 30 min ofsacrifice. Equally sized tissues (2 mm/ 12 mm/ 50 mm
thickness) were fixed in neutral-buffered formalin(10% or 20% NBF) for one (24 h), three (72 h), andseven days (168 h). FFPE blocks were prepared, andDNA and RNA were extracted from each 10 mm
section using spin columns. The DNA/RNA quality
was evaluated using fluorescence-based quantificationand fragment size distribution (DIN for DNA/DV200
for RNA).
Results: DNA integrity was best for samples fixed in
10% NBF for one day. The RNA integrity remained
unchanged irrespective of the NBF concentration. For
RNA, the best fixation duration was one day. Increased
degradation was observed in both DNA and RNA
extracted from samples fixed for three and seven days
versus those fixed for one day. Regarding tissue size infixation, DNA yield per tissue area and the integrity
were best extracted from small (2 mm thickness)tissues and had a great influence over the integrity.
Conversely, RNA yield per tissue area and the integrity
were best when extracted from large (50 mm thickness)tissues and had the minimal impact on the integrity.
Conclusions: Effects of the fixation methods varied
between DNA and RNA. For the best tissue processing
practices, fixation in 10% NBF for one day was suitablefor DNA and RNA. Large tissues should be sliced into
thin sections for effective fixation.
(2) Evaluation of TOP through Advance Medicare Care
B
Background: Comprehensive cancer genome profiling(CGP) has been nationally reimbursed in Japan sinceJune 2019. Less than 10% of the patients have beenreported to undergo recommended treatment. Todai
OncoPanel (TOP) is a dual DNA-RNA panel as well asa paired tumor-normal matched test.
Methods: Two hundred patients underwent Todai
OncoPanel as part of Advanced Medical Care B withapproval by the Ministry of Health, Labour and Welfare
between September 2018 and December 2019. Tests
were performed in patients with cancers without
standard treatment or when patients had alreadyundergone standard treatment.

Results: Data from DNA and RNA panels wereanalyzed in 198 and 191 patients, respectively. The
percentage of patients who were given therapeutic or
diagnostic recommendations was 61% (120/198). One
hundred and four samples (53%) harbored genealterations that were detected with the DNA panel andhad potential treatment implications, and 14 samples(7%) had a high tumor mutational burden. Twenty-two
samples (11.1%) harbored 30 fusion transcripts or MET
exon 14 skipping that were detected by the RNA panel.
Of those thirty transcripts, six had treatment
implications and four had diagnostic implications.
Thirteen patients (7%) were found to have pathogenic
or likely pathogenic germline variants and genetic
counseling was recommended. Overall, 12 patients(6%) received recommended treatment.
Conclusions: Patients benefited from both TOP DNA
and RNA panels while following the same indication as
the approved CGP tests.

Publications
1.

2.

3.

Ando T, Kage H, Shinozaki-Ushiku A, Tatsuno K,
Tsutsumi S, Nagayama K, Nakajima J, Kohsaka S,
Miyagawa K, Aburatani H, Mano H, Nagase T.
Composite Clonal Analysis Reveals Transition of
NSCLC Subtypes Through Accumulation of Gene
Mutations: A Case Report. JTO Clin Res Rep
2022;3:100277. PMID: 35199052
Miyamoto S, Yamazaki T, Shimizu K, Matsubara
T, Kage H, Watanabe K, Kobo H, Matsuyama Y,
Rodin G, Yoshiuchi K. Brief, manualised andsemistructured
individual
psychotherapy
programme for patients with advanced cancer inJapan: study protocol for Managing Cancer and
Living Meaningfully (CALM) phase 2 trial. BMJ
Open 2022;12:e056136. PMID: 35277407
Tanosaki T, Mikami Y, Shindou H, Suzuki T,
Hashidate-Yoshida T, Hosoki K, Kagawa S,
Miyata J, Kabata H, Masaki K, Hamamoto R,
Kage H, Miyashita N, Makita K, Matsuzaki H,
Suzuki Y, Mitani A, Nagase T, Shimizu T,
FukunagaK.
Lysophosphatidylcholine
Acyltransferase
1
Deficiency
Promotes
Pulmonary Emphysema via Apoptosis of Alveolar
Epithelial Cells. Inflammation 2022;45:17651779. PMID: 35338433

444

4.

5.

6.

7.

8.

9.

Naito Y, Sunami K, Kage H, Komine K, Amano T,
Imai M, Koyama T, Ennishi D, Kanai M,
Kenmotsu H, Maeda T, Morita S, Sakai D,
Watanabe K, Shirota H, Kinoshita I, Yoshioka M,
Mamesaya N, Ito M, Kohsaka S, Saigusa Y,
Yamamoto K, Hirata M, Tsuchihara K, Yoshino T.
Concordance Between Recommendations From
Multidisciplinary Molecular Tumor Boards andCentral Consensus for Cancer Treatment in Japan.
JAMA Netw Open 2022;5:e2245081. PMID:
36469316
Mizuno S, Ikegami M, Koyama T, Sunami K,
Ogata D, Kage H, Yanagaki M, Ikeuchi H, Ueno T,
Tanikawa M, Oda K, Osuga Y, Mano H, Kohsaka
S. High-throughput functional evaluation of
MAP2K1 variants in cancer. Mol Cancer Ther
2022;22:227-239 PMID: 36442478
Sunami K, Naito Y, Komine K, Amano T, Ennishi
D, Imai M, Kage H, Kanai M, Kenmotsu H,
Koyama T, Maeda T, Morita S, Sakai D, Kohsaka
S, Tsuchihara K, Saigusa Y, Yoshino T.
Chronological improvement in precision oncology
implementation in Japan. Cancer Sci. 2022;113:
3995-4000. PMID: 35976133
Imai M, Nakamura Y, Sunami K, Kage H, Komine
K, Koyama T, Amano T, Ennishi D, Kanai M,
Kenmotsu H, Maeda T, Morita S, Sakai D, Bando
H, Makiyama A, Suzuki T, Hirata M, Kohsaka S,
Tsuchihara K, Naito Y, Yoshino T. Expert Panel
Consensus Recommendations on the Use of
Circulating Tumor DNA Assays for Patients with
Advanced Solid Tumors. Cancer Sci. 2022;113:
3646-3656 PMID: 35876224
Kage H, Kohsaka S, Tatsuno K, Ueno T, Ikegami
M, Zokumasu K, Shinozaki-Ushiku A, Nagai S,
Aburatani H, Mano H, Oda K. Tumor mutationalburden measurement using comprehensive
genomic profiling assay. Jpn J Clin Oncol 2022;
52:917-921. PMID: 35482395
Tanosaki T, Mikami Y, Shindou H, Suzuki T,
Hashidate-Yoshida T, Hosoki K, Kagawa S,
Miyata J, Kabata H, Masaki K, Hamamoto R,
Kage H, Miyashita N, Makita K, Matsuzaki H,
Suzuki Y, Mitani A, Nagase T, Shimizu T,
FukunagaK.
Lysophosphatidylcholine
Acyltransferase
1
Deficiency
Promotes
Pulmonary Emphysema via Apoptosis of Alveolar

Epithelial Cells. Inflammation 2022;45:17651779. PMID: 35338433
10. Kume A, Shinozaki-Ushiku A, Kunita A, Kondo A,
Ushiku T: Enhanced PD-L1 Expression in LMP1positive Cells of Epstein-Barr Virus-associated
Malignant Lymphomas and Lymphoproliferative
Disorders: A Single-cell Resolution Analysis With
Multiplex Fluorescence Immunohistochemistry
and In Situ Hybridization. Am J Surg Pathol 2022.
PMID:35605962
11. Suzuki T, Masugi Y, Inoue Y, Hamada T, Tanaka
M, Takamatsu M, Arita J, Kato T, Kawaguchi Y,
Kunita A, Nakai Y, Nakano Y, Ono Y, Sasahira N,
Takeda T, Tateishi K, Uemura S, Koike K, Ushiku
T, Takeuchi K, Sakamoto M, Hasegawa K, Kitago
M, Takahashi Y, Fujishiro M, Japan GTKPCSGi:
KRAS variant allele frequency, but not mutation
positivity, associates with survival of patients withpancreatic cancer. Cancer Sci 2022. PMID:
35567350
12. Tanaka M, Kunita A, Yamagishi M, Katoh H,
Ishikawa S, Yamamoto H, Abe J, Arita J,
Hasegawa K, Shibata T, Ushiku T: KRAS
mutation in intrahepatic cholangiocarcinoma:
Linkage with metastasis-free survival and reduced
E-cadherin expression. Liver Int 2022, 42:232940. PMID:35833881
13. Tanaka M, Shinozaki-Ushiku A, Kunita A,
Yasunaga Y, Akamatsu N, Hasegawa K, Ushiku T:
High-grade
transformationofpancreatic
neuroendocrine tumor associated with TP53
mutations: A diagnostic pitfall mimicking
neuroendocrine carcinoma. Pathol Int 2022, 72:
411-8. PMID:35698921

445

Department of Tissue Stem Cells
and Life Dentistry
Project Professor
Makoto Komura, M.D., Ph.D.

Project Lecturer
Yukiyo Asawa, D.V.M., Ph.D.

Homepage

http://plaza.umin.ac.jp/~tsc-lds/manage.html

Introduction and Organization
A social cooperation course, The Department of
Tissue Stem Cells and Life Dentistry was acollaborative department established in the departmentof tissue engineering, the University of Tokyo Hospitalon November 19, 2018.
The research is currently based in University ofTokyo Hospital Tissue Engineering Department,
Department of Oral and Maxillofacial Surgery, andDepartment of Pediatric Surgery.
The goal of our department is to succeed intranslational research, from basic to clinical with thepromotion of technology development on tissue organ
regeneration, funded by Sheep Medical Co., Ltd.
(formerly Dental Assist Co., Ltd.).
Major research projects include: research toelucidate self-renewal mechanisms using templateencapsulated tissue bodies (bio sheet/ bio tube) fortrachea, gingiva and cornea regeneration, developmentof pulp stem cell culture methods, research on humoral
factors in dental pulp culture supernatant fluid,
establishment of techniques to induce bonedifferentiation in human umbilical cord, and analysisof oral microflora.
In 2022, the department is currently headed by a
Project Professor, was assisted by a Project Lecturer.

Teaching activities
We shared the appeal of basic researchundergraduates through laboratory tours.

toWith the cooperation of Department of PediatricSurgery, we are preparing to give lectures to master andPh.D. students. On January 17, 2023, We gave a lectureon "Pediatric Surgery and Regenerative Medicine" inthe Department of Reproductive, Developmental andAging Sciences.
We also gave research guidance to master and Ph.D.
students majoring in pediatric surgery and oral andmaxillofacial surgery through practical training andexercises.

Research activities
In our study, we use somatic stem cell that exists in bio
tissue, and we try to stimulate the somatic cell. By
using dental pulp-derived stem cell, cartilage stem cell,and umbilical cord-derived stem cell, we are working
to make up for the functional and structural defects.
The target organs for this specific reproductions are,bone, cartilage, skin and muscle (including gingiva).
The following are the research topics of ourdepartment in 2020:

Self-regeneration mechanism identification ofskin mold encapsulation tissue
・ Structure analysis of skin-encapsulated tissue
・ Construction of regeneration model using skinencapsulated tissue
・ Factor examination of regeneration model Development of dental pulp stem cell culture
method446

・ 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 anastomosis
site
・ Functional evaluation of human ES cell
 Bone differentiation culture technique of humanumbilical cord
・ Development of umbilical cord cell culture
method while maintaining undifferentiated form
・ Development of bone differentiation induction
method Analysis of oral microflora
・ Identification of bacteria with anti-inflammatory
properties.
Anti-inflammatory action of bacteria against
periodontopathic bacteria.

References
1:

2:

Shimizu R, Asawa Y, Komura M, Hoshi K, Hikita
A. Superior stemness of a rapidly growing
subgroupofisolatedhuman
auricularchondrocytes and the potential for use in cartilage
regenerative therapy. Regen Ther. 2022 Jan 4;19:
47-57.
Yokote F, Yamauchi Y, Komura H, Tanuma T,
Sakao Y, Kawamura M, Komura M. A novel
method of tracheal anastomosis healing using asingle submucosal injection of basic fibroblast
growth factor: initial report. Eur J Cardiothorac
Surg. 2022 Mar 24;61(4):917-924.

Conference Presentations
1:

The 21st Annual Meeting of the Japanese Society
for Regenerative Medicine. SP-13-2 March 17,2022. Asawa, Y., Shiraishi, K., Nishida, T.,

2:

3:

4:

Komura, H., Kumagai, K., Seto, I., Abe, T., Hikita,A., Komura, M., Hoshi, K. Evaluation of cellularcharacteristics and bone differentiation potentialof dental pulp cells derived from humanpermanent and wisdom teeth.
The 21st Annual Meeting of the Japanese Society
for Regenerative Medicine. SP-19-6 March 19,
2022. Komura, H., Suzuki, K., Asawa, Y.,
Kanazawa, S., Shiraishi, K., Nakayama, Y.,
Komura, M. Skin regeneration by subcutaneously
implanted periapical encapsulated tissue body
(bio sheet).
The 76th Annual Meeting of the Japanese Societyof Oral Medicine. April 21-23, 2022. Harada, T.,
Shiraishi, K., Asawa, Y., Abe, T., Komura, M.,
Hoshi, K. Basic study on mouse dental pulp cells
for the development of bone regeneration
technology.
The 76th Annual Meeting of the Japanese Societyof Oral Medicine. April 21-23, 2022. Shiraishi,K., Harada, T., Kawakami, H., Kumagai, K., Abe,
M., Asawa, Y., Komura, M., Hoshi, K.
Characterization of dental pulp cells derived fromhuman permanent teeth and evaluation of bonedifferentiation potential for development of boneregeneration therapy.

447

Department of Digital Mental
HealthProject Professor
Norito Kawakami, M.D., Ph.D.

Project Associate Professor
Kotaro Imamura, Ph.D.

Project Lecturer
Asuka Sakuraya, Ph.D.

Homepage https://dmh.m.u-tokyo.ac.jp/
Introduction and Organization
The Department of Digital Mental Health wasestablished in June 2022 as a social cooperation
program in collaboration with the Graduate School of
Medicine, The University of Tokyo and 15 companies.
We conduct basic and applied research on digitalmental health (DMH) technology and services, such asmeasuring mental health and developing intervention
programs to maintain and promote mental health. We
contribute to society by disseminating researchfindings for mental health and also contribute to
medical education based on these findings. We mainly
research how to apply digital health technology tomental health promotion in the workplace and healthand productivity management systems. The
Department of Digital Mental Health is the world's
first department established in a university to apply
DMH technology in the occupational mental healthfield. From our activity, the following results will be
expected;
1) Innovative digital mental health solutions
applying artificial intelligence (AI) andsimulation models will be developed and widely
disseminated to individuals, companies, andorganizations to promote people's mental health.
2) Scientific evidence about the accuracy ofmeasurement methods and effectiveness ofintervention programs will be accumulated, andevidence-based
services
applying
DMH

technologies will be established.
3) Strategies
forthedissemination
andimplementation of evidence-based DMH services
will be developed, and a framework for their
quality assurance will be proposed to society.

Research activities
Mental health is an important issue for individuals,
companies, organizations, and society. In particular,
mental health became a major public health challenge
during the COVID-19 pandemic. In the post-pandemic
society, it will be important to develop DMH
technology to support mental health in the workplaceand community using digital tools. The main research
topics are as follows:
1) Applying digital technologies such as AI andsimulation models to promote DMH, anddeveloping a fully automated and tailored stressmanagement program guided by AI.
2) Evaluating the effectiveness of evidence-based
DMH measurement and intervention programs
using gold-standard methodology such as
randomized controlled trials.
3) Developing effective strategies for the
dissemination and implementation of evidencebased DMH measurement and intervention
programs to individuals, companies/organizations,and municipalities. We also research quality
assurance frameworks for DMH services.

448

In addition to this, we will conduct extensive
research on mental health in the digital society and"Society 5.0."

References
1.

2.

3.

4.

5.

6.

Fukasawa M, Umeda M, Akiyama T, Horikoshi N,
Yasumura S, Yabe H, Suzuki Y, Bromet EJ,
Kawakami N. Worry about Radiation and Its Risk
Factors Five to Ten Years after the Fukushima
Nuclear Power Plant Disaster. Int J Environ Res
Public Health. 2022 Dec 16;19(24):16943. doi:
10.3390/ijerph192416943. PMID: 36554824;
PMCID: PMC9778659.
Yasuma N, Shiozawa T, Ogawa M, Abe M,
Igarashi M, Kawaguchi T, Sato S, Nishi D,
Kawakami N, Yamaguchi S, Fujii C. Whatoutcomes in community mental health research
are important to caregivers of people withschizophrenia? An exploratory qualitative
analysis of an online survey. Neuropsychopharmacol Rep. 2022 Dec;42(4):526-531.
doi: 10.1002/npr2.12295. Epub 2022 Oct 10.
PMID: 36217559; PMCID: PMC9773637.
Sasaki N, Akiyama H, Kawakami N, Nishi D.
Preconception menstrual cycle disorder andantenatal depression: a cross-sectional study withprerecorded information. J Psychosom Obstet
Gynaecol. 2022 Dec;43(4):411-418. doi: 10.
1080/0167482X.2021.2010699. Epub 2021 Dec 9.
PMID: 34882063.
Obikane E, Sasaki N, Imamura K, Nozawa K,
Vedanthan R, Cuijpers P, Shimazu T, Kamada M,
Kawakami N, Nishi D. Usefulness of
Implementation Outcome Scales for Digital
Mental Health (iOSDMH): Experiences from Six
Randomized Controlled Trials. Int J Environ Res
Public Health. 2022 Nov 27;19(23):15792.
Tsuji R, Nishi D, Sasaki N, Akiyama H, Kuroda
R, Tsuno K, Imamura K, Kawakami N.
Association between meal frequency with others
and psychological distress during the COVID‐19
pandemic: A cross‐sectional study. Psychiatry
Clin Neurosci Rep. 2022 e61. https://doi.org/
10.1002/pcn5.61
Sugiura K, Morita Y, Kawakami N, Kayama M.
How Do Psychiatrists in Japan Choose

7.

8.

9.

10.

11.

12.

13.

Involuntary Admission, and What Do They Thinkof Supported Decision Making? A Thematic
Analysis of Peer to Peer Interviews. Community
Ment Health J. 2022 Nov 3. doi: 10.1007/
s10597-022-01046-1. Epub ahead of print.
PMID: 36327042.
Komase Y, Akiyama H, Kawakami N. Effects of
the Collective Gratitude on Work Engagement: A
Multilevel Cross-sectional Study. J Occup
Environ Med. 2022 Nov 1;64(11):e729-e735. doi:
10.1097/JOM.0000000000002683. Epub 2022
Aug 20. PMID: 35993606.
Tsuno K, Kawakami N, Tsutsumi A, Shimazu A,
Inoue A, Odagiri Y, Shimomitsu T. Victimization
and witnessing of workplace bullying andphysician-diagnosed physical and mental healthand organizational outcomes: A cross-sectional
study. PLoS One. 2022 Oct 26;17(10):e0265863.
doi:
10.1371/journal.pone.0265863.
PMID:
36288324; PMCID: PMC9603991.
Yasuma N, Imamura K, Watanabe K, Iida M,
Takano A. Adolescent cannabis use and the later
onset of bipolar disorder: protocol for asystematic review and meta-analysis of prospective
cohort studies. Neuropsychopharmacol Rep. 2022
Oct 25.
Obikane E, Watanabe K, Nishi D, Kawakami N.
Adverse childhood experiences and personalvalues in adolescence: a cross-sectional study
using community adult samples in Japan. Pediatr
Int. 2022 Sep 27:e15370. doi: 10.1111/ped.15370.
Epub ahead of print. PMID: 36165851.
Kuribayashi K, Takano A, Inagaki A, Imamura K,
Kawakami N. Effect of stress management basedon cognitive-behavioural therapy on nurses as auniversal prevention in the workplace: asystematic review and meta-analysis protocol.
BMJ Open. 2022 Sep 19;12(9):e062516.
Nishi D, Imamura K, Watanabe K, Obikane E,
Sasaki N, Yasuma N, Sekiya Y, Matsuyama Y,
Kawakami N. The preventive effect of internetbased cognitive behavioral therapy for preventionof depression during pregnancy and in the
postpartum period (iPDP): a large scalerandomized controlled trial. Psychiatry Clin
Neurosci. 2022 Aug 12.
Sasaki N, Imamura K, Watanabe K, Hidaka Y,

449

14.

15.

16.

17.

18.

Ando E, Eguchi H, Inoue A, Tsuno K, Komase Y,
Iida M, Otsuka Y, Sakuraya A, Asai Y, Iwanaga
M, Kobayashi Y, Inoue R, Shimazu A, Tsutsumi
A, Kawakami N. The impact of workplace
psychosocial factors on menstrual disorders andinfertility: a protocol for a systematic review andmeta-analysis. Syst Rev. 2022 Sep 7;11(1):195.
Sasaki N, Inoue A, Asaoka H, Sekiya Y, Nishi D,
Tsutsumi A, Imamura K. The Survey Measure of
Psychological Safety and Its Association with
Mental Health and Job Performance: A Validation
Study and Cross-Sectional Analysis. Int J
Environ Res Public Health. 2022 Aug 11;19(16):9879.
Sasaki N, Kuroda R, Tsuno K, Imamura K,
Kawakami N. COVID-19 vaccination did not
improve employee mental health: A prospective
study in an early phase of vaccination in Japan.
Neuropsychopharmacol Rep. 2022 Jun;42(2):230-232.
Kawakami N, Kim Y, Saito M, Fujishiro S.
People's worry about long-term impact of
COVID-19 pandemic on mental health. Asian J
Psychiatr. 2022 Sep;75:103196. doi: 10.1016/j.
ajp.2022.103196. Epub 2022 Jun 24. PMID:
35816936; PMCID: PMC9232257.
Takano A, Miyamoto Y, Shinozaki T, Matsumoto
T, Kawakami N. Effects of a web-based relapse
prevention program on abstinence: Secondary
subgroup analysis of a pilot randomized
controlled trial. Neuropsychopharmacol Rep.
2022 Sep;42(3):362-367. doi: 10.1002/npr2.
12272. Epub 2022 Jun 11. PMID: 35689457;
PMCID: PMC9515705.
Kessler RC, Kazdin AE, Aguilar-Gaxiola S,
Al-Hamzawi A, Alonso J, Altwaijri YA, Andrade
LH, Benjet C, Bharat C, Borges G, Bruffaerts R,
Bunting B, de Almeida JMC, Cardoso G, Chiu
WT, Cía A, Ciutan M, Degenhardt L, deGirolamo G, de Jonge P, de Vries YA, Florescu S,
Gureje O, Haro JM, Harris MG, Hu C, KaramAN, Karam EG, Karam G, Kawakami N, Kiejna
A, Kovess-Masfety V, Lee S, Makanjuola V,
McGrath JJ, Medina-Mora ME, Moskalewicz J,
Navarro-Mateu F, Nierenberg AA, Nishi D,
Ojagbemi A, Oladeji BD, O'Neill S, Posada-Villa
J, Puac-Polanco V, Rapsey C, Ruscio AM,

Sampson NA, Scott KM, Slade T, Stagnaro JC,
Stein DJ, Tachimori H, Ten Have M, Torres Y,
Viana MC, Vigo DV, Williams DR, Wojtyniak B,
Xavier M, Zarkov Z, Ziobrowski HN; WHO
World Mental Health Survey collaborators.
Patterns and correlates of patient-reported
helpfulness of treatment for common mental andsubstance use disorders in the WHO World
Mental Health Surveys. World Psychiatry. 2022
Jun;21(2):272-286. doi: 10.1002/wps.20971.
PMID: 35524618; PMCID: PMC9077614.
19. Eiko Ozasa, Asuka Sakuraya, Yasuto Sato,
Sachiko Takehara, Noriko Kojimahara. How
Doctors in Charge of Medical Education
Recognize and Use Clinical Practice Guidelines
in Education: A Cross-Sectional Study. Tokyo
Women's Medical University Journal https://doi.
org/10.24488/twmuj.
20. Yang CC, Watanabe K, Kawakami N. The
Associations Between Job Strain, Workplace
PERMA Profiler, and Work Engagement. J Occup
Environ Med. 2022 May 1;64(5):409-415. doi:
10.1097/JOM.0000000000002455. Epub 2021
Dec 6. PMID: 34873133.

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Department of Prevention of
Diabetes and Lifestyle-RelatedDiseases
Project Associate Professor
Satoko Yamaguchi, M.D., Ph.D.

Project Lecturer
Akira Okada, M.D., Ph.D.

Homepage https://plaza.umin.ac.jp/prev/
Introduction and Organization
The Department of Prevention of Diabetes andLifestyle-Related Diseases is a Social Cooperation
Program founded in April 2018, which is sponsoredby Asahi Mutual Life Insurance Company and iscooperating with the Department of Nephrology and
Endocrinology (Professor Masaomi Nangaku) and
Department of Diabetes and Metabolic Diseases(Professor Toshimasa Yamauchi).
The objective of our department is to undertake
research on preventing onset and progression ofdiabetes and other lifestyle-related diseases, throughanalyses of big data including medical databases andusage of information and communication technology(ICT), thereby making a contribution to improving
health of people in Japan.
Lifestyle-related diseases including diabetes
account for approximately 30% of medical expenses
and 60% of deaths. Moreover, Japan is facing an
unprecedented super aged society with aging rate of
28.1% in 2018, and an increasing number of people
require long-term care due to conditions caused bylifestyle-relateddiseases.
Analyzing
factors
associated with onset and progression of lifestylerelated diseases is expected to contribute topreventing lifestyle-related diseases and conditions
caused by them, decreasing the number of people
requiring long-term care, as well as optimizing

medical expenses.
Our department intends to conduct multidirectional
analyses of big data including medical databases andconstruct models predicting progression oflifestyle-related diseases.
We are receiving four collaborative researchers
from Asahi Mutual Life Insurance Company.

Research activities
The members of our department are working on thefollowing research topics.
1) Research on long-term care
An increasing number of people require long-termcare in recent years, and as of 2022, approximately 6.9
million people have been certified as being in need forlong-term care in Japan. However, factors anddiseases leading to conditions requiring long-termcare remain largely unknown. In order to identify
factors predicting conditions requiring long-term care,we obtained and have analyzed anonymized data ofComprehensive Survey of Living Conditions, anationwide survey containing household situation andhealth-related questions, from Ministry of Health,
Labor and Welfare.
2) Research on discontinuation of physician visit inpeople with diabetes

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Discontinuation of diabetes care is associated withincreased rate of complications and mortality. We
analyzed JMDC database and showed thatguideline-recommended practices within the firstmonth of physician consultation for diabetes care candecrease subsequent discontinuation of physician
visits in patients with newly diagnosed diabetes.
Additionally, we developed a machine-learning model
for predicting people's failure to attend a follow-up
visit for diabetes care after recommendations from anational screening program.
3) Research on impact of the COVID-19 pandemic on
healthcare service use and health check-ups
The COVID-19 pandemic disrupted healthcare
service and health check-ups globally, especially at its
beginning. We investigated the impact of pandemic on
healthcare service use by analysing hospital-based
claims database.
In addition, we investigated the impact of pandemic
on health check-ups by conducting a nationwide
survey targeting health check-up facilities, incollaboration with Japan Society of Ningen Dock.
This work was supported by MHLW Special
Research (Program Grant Number
JPMH20CA2046) and Research on Emerging andRe-emerging Infectious Diseases and Immunization（Program Grant Number JPMH21HA2011).
4) Research on bleeding complications after liverbiopsy and kidney biopsy in pediatric patients
Little has been reported about bleeding complications
after liver or kidney biopsy in pediatric patients.
Using a nationwide inpatient database, weinvestigated major complications after liver biopsy or
kidney biopsy in pediatric patients.
We performed research using DPC database and
JMDC database in collaboration with the Departmentof Clinical Epidemiology and Health Economics(Professor Hideo Yasunaga) and medical information
database of the University of Tokyo Hospital incollaboration with the Department of Biomedical
Informatics (Professor Kazuhiko Ohe).
In addition to moving these projects forward, we plan
to take on new projects using databases in the future.

References
1. Okada A, Yamana H, Yamaguchi S, Kurakawa KI,
Michihata N, Matsui H, Fushimi K, Nangaku M,
Yamauchi T, Yasunaga H, Kadowaki T. Effect ofBranched-Chain Amino Acid Infusion on
In-Hospital Mortality of Patients With Hepatic
Encephalopathy and End-Stage Kidney Disease:
A Retrospective Cohort Study Using a National
Inpatient Database. J Ren Nutr. 2022;32(4):432440.
2. Okada A, Hashimoto Y, Goto T, Yamaguchi S,
Ono S, Ikeda Kurakawa K, Nangaku M,
Yamauchi T, Yasunaga H, Kadowaki T. A
Machine Learning-Based Predictive Model to
Identify Patients Who Failed to Attend a
Follow-up Visit for Diabetes Care After
Recommendations From a National Screening
Program. Diabetes Care. 2022;45(6):1346-1354.
3. Yamaguchi S, Okada A, Sunaga S, Ikeda
Kurakawa K, Yamauchi T, Nangaku M,
Kadowaki T. Impact of COVID-19 pandemic on
healthcare service use for non-COVID-19
patients in Japan: retrospective cohort study. BMJ
Open. 2022;12(4):e060390.
4. Kurakawa KI, Okada A, Bessho K, Jo T, Ono S,
Michihata N, Kumazawa R, Matsui H, Fushimi K,
Yamaguchi S, Yamauchi T, Nangaku M,
Kadowaki T, Yasunaga H. Major complications
after percutaneous biopsy of native ortransplanted liver in pediatric patients: anationwide inpatient database study in Japan.
BMC Gastroenterol. 2022;22(1):395.
5. Okada A, Yamaguchi S, Jo T, Yokota I, Ono S,
Ikeda Kurakawa K, Nangaku M, Yamauchi T,
Kadowaki T. Impact of body mass index on
in-hospitalmortalityinolderpatients
hospitalized for bacterial pneumonia with
non-dialysis-dependent chronic kidney disease.
BMC Geriatr. 2022;22(1):950.
6. Okada A, Yamada G, Kimura T, Hagiwara Y,
Yamaguchi S, Kurakawa KI, Nangaku M,
Yamauchi T, Matsuyama Y, Kadowaki T.
Diagnostic ability using fatty liver and metabolic
markers for metabolic-associated fatty liverdiseasestratifiedbymetabolic/glycemic
abnormalities. J Diabetes Investig. 2022.

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7.

Okada A, Ikeda Kurakawa K, Harita Y, Shimizu
A, Yamaguchi S, Aso S, Ono S, Hashimoto Y,
Kumazawa R, Michihata N, Jo T, Matsui H,
Fushimi K, Nangaku M, Yamauchi T, Yasunaga H,
KadowakiT.
Comparisonofbleeding
complications after pediatric kidney biopsy
between intravenous sedation and generalanesthesia: a nationwide cohort study. BMC
Pediatr. 2023;23(1):33.

453

Department of Pain and Palliative
Medical Sciences
Project Associate Professor
Maiko Hasegawa-Moriyama, M.D., Ph.D.

Project Assistant Professor
Kirio Kawai, M.D

Homepage

N/A

History and outline of organization
About a half of the cancer patients die by cancer thoughof the recent innovations of anti-cancer treatments. It
mainly depends on the efficacy of the first-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 suchpatients that both sufficient anti-cancer treatments andappropriate approaches to improve their quality of life
(QOL) are simultaneously indispensable.
However, in our nation, most attention has been
entirely paid to the improvement of cure rate andsurvival time of cancer patients. On the other hand, we
have to consider that their QOL is scarcely
concentrated until quite recently.
Palliative care means the combination of active
therapeutic approach and total human care for thepatients no matter which their cancer does or does not
respond to anti-cancer treatments. Pain relief, othersymptom management, psychological, social andspiritual cares are as a top priority for these patients. It
is also emphasized that palliative care is necessary to
be applied in the cancer treatment even for patients inearly stage of their diseases as well as the progressiveor terminal phase of their clinical courses.
In Department of Pain and Palliative Medicine Science,
The University of Tokyo Hospital, we participate inpain and palliative care team and takes a leading role
not only to control physical symptoms of cancer

patients but also to care for the mental and social
support at the same time, and to improve the overall
QOL of patients.
Palliative care is described clearly in the law "Cancer
Control Act" approved by the National Diet on June
2006 that "The medical treatment to aim at relieving
many kinds of pain and problems of cancer patients is
applicable from the early course of the illness".
However, it is possible that the use of analgesic,
especially opioids are not sufficient for cancer pain in
Japan. Therefore, this department work on
development and distribution of pain screening tooland educational program. According to our recent study,
the nationwide adequacy of opioid availability wasapproximately 75%, and the largest gaps in adequacy
between prefectures were more than 65%, suggestingthat opioid might not be adequately prescribednationwide.
Therefore, we analyze the correlation between cancer
pain severity and opioid availability using medical big
data to reduce this regional disparity.
Based on these background and purpose, thedepartment was founded in May, 2021.

Consultation
In The University of Tokyo Hospital, we pain andpalliative care team are composed of many kinds ofspecialists containing three full-time staff doctors, twofull-time doctors, and two certificated cancer andhospice care nurses who take an initiative in this454

multidisciplinary 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.

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 or eightmonths. And then they can participate in the pain andpalliative care team and attend the daily teamconference on weekdays.
Educational･ In the intensive course for the first-year residents, weprepare 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.

Research
The clinical information accumulated from thepalliative care consultation and anesthesia for patients
undergoing cancer surgery is input to the concise
database simultaneously and utilized for various kindsof clinical researches to submit to the international
medical journal.
To date, we the Department of Palliative Mediccal
Sciences have contributed to the progress of following

fields of investigations.
①

Opioid availability for the palliative care ofpatients with advanced cancer is increasing
globally. However, opioid consumption in Japanis still extremely low compared with that in othercountries. We investigated the current situation ofpain control and opioid consumption in patientswith advanced cancer by a nationwide
questionnaire survey in Japan. Caregivers from2000 comprehensive support centres nationwide
answered the web-based questionnaire survey
asking for details about their assigned patients
who died of end-stage cancer. The survey included
the questionnaire of pain intensity and opioidprescription.
② In clinical situation, the use of opioids frequently
induce delirium. As a result, the use of opioids can
be avoided although pain control is not sufficient.
Therefore, we investigate the methods fordiagnostic tool for delirium and its mechanisms.

Publications
1.

2.

3.

4.

Abe H, Sumitani M, Matsui H, Inoue R, Konishi
M, Fushimi K, Uchida K, Yasunaga H.
Gabapentinoid use is associated with reduced
incidence of hyperactive delirium in elderly
cancer patients undergoing chemotherapy: anationwide retrospective cohort study in Japan.
Anesthesia & Analgeisa 2022; 135: 362-9
Mietani K, Hasegawa-Moriyama M, Yagi K,
Inoue R, Ogata T, Kurano M, Shimojo N, Seto Y,
Sumitani M, Uchida K. Preoperative detection ofserum phosphorylated neurofilament heavy chain
subunit predicts postoperative delirium: A
prospective observational study. J Gerontol
Geriatr 2022; 70: 169-77
Ando M, Sumitani M, Fuyuki M, Abe H, Shinoda
Y, Matsubayashi Y, Oshima Y, Inoue R, TsuchidaR, Uchida K. Imaging features inferring symptom
onset due to spinal metastasis progression: A
preliminary study. Ann Palliat Med 2022; 11:2247-56
Abe H, Sumitani M, Matsui H, Inoue R, Fushimi
K, Uchida K, Yasunaga H. Use of naldemedine isassociated with reduced incidence of hyperactive

455

delirium in cancer patients with opioid-induced
constipation: a nationwide retrospective cohort
study in Japan. Pharmacotherapy: Journal of
Human Phramacology and Drug Therapy 2022;
42: 241-9
5. Inoue R, Sumitani M, Otake Y, Ohya R, Tsuchida
R, Konishi M, Abe H, Uchida K. Augmented
reality-supported exercise therapy system
improves physical frailty and musculoskeletal
pain: a preliminary feasibility study. J Muscle
Health 2022; 4: 1013
6. Kurisu K, Inada S, Maeda I, Ogawa A, Iwase S,
Akechi T, Morita T, Imai K, Nakahara R, Kaneishi
K, Nakajima N, Sumitani M, Yoshiuchi K.
Decision tree prediction model for outcome ofpharmacological treatment of delirium inadvanced cancer patients: Pharmacological adultstudy of safety and efficacy in real world (PhaseR). Palliat Support Care 2022; 20: 153-8
7. Saita K, Sumitani M, Nishizawa D, Tamura T,
Ikeda K, Wakai K, Sudo Y, Abe H, Otonari J,
Takeuchi K, Hishida A, Tanaka K, Shimanoe C,
Takezaki T, Ibusuki R, Oze I, Ito H, Ozaki E,
Matsui D, Nakamura Y, Kusakabe M, Suzuki S,
Nakagawa-Senda H, Arisawa K, KatsuuraKamano S, Kuriki K, Kita Y. Genetic
polymorphism of pleiotrophin is associated withpain experience in Japanese adults: case-control
study. Medince (Baltimore) 2022; 101: e30580
8. Mietani K, Hasegawa-Moriyama M, Inoue R,
Ogata T, Shimojo N, Kurano M, Yatomi Y, UchidaK, Sumitani M. Serum levels of apolipoprotein A1 and E are associated with postoperativedelirium: A post-hoc analysis. Medince(Baltimore) 2022; 101: e29906
9. Hao X, Zhou Y, Ling Y, Feng Z, Miyoshi H,
Sumitani M, Chan KY, Park HJ, Rao Y. Effects ofhigh-dose opioid analgesia on survival, pain relief,
quality of life and adverse drug reactions in cancer
and neuropathic pain patients: a retrospective
cohort study in real-world clinical practice. Ann
Transl Med 2022; 10: 998
10. Edamura T, Sumitani M, Hayakawa K, Inoue R,
Abe H, Tsuchida R, Chikuda H, Ogata T, Kurano
M, Aoki J, Yatomi Y, Uchida K. Different profilesof the triad of lysophosphatidylcholine,
lysophosphatidic acid and autotaxin in patientswith neuropathic pain diseases: a preliminary
observational study. Pain and Therapy 2022; 11:1439-49
11. Mietani M, Hasegawa-Moriyama M, Yagi K,
Inoue R, Ogata T, Shimojo N, Seto Y, Uchida K,
Sumitani M. Elevation of serum plasminogenactivator inhibitor-1 predicts postoperativedelirium independent of neural damage: A
sequential analysis. Scientific Reports 2022; 12:17091
12. Abe H, Inoue R, Tsuchida R, Ando M, Saita K,
Konishi M, Edamura T, Ogawa A, Matsuoka Y,
Sumitani M. Efficacy of treatments for pain andnumbness in cancer survivors: a systematic review
and meta-analysis. Ann Palliat Med 2022; 11:1439-49（And, 9 Japanese articles）

456

Department of Innovative
Dementia Prevention
Project Associate Professor
Tomoko Wakabayashi, Ph.D.

Homepage

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

Introduction and Organization

Education

Department of Innovative Dementia Prevention was
launched on July 2017, through the financial support of
Kobayashi Pharmaceuticals, with assistance by the
Department of Neuropathology. Two faculty staffs,
Tadafumi Hashimoto as the Project Associate Professor
and Ryoko Ihara as the Project Assistant Professor
started the research projects, with Dr. Daisuke Izawa of
Kobayashi as a collaborative researcher. From January
2019, Dr. Tomoko Wakabayashi joined in thedepartment in the replacement of Dr. Ryoko Ihara, andDr. Yutaro Ito of Kobayashi also joined in the research
project in the replacement of Dr. Izawa. Dr. Hashimoto
has moved out in September 2021, and Dr.
Wakabayashi has taken up the Project Associate
Professor in December 2021.
The aged society in Japan urges us to challenge thedementing disorders including Alzheimer’s disease(AD), although there have emerged no effective
therapeutic strategies against AD based on its
pathomechanism. Our laboratory will conduct basic
research on the molecular mechanism of dementia anddevelopment of clinical measures for evaluation ofefficacies of the therapeutic drugs in parallel, aiming at
identifying the novel targets for prevention and early
treatment of dementia and establish methods to preventor delay the progression of dementia by drugs andfunctional foods. We also will be actively involved in
the education and outreach activities of basic andclinical research on AD and dementia.

Department of Innovative Dementia Prevention was
involved in the education through research activities ofgraduate students of the Graduate School of Medicine
and medical student belonging to the Medical Scientist
Training Program.

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
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

457

dialysis membrane of ~1,000 kDa cut-off that enables
the recovery of brain interstitial fluids and quantitationof the levels, rates of production and clearance of Aβ in
the hippocampus and other parts of the brains(Yamamoto K, et al., Cell Rep., 2015). In combination
with the in vivo seeding experiments injecting
aggregation seeds for Aβ and evaluate the following Aβ
deposition (Hori Y, et al., J. Biol. Chem., 2015), we
have identified a >200 kDa high molecular weight(HMW) Aβ oligomer species in the soluble fractions ofbrains of APP transgenic mice and AD brains(Hashimoto T, Soc for Neuroscience meeting 2017),
and found that oligomeric structure of HMW A isessential for the induction of -amyloidosis. We also
found that the level of HMW A oligomers in the brainsof amyloid angiopathy-rich AD cases weresignificantly higher than those of amyloid angiopathyminimal AD cases, injection of HMW A oligomers
into cerebrospinal fluid from a cisterna magna induced
CAA in the perivascular space, suggesting that seedcompetent HMW A oligomers may accumulate in theamyloid angiopathy in the brains of AD patients. We
also generated a novel method for purification of HMW
A oligomers using an adeno-associated virus
encoding
BRI-3xFLAG-A1-42.
Using
these
techniques, we will further identify Aβ species that are
involved in the Aβ dynamics in the brain, including
those specifically involved in deposition or toxicity ofAβ.
② Elucidation of the role of apolipoprotein E (apoE)in the pathogenesis of AD, and development of methodof AD prevention targeting apoE
Apolipoprotein E (apoE) is produced by astrocytes andcomprises the major lipoprotein in the central nervous
system. Human APOE gene has three genetic
polymorphisms (ε2, ε3, ε4), resulting in the productionof three protein isoforms (apoE2, apoE3, apoE4)
harboring different amino acids at two critical residues
at positions 112 and 158. The allele frequency of ApoE
ε4 allele is ~8-10% in normal population, whereas it iselevated to >30-40% in AD. Thus, ApoE ε4 is a strong
genetic risk factor of AD, although the mechanism
whereby ApoE ε4 accelerates AD pathophysiology hasremained elusive, without any effective therapeuticstrategies targeting apoE.
We have created a series of bigenic mice by crossing

knock-in (KI) mice expressing human apoE2, E3 or E4
with APP transgenic mice, and we are currently trying
to examine how each human isoform of apoE
influences on Aβ dynamics in the brain. This will lead
us to the intervention into the effect of apoE isoforms
on Aβ, toward the goal of AD prevention. We havefound a significant decrease in Aβ deposition in thebrains of human apoE3 KI/APP transgenic mice. Usingin vivo seeding technique, we have also found that
apoE3 suppressed the deposition of Aβ compared withmurine apoE, and that apoE4 was less able to suupress
the Ab deposition compared to apoE3. We further
found that deletion of the APOE gene in APP tg micemarkedly reduced A deposition, and that no A
deposition was induced by in vivo seeding experimentin the brain of APPtg/apoE KO mice. Furthermore
HMW A oligomers were associated with apoE in thebrain. These data suggested that apoE is an essential
factor for A deposition (Hashimoto T, Soc for
Neuroscience meeting 2021). In vivo microdialysis
experiments, we found that the Aβ levels in theinterstitial fluids of human apoE3 KI/APP transgenic
mice are similar to those in APP transgenic mice bymethod. We also have established a method to monitor
the interaction between Aβ and apoE using a bimolecular complementation assay. We will use thisunique 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.

458

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). Studies using human
autopsy brains, imaging analysis, and mouse models
suggest that insulin resistance, a central pathology ofdiabetes, 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 acommon pathology in both diseases. Therefore, we areinvestigating the effects of metabolic abnormalities
such as diabetes or of genetic suppression of insulin
signaling on the formation of amyloid pathology and its
molecular mechanisms.
In order to elucidate the molecular mechanisms linking
type 2 diabetes and AD, especially the effects on
amyloid pathogenesis, we have been conducting
analyses using APP Tg mice (A7), a mouse model of
Alzheimer's disease. In APP Tg mice, which were fed ahigh-fat diet (HFD) from 3 months of age anddeveloped a diabetic-like condition, there was adecrease in brain responsiveness to insulin stimulationin addition to systemic insulin resistance. In this mouse,
the amount of Aβ in the brain increased significantlywith age compared to the normal diet group, and theaccumulation of amyloid plaques was also accelerated
at 15 months of age. In vivo kinetic analysis showedthat this might be partly due to a decrease in Aβ
clearance in the brain caused by HFD feeding.
We then analyzed the contribution of IRS-1 and IRS-2,
substrates of insulin and IGF-1 receptors, to brain

signaling activity and found that IRS-2 is mainly
involved in brain insulin signaling. While loss of IRS1 did not affect the pathology of the APP Tg mousebrain, IRS-2 deficiency markedly suppressed amyloid
accumulation in the brain, even though it triggered
systemic insulin resistance and led to diabetes. By
contrast, amyloid accumulation was accelerated when
IRS-2-deficient APP Tg mice were fed with HFD. Thissuggests that upstream factors, such as stress associatedwith metabolic overload, rather than decreased insulin
signaling, may be responsible for accelerated amyloid
accumulation.
One of the factors contributing to insulin resistance isendoplasmic reticulum (ER) stress, which is altered bymetabolic stress. In HFD-fed and genetically obese
animals, ER stress in liver and adipose tissue isincreased and unfolded protein response (UPR)
signaling is elevated. Inhibiting ER stress has beenshown to improve insulin resistance. It has also beenreported that ER stress is elevated in the brains of
Alzheimer's disease patients, suggesting that it may bean aggravating factor in both diseases. Therefore, thechemical chaperone TUDCA was administered to theperiphery or brain of aging or HFD-fed APP Tg micewith metabolic abnormalities to analyze the effects ofreduced endoplasmic reticulum stress on Aβ
accumulation. The results showed that administration
of TUDCA to the periphery, but not to the brain,markedly suppressed amyloid accumulation in thebrain. This suggests that stress and inflammationinduced in peripheral tissues due to metabolic
abnormalities may directly regulate brain pathology.
On the other hand, the mechanism by which IRS-2
deficiency exerts a protective effect on Aβ
accumulation has not yet been elucidated. We analyzed
mRNA expression in APP Tg mouse brains lacking
IRS-2 and found that the expression of ECM-related
genes was upregulated. Among these genes, collagen
VI and thrombospondin-1 and -4 were shown tosuppress amyloid fibril formation of Aβ by in vitro
assay. These results indicate that inhibition of insulin
signaling may suppress amyloid accumulation by
upregulating the expression of multiple ECMs in thebrain and inhibiting Aβ fibrillation.

459

References
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4.

Kishino Y, Matsukawa K, Matsumoto T, Miyazaki
R, Wakabayashi T, Nonaka T, Kametani F,
Hasegawa M, Hashimoto T, Iwatsubo T. Casein
kinase 1δ/ε phosphorylates fused in sarcoma(FUS) and ameliorates FUS-mediated neurodegeneration. J Biol Chem 2022; 298:102191
Kaneshiro N, Komai M, Imaoka R, Ikeda A,
Kamikubo Y, Saito T, Saido TC, Tomita T,
Hashimoto T, Iwatsubo T, Sakurai T, Uehara T,
Takasugi N. Lipid flippase dysfunction as atherapeutic target for endosomal anomalies in
Alzheimer's disease. iScience 2022;25:103869
Ishida K, Yamada K, Nishiyama R, Hashimoto T,
Nishida I, Abe Y, Yasui M, Iwatsubo T.
Glymphatic system clears extracellular tau andprotects from tau aggregation and neurodegeneration. J Exp Med 2022; 219:e20211275
An H, Litscher G, Watanabe N, Wei W, Hashimoto
T, Iwatsubo T, Buchman VL, Shelkovnikova TA.
ALS-linked cytoplasmic FUS assemblies arecompositionally different from physiologicalstress granules and sequester hnRNPA3, a novel
modifier of FUS toxicity. Neurobiol Dis 2022;
162:105585

460

Department of Precision Medicine
Neurology
Project Associate Professor
Jun Mitsui, M.D., Ph.D.

Project Research Associate
Niroya Naruse, M.D., Ph.D.

Introduction and Organization

Research activities

The Department of Precision Medicine Neurology wasestablished on September 1, 2022, with the aim ofapplying
state-of-the-art
genomesequencing
technology to elucidate the molecular mechanisms,
and to develop novel therapies that can intervene
against the molecular mechanisms of neurologicaldiseases.

Multiple system atrophy is a neurodegenerative
disease that causes a variety of symptoms, including
autonomic nervous system disturbances, cerebellar
ataxia, and parkinsonism. It is an intractable disease
for which effective treatments are lacking, although
there are drugs that alleviate several symptoms. We
are conducting basic research on multiple system
atrophy and its treatment to overcome this disease.

Clinical activities
Specialized outpatient clinics for multiple system
atrophy are provided in collaboration with the
Department of Neurology. The outpatient clinic
provides consultations, second opinions, and patientregistration for patients with multiple system atrophy.
In the ward, we provide consultation for theexamination and treatment of patients with multiple
system atrophy in cooperation with the Department of
Neurology. Clinical sequencing is performed after
consultation for the diagnosis of hereditaryneurological diseases.

Teaching activities
As for under-graduate education, we provides lectures
on genetic research and therapeutic development forneurological diseases. In postgraduate education, we
collaborates with the Department of Neurology toprovide education on the genetic diseases to residents.
Regarding graduate education, we promotes a wide
range of research according to the wishes of graduate
students.

In previous studies, we identified patients withbiallelic variants in the COQ2 gene in multiplex
families (Mitsui J, et al. N Engl J Med. 2013;369:
233-44). It has been shown that coenzyme Q10 levelin cerebellar tissue is decreased in patients withfamilial multiple system atrophy who have biallelic
COQ2 variants (Mitsui J, et al. N Engl J Med. 2013;
369:233-44), and that coenzyme Q10 administration
improves the rate of cerebral oxygen metabolism(Mitsui J, et al. Cerebellum. 2017;16(3):664-672).
Furthermore, the carrier frequency of the COQ2
variant is higher in patients with sporadic multiple
system atrophy (Porto KJ, et al. J Neurol Sci. 2021;
429:117623), and blood coenzyme Q10 level isdecreased even in patients without COQ2 variants(Mitsui J, et al. JAMA Neurol. 2016;73(8):977-80).
Based on these results, we believe that coenzyme Q10
supplementation may be an effective treatment for thisdisease.
First, an investigator-initiated Phase 1 trial(UMIN000016695) was conducted to investigate

461

safety and pharmacokinetics of coenzyme q10 (Mitsui
J, et al. Neurol Clin Neurosci. 2022;10(1):14-24). A
multicenter, investigator-initiated Phase 2 trial(UMIN000031771) was subsequently conducted to
explore whether coenzyme Q10 is effective against
symptom progression in multiple system atrophy.
Based on the results, a Phase 3 trial is currently being
planned.
The Multiple System Atrophy Registry has been
established and is being operated to assist in patient
recruitment in clinical trials and to obtain natural
history of multiple system atrophy (https://msajp.
org/).
Other than the COQ2 gene, we have reported that
GBA1 variants were associated with multiple system
atrophy (Mitsui J, et al. Ann Clin Transl Neurol. 2015;
2(4):417-26).

References
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2.

3.

Ando T, Riku Y, Akagi A, Miyahara H, Hirano M,
Ikeda T, Yabata H, Koizumi R, Oba C, Morozumi
S, Yasui K, Goto A, Katayama T, Sakakibara S,
Aiba I, Sakai M, Konagaya M, Mori K, Ito Y,
Yuasa H, Nomura M, Porto KJL, Mitsui J, Tsuji S,
Mimuro M, Hashizume Y, Katsuno M, Iwasaki Y,
Yoshida M. Multiple system atrophy variant withsevere hippocampal pathology. Brain Pathol.
2022 Jan;32(1):e13002.
Almansour A, Ishiura H, Mitsui J, Matsukawa T,
Matsukawa MK, Shimizu H, Sugiyama A, Toda T,
Tsuji S. Frequency of FMR1 Premutation Allelesin Patients with Undiagnosed Cerebellar Ataxia
and Multiple System Atrophy in the Japanese
Population. Cerebellum. 2022 Dec;21(6):954962.
Enomoto Y, Yokoi T, Tsurusaki Y, Murakami H,
Tominaga M, Minatogawa M, Abe-Hatano C,
Kuroda Y, Ohashi I, Ida K, Shiiya S, Kumaki T,
Naruto T, Mitsui J, Harada N, Kido Y, Kurosawa
K. Divergent variant patterns among 19 patientswith Rubinstein-Taybi syndrome uncovered bycomprehensive genetic analysis including wholegenome sequencing. Clin Genet. 2022 Mar;
101(3):335-345.

4.

Taniguchi T, Ando M, Okamoto Y, Yoshimura A,
Higuchi Y, Hashiguchi A, Matsuda N, Yamamoto
M, Dohi E, Takahashi M, Yoshino M, Nomura T,
Matsushima M, Yabe I, Sanpei Y, Ishiura H,
Mitsui J, Nakagawa M, Tsuji S, Takashima H.
Elderly patients with suspected Charcot-MarieTooth disease should be tested for the TTR genefor effective treatments. J Hum Genet. 2022 Jun;
67(6):353-362.
5. Ikenaga C, Date H, Kanagawa M, Mitsui J,
Ishiura H, Yoshimura J, Pinal-Fernandez I,
Mammen AL, Lloyd TE, Tsuji S, Shimizu J, Toda
T, Goto J. Ann Neurol. 2022 Mar;91(3):317-328.
6. Ando M, Higuchi Y, Okamoto Y, Yuan J,
Yoshimura A, Takei J, Taniguchi T, Hiramatsu Y,
Sakiyama Y, Hashiguchi A, Matsuura E,
Nakagawa H, Sonoda K, Yamashita T, Tamura A,
Terasawa H, Mitsui J, Ishiura H, Tsuji S,
Takashima H. An NEFH founder mutation causes
broad phenotypic spectrum in multiple Japanesefamilies. J Hum Genet. 2022 Jul;67(7):399-403.
7. Kubota A, Ishiura H, Porto KJL, Tanaka M,
Mitsui J, Unuma A, Maki H, Komuro I, Tsuji S,
Shimizu J, Toda T. DMD exon 2 duplication due
to a complex genomic rearrangement isassociatedwithasomatic
mosaicism.
Neuromuscul Disord. 2022 Mar;32(3):263-269.
8. Yagi H, Takiguchi H, Takeda N, Inuzuka R,
Taniguchi Y, Porto KJ, Ishiura H, Mitsui J,
Morita H, Komuro I. Family with congenital
contractural arachnodactyly due to a novel
multiexon deletion of the FBN2 gene. Clin Case
Rep. 2022 Feb 9;10(2):e05335.
9. Hiramatsu Y, Okamoto Y, Yoshimura A, Yuan JH,
Ando M, Higuchi Y, Hashiguchi A, Matsuura E,
Nozaki F, Kumada T, Murayama K, Suzuki M,
Yamamoto Y, Matsui N, Miyazaki Y, Yamaguchi
M, Suzuki Y, Mitsui J, Ishiura H, Tanaka M,
Morishita S, Nishino I, Tsuji S, Takashima H.
Complex hereditary peripheral neuropathies
caused by novel variants in mitochondrial-related
nuclear genes. Neurol. 2022 Aug;269(8):41294140.
10. Yamakawa K, Nishijima H, Kubota A, Naruse H,
Baba S, Fujimaki Y, Kondo K, Toda T, Yamasoba
T. Clinical and electrophysiological findings offacial palsy in a case of hereditary gelsolin

462

11.

12.

13.

14.

15.

amyloidosis. Auris Nasus Larynx. 2023 Apr;
50(2):305-308.
Ando M, Higuchi Y, Yuan JH, Yoshimura A,
Kitao R, Morimoto T, Taniguchi T, Takeuchi M,
Takei J, Hiramatsu Y, Sakiyama Y, Hashiguchi A,
Okamoto Y, Mitsui J, Ishiura H, Tsuji S,
Takashima H. Novel de novo POLR3B mutations
responsible for demyelinating Charcot-MarieTooth disease in Japan. Ann Clin Transl Neurol.
2022 May;9(5):747-755.
Oike R, Inoue Y, Mitsui J, Ota Y. A case of
idiopathic normal pressure hydrocephalus withfragile X-associated tremor/ataxia syndrome.
Clin Neurol Neurosurg. 2022 Jul;218:107278.
Teranishi Y, Okano A, Miyawaki S, Ohara K,
Ishigami D, Hongo H, Dofuku S, Takami H,
Mitsui J, Ikemura M, Komura D, Katoh H,
Ushiku T, Ishikawa S, Shin M, Nakatomi H,
Saito N. Clinical significance of NF2 alteration ingrade I meningiomas revisited; prognostic impact
integrated with extent of resection, tumour
location, and Ki-67 index. Acta Neuropathol
Commun. 2022 May 15;10(1):76.
Mochizuki H, Aoki M, Ikenaka K, Inoue H,
Iwatsubo T, Ugawa Y, Okazawa H, Ono K,
Onodera O, Kitagawa K, Saito Y, Shimohata T,
Takahashi R, Toda T, Nakahara J, Matsumoto R,
Mizusawa H, Mitsui J, Murayama S, Katsuno M;
Future Vision Committee of Japanese Society of
Neurology; Aoki Y, Ishiura H, Izumi Y, Koike H,
Shimada H, Takahashi Y, Tokuda T, Nakajima H,
HatanoT,
MisawaS,
WatanabeH.
Recommendations (Proposal) for promoting
research for overcoming neurological diseases
2020. Rinsho Shinkeigaku. 2022 Jun 24;62(6):429-442.
Mochizuki H, Aoki M, Ikenaka K, Inoue H,
Iwatsubo T, Ugawa Y, Okazawa H, Ono K,
Onodera O, Kitagawa K, Saito Y, Shimohata T,
Takahashi R, Toda T, Nakahara J, Matsumoto R,
Mizusawa H, Mitsui J, Murayama S, Katsuno M;
Future Vision Committee of Japanese Society of
Neurology; Aoki Y, Ishiura H, Izumi Y, Koike H,
Shimada H, Takahashi Y, Tokuda T, Nakajima H,
HatanoT,
MisawaS,
WatanabeH.
Recommendations (Proposal) for promoting
research for overcoming neurological diseases

16.

17.

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19.

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21.

22.

2020. Rinsho Shinkeigaku. 2022 Jun 24;62(6):443-457
Teranishi Y, Miyawaki S, Nakatomi H, Ohara K,
Hongo H, Dofuku S, Okano A, Takayanagi S, Ota
T, Yoshimura J, Qu W, Mitsui J, Morishita S,
Tsuji S, Saito N. Early prediction of functional
prognosis in neurofibromatosis type 2 patients
based on genotype-phenotype correlation withtargeted deep sequencing. Sci Rep. 2022 Jun 9;
12(1):9543.
Ishigami D, Koizumi S, Miyawaki S, Hongo H,
Teranishi Y, Mitsui J, Saito N. Symptomatic andStenotic Developmental Venous Anomaly with
Pontine Capillary Telangiectasia: A Case Reportwith Genetic Considerations. NMC Case Rep J.
2022 May 31;9:139-144.
Sakai Y, Miyawaki S, Teranishi Y, Okano A,
Ohara K, Hongo H, Ishigami D, Shimada D,
Mitsui J, Nakatomi H, Saito N. NF2Alteration/22q Loss Is Associated with
Recurrence in WHO Grade 1 Sphenoid Wing
Meningiomas. Cancers (Basel). 2022 Jun 29;
14(13):3183.
Ando M, Higuchi Y, Yuan J, Yoshimura A,
Taniguchi T, Kojima F, Noguchi Y, Hobara T,
Takeuchi M, Takei J, Hiramatsu Y, Sakiyama Y,
Hashiguchi A, Okamoto Y, Mitsui J, Ishiura H,
Tsuji S, Takashima H. Comprehensive Genetic
Analyses of Inherited Peripheral Neuropathies inJapan: Making Early Diagnosis Possible.
Biomedicines. 2022 Jun 29;10(7):1546.
Yuan JH, Higuchi Y, Ando M, Matsuura E,
Hashiguchi A, Yoshimura A, Nakamura T,
Sakiyama Y, Mitsui J, Ishiura H, Tsuji S,
Takashima H. Multi-type RFC1 repeat
expansions as the most common cause ofhereditary sensory and autonomic neuropathy.
Front Neurol. 2022 Aug 17;13:986504.
Matsukawa T, Porto KJL, Mitsui J, Chikada A,
Ishiura H, Takahashi Y, Nakamoto FK, Seki T,
Shiio Y, Toda T, Tsuji S. Clinical and Genetic
Features of Multiplex Families with Multiple
System Atrophy and Parkinson's Disease.
Cerebellum. 2022 Sep 13. doi: 10.1007/s12311022-01426-z.
Miller TM, Cudkowicz ME, Genge A, Shaw PJ,
Sobue G, Bucelli RC, Chiò A, Van Damme P,

463

Ludolph AC, Glass JD, Andrews JA, Babu S,
Benatar M, McDermott CJ, Cochrane T, Chary S,
Chew S, Zhu H, Wu F, Nestorov I, Graham D,
Sun P, McNeill M, Fanning L, Ferguson TA,
Fradette S; VALOR and OLE Working Group.
Trial of Antisense Oligonucleotide Tofersen for
SOD1 ALS. N Engl J Med. 2022 Sep 22;387(12):1099-1110.
23. Hama Y, Date H, Fujimoto A, Matsui A, Ishiura
H, Mitsui J, Yamamoto T, Tsuji S, Mizusawa H,
Takahashi Y. A Novel de novo KIF1A Mutation
in a Patient with Ataxia, Intellectual Disability
and Mild Foot Deformity. Cerebellum. 2022 Oct
13. doi: 10.1007/s12311-022-01489-y.
24. Kobayashi R, Naruse H, Kawakatsu S, Iseki C,
Suzuki Y, Koyama S, Morioka D, Ishiura H,
Mitsui J, Ohta Y, Tsuji S, Toda T, Otani K.
Valosin-containing protein Asp395Gly mutation
in a patient with frontotemporal dementia: a casereport. BMC Neurol. 2022 Nov 3;22(1):406.

464

Department of Health Services
Research
Project Associate Professor
Taisuke Jo, M.D.,Ph.D.

Project Lecturer/Project Assistant Professor
Hayato Yamana, M.D., PhD.
Project Assistant Professor
Nobuaki Michihata, M.D., PhD.

Homepage

http://webpark1902.sakura.ne.jp/wp/

Introduction and Organization

Teaching activities

The Department of Health Services Research (HSR),
a Social Cooperation Program, was founded byProfessor Hideo Yasunaga, Department of Clinical
Epidemiology & Health Economics with the supportof Professor Takahide Nagase, Department ofRespiratory Medicine in April 2016. The program wasfunded by Tsumura & Co., Tokyo, Japan.
The objective of the Department of HSR was toconvey and develop HSR, which encompasses clinicalmedicine, clinical epidemiology and health economics,
to pursue the maintenance of health services
particularly in the ageing society in Japan. Educationand training of personnel to cultivate human resources
such as researchers and analysts in HSR is anotherimportant mission of this program.
The founding staff members were Taisuke Jo(Project Associate Professor), Nobuaki Michihata(Project Assistant Professor) and Yusuke Sasabuchi(Project Assistant Professor). Hayato Yamana (Project
Assistant Professor) started to take part in thisprogram in April 2018 with two other staff members,
Taisuke Jo and Nobuaki Michihata. Hayato Yamana
was promoted to Project Lecturer in 2021 andresigned at the end of November 2022.

All the members of HSR participated in the lecturesof Clinical Epidemiology, a curriculum of School of
Public Health (SPH) in The University of Tokyo. The
members also contributed to the education andtraining of individual students of SPH as well as
students of the Graduate School of Medicine, The
University of Tokyo.
Taisuke Jo (Project Associate Professor)
participated in the series of clinical lectures in
Respiratory Medicine for students of Faculty of
Medicine, The University of Tokyo.

Research activities
Health Services Research covers a broadcross-disciplinary field involving studies of structures,processes and outcomes assessment in clinicalepidemiology and health services, studies evaluating
the quality of health care and analysis of healtheconomics, finance and allocation of medical
resources. Utilizing large databases, the members of
HSR were working to address the following issue.
1) Clinical and epidemiological research questions related to various diseases, including respiratory
disease.
2) Outcomes and cost-effectiveness in both western
medicine and eastern medicine in Japan.

4653) Impact of super-ageing society on population
dynamics and demand for health services.
4) Efficient distribution of medical staff, medical
institutions, and armamentariums.
The following are the examples of studies
conducted in 2022. More than 72 articles were
published.
1) Recombinant human soluble thrombomodulin for
acute exacerbation of idiopathic pulmonary fibrosis: anationwide observational study
Background: Acute exacerbation of idiopathic
pulmonary fibrosis (AE-IPF) is the leading cause ofdeath among patients with IPF. However, there is noestablished treatment for this condition. Hence, we
aimed to investigate the effectiveness and safety ofrecombinant human soluble thrombomodulin (rTM)
for the treatment of AE-IPF. Methods: Data wereretrospectively collected from the Japanese Diagnosis
Procedure Combination database from 1 January 2014
to 31 March 2018. We identified adult patients with
IPF who received high-dose methylprednisolone(mPSL) therapy and mechanical ventilation uponadmission. Eligible patients (n = 2814) were divided
into those receiving high-dose mPSL alone (mPSL
alone group, n = 2602) and rTM combined withhigh-dose mPSL (rTM group, n = 212). A stabilised
inverse probability of treatment weighting (IPTW)
using propensity scores was performed to compare
outcomes between the two groups. The primary
outcome was in-hospital mortality, and the secondary
outcomes were 14- and 28-day mortality, bleeding
events and length of hospital stay. Results: The
in-hospital mortality rates of the mPSL alone and rTM
groups were 75.9% and 76.9%, respectively. The
results did not significantly differ between the twogroups after performing a stabilised IPTW. The odds
ratio of the rTM group compared to the mPSL alonegroup was 1.15 (95% confidence interval: 0.71–1.84;
p = 0.57). Moreover, the secondary outcomes did not
differ significantly between the two groups.
Conclusions: In patients with AE-IPF who developed
severe respiratory failure, rTM in addition tohigh-dose mPSL was not associated with a better
outcome.

2) Safety of topical ophthalmic antibiotics in pregnant
women with hordeola, chalazia, blepharitis, orbacterial conjunctivitis: propensity score analyses
Objective: To investigate the association between
exposure to topical ophthalmic antibiotics during
pregnancy and adverse neonatal outcomes. Methods:
In this retrospective cohort study, we identified
pregnant women with hordeola, chalazia, blepharitis,or bacterial conjunctivitis from 2005 to 2018 using theJapanese Medical Data Centre Claims Database. Fromthe eligible women, we extracted women who weredispensed no topical antibiotics during the firsttrimester (non-antibiotic group), women who weredispensed topical fluoroquinolones alone at least once
(fluoroquinolone alone group), and women who weredispensed
anysingletypeofantibiotic(single-antibiotic group). We compared the frequency
of congenital anomalies (CA), preterm birth (PB), lowbirth weight (LBW), and the composite outcome ofthese three between the fluoroquinolone andnonantibiotic groups and between the single-antibiotic
and non-antibiotic groups, using propensity scoreadjustment. Results: A total of 891 eligible women
were identified. In the fluoroquinolone (n = 409) andnon-antibiotic (n = 309) groups, CA occurred in 6.8%
and 6.8%, PB in 2.4% and 3.2%, LBW in 2.9% and3.2%, and the composite outcome in 10.5% and 11.3%,
respectively. Analysis using propensity scoreadjustment showed no significant difference between
the groups in the frequency of CA (adjusted odds ratio,
1.15; 95% confidence interval, 0.61–2.18), PB (0.80;
0.30–2.17), LBW (1.08; 0.45–2.63), or the composite
outcome (1.12; 0.67–1.87). Comparison of thesingle-antibiotic and non-antibiotic groups showedsimilar results. Conclusions: Topical ophthalmic
antibiotics for hordeola, chalazia, blepharitis, orbacterial conjunctivitis during the first trimester were
not associated with increased adverse neonatal
outcomes.
3)Association between comprehensive geriatricassessment and polypharmacy at discharge in patientswith ischaemic stroke: A nationwide, retrospective,
cohort study
Background Polypharmacy and its adverse drug
events are a major healthcare challenge related to falls,
hospitalisations and mortality. Comprehensive

466

geriatric assessment (CGA) may contribute topolypharmacy improvement, however, there is noclear evidence so far.
Methods Using a national inpatient database in Japan
from April 1, 2014 to March 31, 2018, we investigated
the association between CGA and polypharmacy. We
identified patients aged ≥65 years admitted for
ischaemic stroke who could receive oral medications.
Propensity score matching was conducted for patientswith and without CGA during hospitalisation. The
outcomes were polypharmacy (defined as use of fiveor more types of oral medications) at discharge, thenumber of medication types prescribed at discharge,
and the difference between the numbers of medication
types prescribed on admission and at discharge.
Findings A total of 162,443 patients were analysed, ofwhom 39,356 (24.2%) received CGA, and propensity
score matching identified 39,349 pairs. Comparedwith non-CGA group, the CGA group had asignificantly lower proportion of polypharmacy atdischarge (34.3% vs. 32.9%, p < 0.001) and a smaller
number of medication types prescribed at discharge(3.84 vs. 3.76, p < 0.001).
Interpretation This study shows the clear evidence that
there is a positive relationship between CGA and areduction in the number ofmedications in older
inpatients with ischaemic stroke.

3:

4:

5:

6:

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(Due to space constraints, only a portion of the
publications is listed below.)
1: Isogai T, Saad AM, Michihata N, Ahuja KR,
Shekhar S, Abdelfattah OM, Kaur M, Gad MM,
Svensson LG, Kapadia SR. Association of
hospital procedural volume with incidence andoutcomes of surgical bailout in patients undergoing transcatheter aortic valve replacement.
Catheter Cardiovasc Interv. 2022;99:160-168.
2: Matsuoka S, Kaneko H, Okada A, Morita K, Itoh
H, Michihata N, Jo T, Takeda N, Morita H, Fujiu
K, Nakamura S, Node K, Yasunaga H, Komuro I.

7:

8:

9:

Age Modified Relationship Between Modifiable
Risk Factors and the Risk of Atrial Fibrillation.
Circ Arrhythm Electrophysiol. 2022;15:e010409.
Konishi T, Fujiogi M, Michihata N, Niwa T,
Morita K, Matsui H, Fushimi K, Tanabe M, Seto
Y, Yasunaga H. Impact of body mass index on
short-term outcomes after differentiated thyroid
cancer surgery: a nationwide inpatient databasestudy in Japan. Eur Thyroid J. 2022;11:e210081.
Suzuki Y, Kaneko H, Okada A, Itoh H, Morita K,
Fujiu K, Michihata N, Jo T, Takeda N, Morita H,
Yamaguchi S, Kamiya K, Matsunaga A, Ako J,
Fukui A, Nishiyama A, Yokoo T, Node K,
Yamauchi T, Nangaku M, Yasunaga H, Komuro I.
Change in Cardiovascular Health Metrics andRisk for Proteinuria Development: Analysis of a
Nationwide Population-Based Database. Am J
Nephrol. 2022;53:240-248.
Suzuki Y, Kaneko H, Okada A, Itoh H, Fujiu K,
Michihata N, Jo T, Takeda N, Morita H,
Yamaguchi S, Kamiya K, Matsunaga A, Ako J,
Node K, Yamauchi T, Nangaku M, Yasunaga H,
Komuro I. Impact of Glucose Tolerance and Its
Change on Incident Proteinuria: Analysis of a
Nationwide Population-Based Dataset. Am J
Nephrol. 2022;53(4):307-315.
Nagata S, Ohbe H, Jo T, Matsui H, Fushimi K,
Yasunaga H. Glucocorticoids and Rates ofBiphasic Reactions in Patients with AdrenalineTreated Anaphylaxis: A Propensity Score
Matching Analysis. Int Arch Allergy Immunol.
2022;183:939-945
Tamiya H, Mitani A, Abe T, Nagase Y, Suzuki H,
Jo T, Tanaka G, Nagase T. Association between
Inhalation Instruction Method in Community
Pharmacies and Inhaler Device Handling Error inPatients with Obstructive Lung Disease: An
Evaluation of the Impact of Practical Demonstration by Pharmacists. Biol Pharm Bull. 2022;
45(12):1764-1771.
Suzuki Y, Kaneko H, Okada A, Fujiu K,
Michihata N, Jo T, Takeda N, Morita H, Kamiya
K, Matsunaga A, Ako J, Node K, Nangaku M,
Yasunaga H, Komuro I. Proteinuria and Risk forHeart Failure in 55,191 Patients Having Historyof Cancer. Am J Nephrol. 2022;53:753-760.
Nomura O, Michihata N, Kaneko K, Yoshikawa T,

467

10:

11:

12:

13:

14:

15:

16:

Ishiguro A; Japan Pediatric Society Steering
Committee for Board Examinations. Research
Publication Experience as a Requirement for
Board Examination Acceptance to Promote
Scholarly Activities of Pediatric Residents. JMA
J. 2022;5:93-98.
Matsui H, Yamana H, Fushimi K, Yasunaga H.
Development of Deep Learning Models for
Predicting In-Hospital Mortality Using an
Administrative Claims Database: Retrospective
Cohort Study. JMIR Med Inform. 2022;10:e27936.
Miyakawa T, Michihata N, Morita K, Matsui H,
Honda M, Yasunaga H. Ambient temperature andhospital admissions for acute cholecystitis: anationwide inpatient database study in Japan.
HPB (Oxford). 2022;24:398-403.
Hashimoto Y, Matsui H, Michihata N, Ishimaru
M, Yasunaga H, Aihara M, Kaburaki T. Incidenceof Sympathetic Ophthalmia after Inciting Events:
A National Database Study in Japan.
Ophthalmology. 2022;129:344-352.
Sugawara C, Yamana H, Sasagawa E, Yonezawa
K, Hikita N, Morita K, Matsui H, Yasunaga H,
Haruna M. Factors Associated with SurgicalTreatment in Postpartum Women with Mastitis or
Breast Abscess: A Retrospective Cohort Study.
Breastfeed Med. 2022;17:233-238.
Kodama S, Jo T, Yasunaga H, Michihata N,
Matsui H, Kumazawa R, Shirota Y, Fushimi K,
Toda T, Hamada M. Outcomes of gastrointestinal
cancer surgeries in Parkinson's disease patients: A
nationwide study. Parkinsonism Relat Disord.
2022;96:45-49.
Awano N, Jo T, Izumo T, Inomata M, Morita K,
Matsui H, Fushimi K, Urushiyama H, Nagase T,
Yasunaga H. Recombinant human soluble
thrombomodulin for acute exacerbation of idiopathic pulmonary fibrosis: a nationwide observational study. J Intensive Care. 2022;10:14.
Ueno K, Kamiya K, Kaneko H, Okada A, Itoh H,
Fujiu K, Takeda N, Morita H, Michihata N, Jo T,
Yasunaga H, Komuro I. Acute-Phase Initiation of
Cardiac Rehabilitation for Short-Term Improvement in Activities of Daily Living in Patients
Hospitalized for Acute Heart Failure. J
Cardiovasc Dev Dis. 2022;9:97.

17: Konishi T, Goto T, Fujiogi M, Michihata N,
Kumazawa R, Matsui H, Fushimi K, Tanabe M,
Seto Y, Yasunaga H. New machine learning
scoring system for predicting postoperative
mortality in gastroduodenal ulcer perforation: A
study using a Japanese nationwide inpatient
database. Surgery. 2022;171:1036-1042.
18: Yamana H, Tsuchiya A, Horiguchi H, Morita S,
Kuroki T, Nakai K, Nishimura H, Jo T, Fushimi
K, Yasunaga H. Validity of a model using
routinely collected data for identifying infections
following gastric, colon, and liver cancer
surgeries. Pharmacoepidemiol Drug Saf. 2022;
31:452-460.
19: Sato M, Yamana H, Ono S, Ishimaru M, Matsui
H, Yasunaga H. Trends in prophylactic antibiotic
use for tooth extraction from 2015 to 2018 in
Japan: An analysis using a health insurance
claims database. J Infect Chemother. 2022;28:504-509
20: Suzuki Y, Kaneko H, Okada A, Itoh H, Fujiu K,
Michihata N, Jo T, Takeda N, Morita H,
Yamaguchi S, Yano Y, Kamiya K, Matsunaga A,
Ako J, Fukui A, Yokoo T, Nishiyama A, Node K,
Yamauchi T, Nangaku M, Yasunaga H, Komuro I.
Risk for Proteinuria in Newly Defined
Hypertensive People Based on the 2017
American College of Cardiology/American Heart
Association Blood Pressure Guideline. Am J
Cardiol. 2022;168:83-89.
21: Matsuoka S, Kaneko H, Okada A, Fukui A, Yano
Y, Itoh H, Morita K, Fujiu K, Michihata N, Jo T,
Takeda N, Morita H, Yamaguchi S, Nakamura S,
Nishiyama A, Yokoo T, Node K, Yamauchi T,
Nangaku M, Yasunaga H, Komuro I. Association
between proteinuria and incident colorectal
cancer: analysis of a nationwide population-based
database. BMJ Open. 2022;12:e056250.
22: Seike Y, Matsuda H, Shimizu H, Ishimaru S,
Hoshina K, Michihata N, Yasunaga H, Komori K;
Japanese Committee for Stentgraft Management(JACSM)*. Nationwide Analysis of PersistentType II Endoleak and Late Outcomes ofEndovascular Abdominal Aortic Aneurysm
Repair in Japan: A Propensity-Matched Analysis.
Circulation. 2022;145:1056-1066.
23: Honda A, Michihata N, Iizuka Y, Uda K, Morita

468

24:

25:

26:

27:

28:

29:

30:

K, Mieda T, Takasawa E, Ishiwata S, Tajika T,
Matsui H, Fushimi K, Yasunaga H, Chikuda H.
Risk factors for severe lower extremity ischemia
following venoarterial extracorporeal membrane
oxygenation: an analysis using a nationwide
inpatient database. Trauma Surg Acute Care
Open. 2022;7:e000776
Hashimoto Y, Michihata N, Yamana H, Shigemi
D, Morita K, Matsui H, Yasunaga H, Aihara M.
Safety of topical ophthalmic antibiotics inpregnant women with hordeola, chalazia,
blepharitis, or bacterial conjunctivitis: propensity
score analyses. Eye (Lond). 2022;36:1066-1073.
Yoshii K, Michihata N, Hirasawa K, Nagata S,
Morisaki N. Secular trends in early motor
development between 1980 and 2010 in Japan.
Arch Dis Child. 2022 May;107(5):468-473.
Matsuda K, Jo T, Shimura A, Honda A, Taoka K,
Masamoto Y, Matsui H, Fushimi K, Yasunaga H,
Kurokawa M. Risk of febrile neutropenia in very
elderly patients aged ≥80 years receiving theirfirst cycle of R-CHOP regimen: a nationwide
real- world study in Japan. Br J Haematol. 2022;
197:e37-e41.
Konishi T, Fujiogi M, Sato A, Michihata N,
Kumazawa R, Matsui H, Fushimi K, Tanabe M,
Seto Y, Yasunaga H. Short-Term Outcomes
Following Breast Cancer Surgery With andWithout
Neoadjuvant
Chemotherapy:A
Nationwide Administrative Database Study inJapan. Ann Surg Oncol. 2022;29:3000-3010.
Suzuki T, Michihata N, Yoshikawa T, Saito K,
Matsui H, Fushimi K, Yasunaga H. Low- versus
high-concentration intravenous immunoglobulin
for children with Kawasaki disease in the acutephase. Int J Rheum Dis. 2022;25:576-583
Matsuoka S, Kaneko H, Okada A, Itoh H, Suzuki
Y, Fujiu K, Michihata N, Jo T, Takeda N, Morita
H, Nakamura S, Node K, Yasunaga H, Komuro I.
Association of retinal atherosclerosis assessedusing Keith-Wagener-Barker system withincident heart failure and other atherosclerotic
cardiovascular disease: Analysis of 319,501
individuals from the general population.
Atherosclerosis. 2022;348:68-74.
Ueno K, Kaneko H, Kamiya K, Itoh H, Okada A,
Suzuki Y, Matsuoka S, Fujiu K, Michihata N, Jo

T, Takeda N, Morita H, Ako J, Node K, Yamauchi
T, Yasunaga H, Komuro I. Relationship ofnormal-weight central obesity with the risk forheart failure and atrial fibrillation: analysis of anationwide health check-up and claims database.
Eur Heart J Open. 2022;2:oeac026
31: Suzuki Y, Kaneko H, Yano Y, Okada A, Itoh H,
Matsuoka S, Fujiu K, Yamaguchi S, Michihata N,
Jo T, Takeda N, Morita H, Node K, Kim HC,
Viera AJ, Oparil S, Yasunaga H, Komuro I.
Age-Dependent Relationship of Hypertension
Subtypes With Incident Heart Failure. J Am
Heart Assoc. 2022;11:e025406.
32: Suzuki Y, Kaneko H, Okada A, Itoh H, Matsuoka
S, Fujiu K, Michihata N, Jo T, Takeda N, Morita
H, Kamiya K, Matsunaga A, Ako J, Node K,
Yasunaga H, Komuro I. Comparison ofcardiovascular outcomes between SGLT2
inhibitors in diabetes mellitus. Cardiovasc
Diabetol. 2022;21:67.
33: Ohisa K, Yamana H, Morita K, Matsui H,
Fushimi K, Yasunaga H. Association between
subcutaneous steroid injection for extravasationof vesicant anticancer drugs and skin ulcers
requiring surgery. Eur J Oncol Nurs. 2022;58:102119.
34: Suzuki Y, Kaneko H, Okada A, Matsuoka S, Itoh
H, Fujiu K, Michihata N, Jo T, Takeda N, Morita
H, Yamaguchi S, Node K, Yamauchi T, Yasunaga
H, Komuro I. Prediabetes in Young Adults and Its
Association With Cardiovascular Health Metrics
in the Progression to Diabetes. J Clin Endocrinol
Metab. 2022;107:1843-1853.
35: Okada A, Yamana H, Yamaguchi S, Kurakawa KI,
Michihata N, Matsui H, Fushimi K, Nangaku M,
Yamauchi T, Yasunaga H, Kadowaki T. Effect ofBranched-Chain Amino Acid Infusion on
In-Hospital Mortality of Patients With Hepatic
Encephalopathy and End-Stage Kidney Disease:
A Retrospective Cohort Study Using a National
Inpatient Database. J Ren Nutr. 2022;32:432-440.
36: Konishi T, Fujiogi M, Michihata N, Kumazawa R,
Ohbe H, Matsui H, Fushimi K, Ogita M, Tanabe
M, Seto Y, Yasunaga H. Interstitial lung disorders
following postoperative radiotherapy withconcurrent or sequential hormonal therapy forbreast cancer: a nationwide database study in469

Japan. Breast Cancer. 2022;29:688-697
37: Kumazawa R, Jo T, Matsui H, Fushimi K,
Yasunaga H. Direct oral anticoagulants versus
warfarin for secondary prevention of cerebral
infarction and bleeding in older adults with atrial
fibrillation. J Am Geriatr Soc. 2022;70:20292039.
38: Konishi T, Fujiogi M, Michihata N, Matsui H,
Tanabe M, Seto Y, Yasunaga H. Association
between body mass index and incidence of breast
cancer in premenopausal women: a Japanesenationwide database study. Breast Cancer Res
Treat. 2022;194:315-325
39: Ueno K, Kaneko H, Kamiya K, Itoh H, Okada A,
Suzuki Y, Matsuoka S, Fujiu K, Michihata N, Jo
T, Takeda N, Morita H, Ako J, Yasunaga H,
Komuro I. Clinical utility of simple subjective
gait speed for the risk stratification of heart
failure in a primary prevention setting. Sci Rep.
2022;12:11641.
40: Konishi T, Fujiogi M, Michihata N, Morita K,
Matsui H, Fushimi K, Tanabe M, Seto Y,
Yasunaga H. Association of Operative Day of the
Week with the Length of Stay and Total
Hospitalization Costs in Patients with Partial
Mastectomy: A Nationwide Database Study inJapan. JMA J. 2022;5:319-327.
41: Hashimoto Y, Yamana H, Michihata N, Shigemi
D, Ishimaru M, Matsui H, Yasunaga H, Aihara M.
Eye drops for dry eye disease during pregnancy
andadverseneonatal
outcomes:
highdimensional
propensity
score
analyses.
Ophthalmic Epidemiol. 2022;29:384-393.
42: Kaneko H, Yano Y, Lee HH, Lee H, Okada A,
Itoh H, Morita K, Fukui A, Fujiu K, Suzuki Y,
Matsuoka S, Nakamura S, Michihata N, Jo T,
Takeda N, Morita H, Yokoo T, Nishiyama A,
Node K, Viera AJ, Muntner P, Oparil S, Kim HC,
Yasunaga H, Komuro I. Medication-Naïve Blood
Pressure and Incident Cancers: Analysis of 2
Nationwide Population-Based Databases. Am J
Hypertens. 2022;35:731-739.
43: Fuseda Y, Michihata N, Kumazawa R, Fushimi K,
Yasunaga H. Annual Trend in Lumbar Puncture
for Infants Younger Than 3 Months Hospitalized
With Suspected Serious Bacterial Infection: A
Nationwide Inpatient Database Study. Pediatr

Infect Dis J. 2022;41:631-635.
44: Michihata N, Suzuki T, Honda A, Oka I,
Yoshikawa T, Saito K, Matsui H, Fushimi K,
Yasunaga H. Clinical Features of Kawasaki
Disease With Atlantoaxial Rotatory Fixation.
Pediatr Infect Dis J. 2022;41:626-630.
45: Hosoi T, Yamana H, Tamiya H, Matsui H,
Fushimi K, Akishita M, Yasunaga H, Ogawa S.
Association between comprehensive geriatricassessment and polypharmacy at discharge inpatients with ischaemic stroke: A nationwide,
retrospective, cohort study. EClinicalMedicine.
2022;50:101528
46: Itoh H, Kaneko H, Okada A, Suzuki Y, Fujiu K,
Matsuoka S, Michihata N, Jo T, Nakanishi K,
Takeda N, Morita H, Node K, Di Tullio MR,
Homma S, Yasunaga H, Komuro I. Age-Specific
Relation of Cardiovascular Health Metrics With
Incident Cardiovascular Disease. Am J Cardiol.
2022;177:34-39.
47: Fukui A, Kaneko H, Okada A, Yano Y, Itoh H,
Matsuoka S, Morita K, Kiriyama H, Kamon T,
Fujiu K, Michihata N, Jo T, Takeda N, Morita H,
Nakamura S, Nishiyama A, Node K, Yokoo T,
Nangaku M, Yasunaga H, Komuro I.
Semiquantitative assessed proteinuria and risk ofheart failure: analysis of a nationwide
epidemiological
database.
Nephrol
Dial
Transplant. 2022;37:1691-1699
48: Kurakawa KI, Okada A, Bessho K, Jo T, Ono S,
Michihata N, Kumazawa R, Matsui H, Fushimi K,
Yamaguchi S, Yamauchi T, Nangaku M,
Kadowaki T, Yasunaga H. Major complications
after percutaneous biopsy of native ortransplanted liver in pediatric patients: anationwide inpatient database study in Japan.
BMC Gastroenterol. 2022;22:395.
49: Honda A, Iizuka Y, Michihata N, Uda K, Mieda T,
Takasawa E, Ishiwata S, Kakuta Y, Tomomatsu Y,
Ito S, Inomata K, Matsui H, Fushimi K, Yasunaga
H, Chikuda H. Effect of Intraoperative
Tranexamic Acid on Perioperative Major
Hemorrhage Requiring Transfusion in Patients
Undergoing Elective Spine Surgery: A Propensity
Score-Matched Analysis Using a National
Inpatient Database. Global Spine J. 2022:
21925682221123317.

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Division of Chronic Kidney Disease(CKD) Pathophysiology
Division Chief (Professor)
Reiko Inagi, Ph.D.

Assistant Professor
Sho Hasegawa, M.D., Ph.D.

PhD Students
Haruki Ouchi, M.D. (Division of Nephrology and Endocrinology)
Yuto Takenaka, M.D. (Division of Nephrology and Endocrinology)
Chigusa Kitayama, M.D. (Division of Nephrology and Endocrinology)
Li Qi, M.D. (Division of Nephrology and Endocrinology)

Visiting Reseracher
Kamolwan Pakchotanon, M.D.（2022 September – 2023 February）

Lab Technician
Ikumi Okuaki, B.S.
Keiko Miyamoto, B.S.

Homepage

http://www.todai-ckd.com

Introduction and Organization
In Japan, more than 13 million people suffer fromchronic kidney disease (CKD), or roughly one inevery eight adults. Why has the number of CKD
patients increased so remarkably? One major cause is
the sharp increase in the number of people withdiabetic nephropathy, which is a complication ofdiabetes; since 1998, this has been the most importantcause among diseases which require incipient dialysis
in Japan. Additional causes include the aging ofsociety and other social factors. The kidney is called asilent organ, and CKD progresses without subjective
symptoms. It is now evident, however, thatasymptomatic CKD which progresses over time
carries a number of risks.
One risk is the possible progression of CKD to

end-stage renal disease (ESRD), which requires renal
replacement therapy. A second risk is the development
and progression of lifestyle-related diseases, such asheart attack and arteriosclerosis. The kidneys work
closely with the heart and other organs, and a decrease
in renal function causes dysfunction of the heart andblood vessels. This adverse impact of the progressionof CKD on other organs underlines the importance of
the kidneys in maintaining general health. Further,many researchers have also focused on the vicious
spiral of aging and CKD: aging worsens the
progression of CKD, while CKD accelerates aging.
With our modern lifestyles and the super-aging society,
CKD cannot be separated from lifestyle-relateddiseases, and senility cannot be separated from CKD.
Creating a healthy, long-lived society full of energy

471

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
CKD6) Identifying a novel renoprotective mechanism
based on the molecular inflammatory axis in
kidney injury7) Pathophysiological role of organelleorganelle crosstalk damage in renal injury

stress,Research Funds (PI) Japan Society for the Promotion of Science, Grantsin-Aid for Scientific Research
21H02824 (to Reiko Inagi, Novel tubular
homeostasis mechanism mediated by primary cilia),
21K9439 (to Reiko Inagi, Pathophysiological roleof organelle contact site in tubular homeostasis),
21K6159 (to Sho Hasegawa, Unraveling the roleof ER-mitochondria crosstalk in the pathogenesis of
diabetic kidney disease), Japan Agency for Medical Research andDevelopment (AMED)CREST 20gm1410005s0101 (to Reiko Inagi, Studyon understanding of the molecular mechanisms oftissue-specific unfolded protein responses forradical cure of human chronic diseases)
 SENSHIN Medical Research Foundation (to Reiko
Inagi, Elucidating the Role of plasma exosome on
vasoprotection in kidney disease) MSD Life Science Foundation, Public Interest
Incorporated Foundation, Additional Research
Grant (to Sho Hasegawa, Pathophysiological roleof ER-mitochondria crosstalk in diabetic kidneydisease) Kowa Life Science Research Foundation (to Sho
Hasegawa, Elucidating the Role of Neurotransmitters in the Repair Process of Renal Tissue)
 Japan Kidney Foundation, Grant for research in
chronic kidney disease (to Sho Hasegawa,Comprehensive analysis of the effects of HIF-PH
inhibitors on intestinal homeostasis)AwardsDr. Sho Hasegawa received the Young InvestigatorAward from the Japanese Society of Nephrology.
Dr. Sho Hasegawa received the 11th Banyu MedicalAward from MSD Life Science Foundation.

References
1.

Inoue T, Nakamura Y, Tanaka S, Kohro T, Li LX,
Huang L, Yao J, Kawamura S, Inoue R, Nishi H,

472

2.

3.

4.

5.

6.

Fukaya D, Uni R, Hasegawa S, Inagi R, Umene R,
Wu CH, Ye H, Bajwa A, Rosin DL, Ishihara K,
Nangaku M, Wada Y, Okusa MD. Bone marrowstromal cell antigen-1 (CD157) regulated bysphingosine kinase 2 mediates kidney fibrosis.
Front Med (Lausanne). 2022 Oct 4;9:993698.
doi:
10.3389/fmed.2022.993698.
PMID:
36267620; PMCID: PMC9576863.
Hirakawa Y, Yoshioka K, Kojima K, Yamashita
Y, Shibahara T, Wada T, Nangaku M, Inagi R.
Potential progression biomarkers of diabetic
kidney disease determined using comprehensive
machine learning analysis of non-targeted
metabolomics. Sci Rep. 2022 Sep 29;12(1):16287. doi: 10.1038/s41598- 022-20638-1.
PMID: 36175470; PMCID: PMC9523033.
Okpechi IG, Caskey FJ, Gaipov A, Tannor EK,
Noubiap JJ, Effa E, Ekrikpo UE, Hamonic LN,
Ashuntantang G, Bello AK, Donner JA,
Figueiredo AE, Inagi R, Madero M, Malik C,
Moorthy M, Pecoits-Filho R, Tesar V, Levin A,
Jha V. Early Identification of CKD-A Scoping
Review of the Global Populations. Kidney Int
Rep. 2022 Apr 6;7(6):1341-1353. doi: 10.1016/j.
ekir.2022.03.031. PMID: 35685314; PMCID:
PMC9171699.
Inagi R. Organelle Stress and Metabolic
Derangement in Kidney Disease. Int J Mol Sci.
2022 Feb 2;23(3):1723. doi: 10.3390/ ijms
23031723. PMID: 35163648; PMCID: PMC
8836232.
Wu CH, Inoue T, Nakamura Y, Uni R, Hasegawa
S, Maekawa H, Sugahara M, Wada Y, Tanaka T,
Nangaku M, Inagi R. Activation of α7 nicotinic
acetylcholine receptors attenuates monocyteendothelial adhesion through FUT7 inhibition.
Biochem Biophys Res Commun. 2022 Jan
29;590:89-96. doi: 10.1016/j.bbrc. 2021.12.094.
Epub 2021 Dec 27. PMID: 34973535.
Yoshioka K, Hirakawa Y, Kurano M, Ube Y,
Ono Y, Kojima K, Iwama T, Kano K, Hasegawa
S, Inoue T, Shimada T, Aoki J, Yatomi Y,
Nangaku M, Inagi R. Lysophosphatidylcholine
mediates fast decline in kidney function indiabetic kidney disease. Kidney Int. 2022 Mar;
101(3):510-526. doi: 10.1016/j.kint. 2021.10.039.
Epub 2021 Nov 29. PMID: 34856312.

7.

8.

Hasegawa S, Inagi R. The subtle long-lastingburden of mitochondrial DNA variants. Nat Rev
Nephrol. 2022 Jan;18(1):4-5. doi: 10.1038/
s41581-021- 00500-9.PMID: 34663981.
Muso E, Sakai S, Ogura Y, Yukawa S, Nishizawa
Y, Yorioka N, Saito T, Mune M, Sugiyama S,
Iino Y, Hirano T, Hattori M, Watanabe T,
Yokoyama H, Sato H, Uchida S, Wada T, Shoji T,
Oda H, Mori K, Kimura H, Ito O, Nishiyama A,
Maruyama S, Inagi R, Fujimoto S, Tsukamoto T,
Suzuki Y, Honda H, Babazono T, Tsuruya K,
Yuzawa Y. Favorable therapeutic efficacy of
low-density lipoprotein apheresis for nephrotic
syndrome with impaired renal function. Ther
Apher Dial. 2022 Feb;26(1):220-228. doi:
10.1111/ 1744 -9987.13694.

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Department of Retinal Biology andPathology
Project Professor
Sumiko Watanabe, Ph.D.

Project Assistant Professor
Toshiro Iwagawa, Ph.D

Introduction and Organization
We are focusing on analysis of retinal development andbasic mechanisms of retinal degenerative diseases withultimate goal to elucidate new targets for drug designin ocular diseases. Faculties are Ph.D, basic medical
scientists, and graduate students consist of both Ph.D
type and MD background students. Our laboratory had
been established 2021 July and is supported by Chugaipharmaceutical co. The basis of our laboratory is
Department of Molecular and Developmental Biology,
which was in The Institute of Medical Science.
University of Tokyo (IMSUT) until 2021. Major
members of current laboratory including the faculties
were working on molecular basis of retinal
development especially focusing on transcriptional
mechanisms including epigenetics of retinal
development at this laboratory in IMSUT. Recent few
years, we had focused on working on retinitis
pigmentosa, which is the inherited severe retinaldegenerative disease. Analysis of impact of the genemutations, which was reported from patients genomic
analysis, for maintenance of photoreceptor homeostasis
was main strategy of our research. However, we had
started analysis of roles of inflammation for onset andprogression of retinal degeneration. Determination of
the cells which contribute to build the inflammatoryenvironment within retina is an important issue to besolved. There are several retinal immunocompetentcells, such as microglia, astrocyte, Mueller glia, andretinal pigment epithelium (RPE), and we haveparticular interests with the microglia. After starting the

new laboratory in the hospital, we expanded our focus
from retina to retina and sclera with particular interest
with blood vessels. Therefore, not only retinitis
pigmentosa, various vessel related retinal diseases suchas ocular complications of diabetic mellitus and aged
macular degeneration (AMD) are our research targets.
Microglia and inflammatory environment in retina may
play pivotal roles for the vessel related retinaldegenerative diseases, and we had established several
assay systems related to this point both in in vitro andin vivo.
The laboratory also aims to bridge the basic research and the clinical-team. We have regular discussion of
our laboratory members and ophthalmology
department clinicians, and exchange knowledge andtechniques between two groups. By such efforts, we
aim to establish basic/clinical collaborative researchgroup in ophthalmology field.

Teaching activities
The graduate students (2 Ph.D candidates) areclinicians, and have their own project. In 2022, wepublished 2 papers of the students projects to scientificjournals. Group data discussion, laboratory data
discussion, journal club, and individual data discussion
are regularly hold by onsite as well as online. One of
our purposes to establish the lab here from IMSUT is
to establish structure of mutual collaboration between
clinicians and basic science researchers. For that
purpose, we have regular data conference between
ophthalmology department and us, and faculties of both

474

laboratories also have regular meeting to discussproject direction. We also participate to train Ph.D
candidate students of the ophthalmology department byteaching principles of experimental techniques anddiscussing research data. Vice versa, we learnt how to
do ophthalmology related several image analyses, suchas OCT and fundus photography of the mouse. These
techniques help us to expand choice of analyses of
disease model mice. In addition, as a hub laboratory inthe basic ophthalmology related works, students andyoung researchers in the University of Tokyo and otheruniversities often visit us to learn techniques andknowledge in this field.

Research activities
Summary of the research: Retinal degeneration miceand human iPS cells are two major models used in our
research, and several projects of the retina and cornea
are ongoing. Technically, we employ molecular biology,
biochemistry, electroretinogram, and several imaging
analyses. In addition, the LC-MS based membrane lipid
analysis and the proteome in collaboration with theexperts are often used. Ophthalmological techniques
also facilitate to make our research activities deepen
with broad spectrum. We had focused on retinal
neurons and microglia, but now include more posterior
segment of the eye, such as RPE, choriocapillaris, andchoroid. Details of some of specific projects are as
follows.
＊Roles of CSF2 as a modulator of inflammation
during retinal degeneration
Colony-stimulating factor 2 (CSF2) is a potent cytokine
that stimulates myeloid cells, such as dendritic cells
and macrophages. We have been analyzing the roles of
microglia in retinal degeneration through themodulation of inflammation in the eye, and examined
the roles of CSF2 in this process. Transcripts of bothsubunits of the CSF2 receptor are expressed in
microglia, but no evidence suggesting the involvementof CSF2 in inflammation in the degenerating eye has
been reported. We found that Csf2 transcripts were
induced in the early phase of in vitro mouse adult retina
culture, used as degeneration models, suggesting thatCSF2 induction is one of the earliest events occurringin the pathology of retinal degeneration. To examine

the roles of CSF2 in retinal inflammation, we
overexpressed CSF2 in retinal explants. Induction of
CSF2 activated microglia and Müller glia, and the layer
structure of the retina was severely perturbed. C–C
motif chemokine ligand 2 (Ccl2) and C-X-C motif
chemokine ligand 10 (Cxcl10), both of which are
expressed in activated microglia, were strongly inducedby the expression of CSF2 in the retina. However,addition of CSF2 to microglial cell lines MG5 and BV2
did not show apparent effects of CSF2 except weak
induction of Ccl2 transcripts and proliferation,suggesting that CSF2 induced strong inflammation in
the context of the retinal environment, probably
through editing molecular network of initial phase ofdegeneration.
*Downregulation of VEGF in the Retinal Pigment
Epithelium Followed by Choriocapillaris Atrophy
After NaIO3 Treatment in Mice
Sodium iodate (NaIO3) induces retinal pigment
epithelium (RPE) dysfunction, which leads tophotoreceptor degeneration. This system is widely used
as retinitis pigmentosa model. Previously, we usedelectron microscopy to show that the administration of
NaIO3 resulted in the accumulation of cell debris in thesubretinal space, which was thought to be caused by
failed phagocytosis in the outer segment of thephotoreceptor due to RPE dysfunction. We further
analyzed the pathological changes in the retina andchoroid of NaIO3-injected mice, and found that theexpression of OTX2, an RPE marker, disappeared from
central part of the RPE 1 day after NaIO3
administration. Furthermore, fenestrated capillaries(choriocapillaris, CC) adjacent to the RPE could not be
identified only 2 days after NaIO3 administration. An
examination of the expression of the CC-specificprotein plasmalemma vesicle-associated protein(PLVAP), in sections and flat-mount retina/choroid
specimens showed destruction of the CC, and complete
disappearance of the PLVAP signal 7 days after NaIO3
administration. In contrast, CD31 flat-mountimmunohistochemistry of the retina indicated nodifference in retinal vessels between NaIO3-treatedmice and controls. Electron microscopy showed thatthe fenestrated capillaries in the kidney and duodenum
were morphologically indistinguishable between
control and NaIO3-treated mice. We examined475

cytokine production in the retina and RPE, and foundthat the Vegfa transcript level in the RPE decreased
starting 1 day after NaIO3 administration. Taken
together, these observations show that NaIO3 reduces
the CC in the early stages of the pathology, which isaccompanied by a rapid decrease in Vegfa expression in
the RPE.
A loss of the CC has been reported in various oculardegenerative diseases, mainly based on recent technicaldevelopment of optical coherence tomography
angiography (OCTA). CC flow alterations were shown
to be associated with the development and progressionof AMD, and retinitis pigmentosa. Our observation of
the loss of the CC in the early phase of NaIO3-induced
pathogenesis may contribute to understanding of rolesof alteration of CC in pathogenesis of the retinaldegenerative diseases.

References
1.

2.

3.

Azuma, K., Koumura, T., Iwamoto, R., Matsuoka,
M., Terauchi, R., Yasuda, S., Shiraya, T.,
Watanabe, S., Aihara, M., Imai, H., Ueta, T.,
Mitochondrial GPx4 is indispensable forphotoreceptor development and survival in mice,
JBC, 2022, 298, 101824
Nagata, K., Hishikawa, D., Sagara, H., Saito, M.,
Watanabe, S., Shimizu, T., Shindou, H.
Lysophosphatidylcholine
acyltransferase
1
controls mitochondrial reactive oxygen species
generation and survival of retinal photoreceptor
cells, JBC, 2022, 298, 101958
Saita, K., Moriuchi, Y., Iwagawa, T., Aihara, M.,
Takai, Y., Uchida, K., Watanabe, S., Roles of
CSF2 as a modulator of inflammation during
retinal degeneration, Cytokine, 2022 158, 155996

476

Department of Real-world
Evidence
Project Associate Professor
Yusuke Sasabuchi, M.D., M.P.H, Ph.D.

Project Lecturer
Shotaro Aso, M.D., M.P.H, Ph.D.

History andOrganization

OverviewoftheReal-World Data (RWD) refers to patient datacollected in daily clinical settings, distinct from thecontrolled environments of Randomized Controlled
Trials (RCTs). This includes data from insurance
databases, health check-ups, and electronic medical
records. Evidence derived from RWD research is
known as Real-World Evidence (RWE). RWD
research is rapidly evolving globally. Regulatory
authorities in Europe and America have opted toutilize RWE for expanding indications and safety
monitoring of pharmaceuticals and medical devices.
This has promoted an integrated approach to theutilization of RWD among industry, government, andacademia.
In this context, the Department of
Real-world Evidence was established in December
2022 as a social collaboration department withfunding from DeSC Healthcare Corporation. The
department aims to enhance public health andwell-being by promoting multidisciplinary researchusing Japan's RWD to generate RWE anddisseminating these findings to society. The
collaborating department is the Department of Clinical
Epidemiology & Economics (Professor Hideo
Yasunaga).
The founding faculty members include
Project Associate Professor Yusuke Sasabuchi(appointed December 2022) and Project Lecturer
Shotaro Aso (appointed April 2023).
The creation of RWE can enhance daily clinicalpractice through updated medical knowledge, improvethe efficacy and safety of pharmaceuticals andmedical devices, and contribute to their development.
RWD research can fill gaps in evidence where RCTs
are challenging to implement, thereby contributing toevidence-based medicine. It can also contribute tobuilding a sustainable medical system through healtheconomic policy research. Additionally, thedepartment aims to reflect research outcomes inmedical education and train data scientists.

Educations
The Department of Real-world Evidence provides
support for lectures and guidance to students
specializing in the School of Public Health at thecollaborating Department of Clinical Epidemiology &Health Economics, as well as lectures and guidance
for students in the Medical Real-World Data
Utilization Personnel Training Program.
 For students specializing in the School of
Public Health: Support is provided forClinical Epidemiology & Health Economics
exercises including a lecture in Clinical
Epidemiology (1 session) by Sasabuchi.
 Sasabuchi and Aso provide guidance tostudents specializing in the School of Public
Health.
 Medical
Real-World
Data
Utilization
Personnel Training Program: Introduction to
Medical Real-World Data Construction (1session) Clinical Issue Analysis and Practical
Management (4 sessions) Practical Task

477



Training 2 (task presentation and evaluation)
Guidance for specialized students: Sasabuchi,
Aso
In the Medical Real-World Data Utilization
Personnel Training Program, the curriculum
includes 'Introduction to Medical Real-World
Data Construction' (1 session), 'Clinical Issue
Analysis and Practical Management' (4sessions), and 'Practical Task Training 2' (taskpresentation and evaluation), with Sasabuchi
and Aso providing guidance to specialized
students.

4.

5.

Research activities
Two faculty members from the Department of
Real-world Evidence directly guide students andresearchers in RWD research, thereby fostering theirskills as data scientists. The department's research
activities focus on pharmacological epidemiology,
clinical epidemiology, and health economic policy
research. This focus emphasizes utilizing RWD fromvarious sources, including the DeSC database, thenational database (NDB), the DPC database, patientregistries, and electric medical records. Through theseeducational and research activities, the department
aims to respond to the societal demand for RWD
research and RWE utilization, promote research using
Japan's RWD, and contribute to overall healthimprovement.

References
1.

2.

3.

Nishimoto Y, Ohbe H, Matsui H, Nakajima M,
Sasabuchi Y, Sato Y, Watanabe T, Yamada T,
Fukunami M, Yasunaga H. Effectiveness of
systemic thrombolysis on clinical outcomes inhigh-risk pulmonary embolism patients withvenoarterial extracorporeal membrane oxygenation: a nationwide inpatient database study. J
Intensive Care. 2023 Feb 6;11(1):4.
Sugihara T, Kamei J, Yasunaga H, Sasabuchi Y,
Fujimura T. Prescription of Choreito, a Japanese
Kampo Medicine, with Antimicrobials for
Treatment of Acute Cystitis: A Retrospective
Cohort Study. Antibiotics (Basel). 2022 Dec 18;
11(12):1840.
Ohbe H, Sasabuchi Y, Matsui H, Yasunaga H.

6.

7.

8.

Impact of the COVID-19 pandemic on criticalcare utilization in Japan: a nationwide inpatient
database study. J Intensive Care. 2022 Dec 2;
10(1):51.
Shiotsuka J, Uchino S, Sasabuchi Y, Masuyama T,
Lefor AK, Sanui M. Reducing the effect ofimmortal time bias affects the analysis ofprevention of delirium by suvorexant in criticallyill patients: A retrospective cohort study. PLoS
One. 2022 Dec 1;17(12):e0277916.
Hayashi K, Sasabuchi Y, Matsui H, Nakajima M,
Ohbe H, Fushimi K, Ono K, Yasunaga H.
Additive effectiveness of acrylonitrile-comethallyl sulfonate surface-treated membranes inthe treatment of pneumonia: A propensity
score-matched retrospective cohort study. Artif
Organs. 2023 Feb;47(2):408-416
Wada Y, Takahashi H, Matsui H, Yasunaga H,
Fujiwara H, Sasabuchi Y. Adhesion barriers andintraperitoneal or uterine infections after cesarean
section: A retrospective cohort study. Surgery.
2022 Dec;172(6):1722-1727.
Shinmoto K, Ohbe H, Nakajima M, Miyamoto Y,
Sasabuchi Y, Yasunaga H, Hiraoka E. Outcomes
after early versus delayed antibiotic treatment ofliver abscess in Japan: A nationwide retrospective
cohort study. J Infect Chemother. 2023 Jan;29(1):1-6.
Ohbe H, Sasabuchi Y, Iwagami M, Ogura T, Ono
S, Matsui H, Yasunaga H. Intensive Care Unit
versus High-dependency Care Unit for
COVID-19 Patients with Invasive Mechanical
Ventilation. Ann Am Thorac Soc. 2023 Jan;20(1):102-109.

478

Department of Lipidomics
Professor
Yoshiya Oda, Ph.D.

Assistant Professor
Suzumi M Tokuoka, Ph.D.

Homepage

http://lipidomics.m.u-tokyo.ac.jp/index-e.html

Introduction and Organization
The Department of Lipidomics was established in
April 2011, funded by Shimadzu Corp. and Ono
Pharmaceutical Co., Ltd. The objective of the laboratory is to establish and improve mass spectrometrybased lipidomics methodologies, and its application tobiomedical studies including basic lipid biology as
well as clinical research.
The laboratory was started with three staff scientists,
Takao Shimizu (Professor), Yoshihiro Kita (Associate
Professor. He moved to Life Science Core Facility in
Dec. 2013), and Suzumi Tokuoka (Assistant Professor). In April, 2014, Fuyuki Tokumasu joined as an
Associate Professor (he moved to Nagasaki University
in April, 2019) and in May 2018, Yoshiya Oda joined
as a professor. In 2021, we have three guest
researchers and two technical assistants. This year
marks the 20th year since the launch of the former
donated laboratory for metabolomics.

Teaching activities
The department staffs gave several lectures forundergraduate and graduate students. For undergraduate students, Drs. Shimizu and Kita delivered
several lectures on biochemistry. Dr. Kita gave
lectures on “Proteome and metabolome” for master’s
students and “Principles and Applications of Mass
Spectrometry” for doctoral students.

Research activities
Our research interests cover following topics.

Methods for clinical samples
Studies using human specimens are more reflectiveof human diseases than experimental data using
laboratory animals and cell lines. However, lipidomics
analysis on human clinical specimens such as blood,urine, feces, and biopsy samples is not always
optimized for lipidomics analysis because of the large
variability of data depending on individual differencescompared to animal experiments. We are developing atechnique for handling clinical samples for lipidomics
analysis, and are working to create a highly practicallipidomics analysis method. Furthermore, in theclinical field, it is required to measure a large numberof samples to take into account individual differences.
Therefore, we are developing high-throughput andhighly reliable assays and applying them to clinicalpractice.
Lipid biomarker discovery
Lipid biomarker discovery by liquid chromatographymass spectrometry-based method requires a high-level
integration of chromatography and mass spectrometry,
which ensures lipid separation, semi-quantitative detection, and identification. We are collaborating withindustries to overcome known difficulties in lipid
chromatography, develop differential analyses andfeature-extraction methods, and establish an intelligent analytical system linked with lipid database.
Metabolic flux analysis of lipids
A simple lipidomics analysis provides large datasetsthat describe the amount-based profile of lipidome.
However, such a ‘snapshot’ analysis is not sufficientto understand the dynamics of lipid metabolic pathway,

479

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.
Multiplex quantitation strategy for biologically
active lipids
Lipid mediators, including prostaglandins, leukotrienes, platelet-activating factor, bile acids and manyother bioactive lipid metabolites are attracting great
attention as disease-related or physiologically important molecules. Comprehensive analysis of known
lipids is a useful, unbiased method in diseasemechanism studies, and the lipid profile is a usefulparameter that characterizes disease status as well. We
have developed an original multiplex quantification
method for trace amounts of biologically active lipids
usingliquidchromatography-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 lipids and their related
molecules 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.

Automating Metabolite Analysis and Improving
Coverage
Various methods are used to improve the coverageof metabolomics and lipidomics. One such method isgaschromatography
(GC),
which
requiresderivatization of the molecule to be analyzed. We aredeveloping protocols to enable various derivatization
methods using an automated derivatization system.
Although individual molecules cannot be identified,
we are investigating the possibility of risk diagnosis
based on the profiles of blood components using a
Fourier transform infrared spectrophotometer, which
is fast, reproducible, and easy to operate. Our goal is
to contribute to medical care by incorporating various
technologies without limiting measurement methods.

References
1.

2.

3.

4.

5.

Hosoi T, Yakabe M, Sasakawa H, Sasako T, Ueki K,
Kato S, Tokuoka SM, Oda Y, Abe M, Matsumoto T,
Akishita M, Ogawa S. Sarcopenia phenotype andimpaired muscle function in male mice with
fast-twitch muscle-specific knockout of theandrogen receptor. Proc Natl Acad Sci U S A. 2023
Jan 24;120(4):e2218032120.
Kita Y, Tokuoka SM, Oda Y, Shimizu T. TRACES:
A lightweight browser for liquid chromatography–
multiple reaction monitoring–mass spectrometry
chromatograms. Metabolites, 12, 354 (2022)(Published: 15 April 2022).
Tokuoka SM, Kita Y, Sato M, Shimizu T, Yatomi Y,
Oda Y. Lipid profiles of human serum fractions
enhanced with CD9 antibody-immobilized
magnetic beads. Metabolites, 12, 230 (2022)(Published: 5 March 2022).
Hamano F, Tokuoka SM, Ishibashi M, Yokoi Y,
Tourlousse DM, Kita Y, Sekiguchi Y, Yasui H,
Shimizu T, Oda Y. Multi-omics analysis to generate
hypotheses for mild health problems in monkeys.
Metabolites, 11, 701 (2021) (Published: 13 October2021).
Tokuoka SM, Kita Y, Sato M, Shimizu T, Yatomi Y,
Oda Y. Development of Tandem Mass Tag Labeling
Method for Lipid Molecules Containing Carboxy
and Phosphate Groups, and Their Stability in
Human Serum. Metabolites. 2020 Dec 30;11(1):19.

480

6.

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.
7. 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.
8. 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)
9. 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)
10. 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)11. 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)12. 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)

13. Kita Y, Shiudou H, Shimizu T. Cytosolic
phospholipase A2 and lysophospholipid acyltransferases. Biochim Biophys Acta, 1864, 838-845(2019) (Available online 9 August 2018)
14. 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)
15. 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)

481

Department of Preventive Medicine
for Locomotive Organ Disorders
Project Professor
Noriko Yoshimura, M.D., Ph.D.

Project Research Associate
Toshiko Iidaka, M.D., Ph.D.

Homepage

http:// www.h.u-tokyo.ac.jp/research/center22/index.html

Introduction and Organization
The department of Preventive Medicine for
Locomotive Organ Disorders in 22nd Century
Medical and Research Center, The University ofTokyo Hospital, on April 1st, 2020, which is a social
collaboration department with NIPPON TELEGRAPH
AND TELEPHONE CORPORATION (NTT), Suntory
Wellness
Ltd.,
ASAHI
KASEI
PHARMA
CORPORATION, and Fujifilm Corporation, and inclose collaboration with departments of Orthopaedic
Surgery and Rehabilitation Medicine in the hospital.
Our department has been established to clarify the
epidemiological profiles of locomotive organ
disorders, such as, osteoarthritis (OA), osteoporosis(OP) and sarcopenia (SP). Further, we also try to
elucidate the frequencied and risk factors forlocomotive syndrome, which was defined by theJapanese Orthopaedic Association (JOA) in 2014.

Research activities
Although locomotive organ disorders are major causesof disability and require support, little information isavailable regarding their epidemiology. The Research
on Osteoarthritis/Osteoporosis Against Disability(ROAD) study, which started in 2005-7, is a
prospective cohort study that aims to elucidate theenvironmental and genetic background for bone andjoint diseases. It was designed to examine the extent
to which risk factors for these diseases are related toclinical features, laboratory and radiographic findings,

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 thefollow-up survey since 2022.

References
1.

Vandenput L, Johansson H, McCloskey EV, Liu
E, Åkesson KE, Anderson FA, Azagra R, Bager
CL, Beaudart C, Bischoff-Ferrari HA, Biver E,
Bruyère O, Cauley JA, Center JR, Chapurlat R,
Christiansen C, Cooper C, Crandall CJ,
Cummings SR, da Silva JAP, Dawson-Hughes B,
Diez-Perez A, Dufour AB, Eisman JA, Elders
PJM, Ferrari S, Fujita Y, Fujiwara S, Glüer CC,
Goldshtein I, Goltzman D, Gudnason V, Hall J,
Hans D, Hoff M, Hollick RJ, Huisman M, Iki M,
Ish-Shalom S, Jones G, Karlsson MK, Khosla S,
Kiel DP, Koh WP, Koromani F, Kotowicz MA,
Kröger H, Kwok T, Lamy O, Langhammer A,
Larijani B, Lippuner K, Mellström D, Merlijn T,
Nordström A, Nordström P, O'Neill TW,
Obermayer-Pietsch B, Ohlsson C, Orwoll ES,
Pasco JA, Rivadeneira F, Schei B, Schott AM,
Shiroma EJ, Siggeirsdottir K, Simonsick EM,

482

2.

3.

4.

5.

Sornay-Rendu E, Sund R, Swart KMA, Szulc P,
Tamaki J, Torgerson DJ, van Schoor NM, vanStaa TP, Vila J, Wareham NJ, Wright NC,
Yoshimura N, Zillikens MC, Zwart M, Harvey
NC, Lorentzon M, Leslie WD, Kanis JA: Updateof the fracture risk prediction tool FRAX: asystematic review of potential cohorts andanalysis plan. Osteoporos Int 33(10): 2103-2136,
2022, doi: 10.1007/s00198-022-06435-6.
Yoshimura N, Iidaka T, Horii C, Muraki S, Oka
H, Kawaguchi H, Nakamura K, Akune T, Tanaka
S: Trends in osteoporosis prevalence over a
10-year period in Japan: The ROAD study
2005–2015. J Bone Miner Metab 40(5): 829-838,
2022, doi: 10.1007/s00774-022-01352-4.
Chotiyarnwong P, McCloskey EV, Harvey NC,
Lorentzon M, Prieto-Alhambra D, Abrahamsen B,
Adachi JD, Borgström F, Bruyere O, Carey JJ,
Clark P, Cooper C, Curtis EM, Dennison E,
Diaz-Curiel M, Dimai HP, Grigorie D,
Hiligsmann M, Khashayar P, Lewiecki EM, Lips
P, Lorenc RS, Ortolani S, Papaioannou A,
Silverman S, Sosa M, Szulc P, Ward KA,
Yoshimura N, Kanis JA: Is it time to consider
population screening for fracture risk inpostmenopausal women? A position paper fromthe International Osteoporosis Foundation
Epidemiology/Quality of Life Working Group.
Arch Osteoporos 17(1): 87, 2022, doi: 10.1007/
s11657-022-01117-6.
Teraguchi M, Hashizume H, Oka H, Cheung JPY,
Samartzis D, Tamai H, Muraki S, Akune T,
Tanaka S, Yoshida M, Yoshimura N, Yamada H:
Detailed subphenotyping of lumbar modicchanges and their association with low back pain
in a large population-based study: The Wakayama
Spine Study. Pain Ther 11(1): 57-71, 2022, doi:
10.1007/s40122-021-00337-x.
Horii C, Iidaka T, Muraki S, Oka H, Asai Y,
Tsutsui S, Hashizume H, Yamada H, Yoshida M,
Kawaguchi H, Nakamura K, Akune T, Oshima Y,
Tanaka S, Yoshimura N: The cumulative
incidence of and risk factors for morphometricsevere vertebral fractures in Japanese men andwomen: the ROAD study third and fourth
surveys. Osteoporos Int 33(4): 889-899, 2022,
doi: 10.1007/s00198-021-06143-7.

6.

Shoji A, Gao Z, Arai K, Yoshimura N: 30-year
trends of hip and vertebral fracture incidence inJapan: a systematic review and meta-analysis. J
Bone Miner Metab 40(2): 327-336, 2022, doi:
10.1007/s00774-021-01288-1.
7. Asai Y, Tsutsui S, Yoshimura N, Hashizume H,
Oka H, Muraki S, Iidaka T, Horii C, Kawaguchi
H, Nakamura K, Tanaka S, Yoshida M, Yamada
H: Relationship between age-related spinopelvic
sagittal alignment and low back pain in adults of
population-based cohorts: The ROAD Study. J
Pain Res 15: 33-38, 2022, doi: 10.2147/JPR.
S339712.
8. Matsumoto T, Higuchi J, Maenohara Y, ChangSong Ho, Iidaka T, Horii C, Oka H, Muraki S,
Hashizume H, Yamada H, Yoshida M, Nakamura
K, Tanaka S, Yoshimura N: The discrepancy
between radiographically-assessed and selfrecognized hallux valgus in a large populationbased cohort. BMC Musculoskelet Disord 23(1):31, 2022, doi: 10.1186/s12891-021-04978-z.
9. Yoshimura N, Iidaka T, Horii C, Mure K, Muraki
S, Oka H, Kawaguchi H, Akune T, Ishibashi H,
Ohe T, Hashizume H, Yamada H, Yoshida M,
Nakamura K, Tanaka S: Epidemiology oflocomotive syndrome using updated clinicaldecision limits: 6-year follow-ups of the ROAD
study. J Bone Miner Metab 40(4): 623-635, 2022,
doi: 10.1007/s00774-022-01324-8.
10. Harada T, Hashizume H, Taniguchi T, Iidaka T,
Asai Y, Oka H, Muraki S, Akune T, Kawaguchi H,
Nakamura K, Yoshida M, Tanaka S, Yoshimura N,
Yamada H. Association between acetabular
dysplasia and sagittal spino‑pelvic alignment in a
population‑based cohort in Japan. Scientific
Reports 12(1): 12686, 2022, doi: 10.1038/
s41598-022-16865-1.
11. Arita S, Ishimoto Y, Hashizume H, Nagata K,
Muraki S, Oka H, Takami M, Tsutsui S, Iwasaki
H, Yukawa Y, Akune T, Kawaguchi H, Tanaka S,
Nakamura K, Yoshida M, Yoshimura N, Yamada
H; Consortium. Is radiographic lumbar spinal
stenosis associated with the quality of life?: The
Wakayama Spine Study. PLos One 17(2):e0263930, 2022, doi: 10.1371/journal.pone.
0263930.
12. Uehara M, Wada-Hiraike O, Hirano M, Koga K,

483

Yoshimura N, Tanaka S, Osuga Y: Relationshipbetween bone mineral density and ovarianfunction and thyroid function in perimenopausal
women with endometriosis: a prospective study.
BMC Womens Health 22(1):134, 2022, doi:
10.1186/s12905-022-01711-3.
13. Tamai H, Teraguchi M, Hashizume H, Oka H,
Cheung JPY, Samartzis D, Muraki S, Akune T,
Kawaguchi H, Nakamura K, Tanaka S, Yoshida
M, Yoshimura N, Yamada H. A Prospective,
3-year Longitudinal Study of Modic Changes of
the Lumbar Spine in a Population-based Cohort:
The Wakayama Spine Study. Spine 47(6):490497, 2022, doi: 10.1097/BRS.000000000000
4301.
14. Iidaka T, Horii C, Muraki S, Oka H, Kawaguchi
H, Nakamura K, Akune T, Tanaka S, Yoshimura
N. Trends in prevalence of hip osteoarthritis overa 10-year period in Japan: The ROAD study
2005–2015. Osteoarthr Cartil Open 4(3):100285,
2022, doi: 10.1016/j.ocarto.2022.100285.
15. Uehara M, Wada-Hiraike O, Hirano M, Harada M,
Koga K, Yoshimura N, Tanaka S, Osuga Y:
EvaluationofAtherosclerosis-Related
Biomarkers during Perimenopause: A Prospective
Cohort Study in Women with Endometriosis. J
Obstet Gynaecol Res 48(12): 3160-3170, 2022,
doi: 10.1111/jog.15447.

University Hospital
Central Clinical Services

485

Advanced Medical Center forHeart Failure
Director, Associate Professor
Masaru Hatano, M.D.,Ph.D.

Vice Director
Masahiko Ando, M.D., Ph.D.

Homepagehttps://www.h.u-tokyo.ac.jp/patient/depts/shinfuzen/

Introduction and Organization
Advanced medical center for heart failure
collaborates with a wide range of university hospitals
and core regional medical institutions to accept patients
who require heart transplantations of ventricular assist
device (VAD) implantation. In addition to
cardiovascular medicine and cardiovascular surgery,the center provides medical care with a heart teamconsisting of recipient transplant coordinators,
pharmacists, medical engineers and physical therapists.
In addition to such medical cooperation efforts, thecenter is also responsible for training heart failure
specialists and other specialized staff by accepting
trainees.

Clinical activities
Target diseases include idiopathic cardiomyopathies
such as dilated cardiomyopathy and hypertrophic
cardiomyopathy, various types of secondary
cardiomyopathy, and all causes of heart failure
regardless of underlying disease
・Heart transplantation : Performed 213
Heart transplantation to date (as of 25 Dec 2023),
the largest number in Japan・ Ventricular Assist Device (VAD): The center canemploy all types of VADs approved in Japan,
making it possible to choose the most suitablemodel according to each patient’s physical and heart
failure condition. It is also recognized as a facility
that can perform destination therapy.

・ Drug therapy for heart failure: The center has
extensive experience in the use of heart failuredrugs, including those that have been in recent years.
・Introduction of Vyndaqel for cardiac amyloidosis:
The center has been certified to prescribe Vyndaqelby The Japanese Circulation Society and havealready gained a significant amount of experience
with the drug.
・ HeartSeet: The center participates in a postmarketing clinical trial of HeartSeet, a skeletal
myoblast sheet to be transplanted onto the surfaceof the heart.

Teaching and Research activities
In addition to medical care, we accept training in
advanced heart failure management from medical
facilities nationwide and play an important role intraining heart failure specialists and specialized staff.
We are also focusing on research and in addition todisseminating many research results, we are promoting
translational research that bridges basic research andclinical practice. In addition, while treating a large
number of heart failure patients, we are also striving toestablish optimal prevention and treatment strategy(precision medicine) that consider individual
differences.

References
1.

F Fujiwara T, Takeda N, Hara H, Ishii S, Numata
G, Tokiwa H, Katoh M, Maemura S, Suzuki T,

486

2.

3.

4.

5.

6.

7.

Takiguchi H, Yanase T, Kubota Y, Nomura S,
Hatano M, Ueda K, Harada M, Toko H, Takimoto
E, Akazawa H, Morita H, Nishimura S, Komuro I.
PGC-1α-mediatedangiogenesis
prevents
pulmonary hypertension in mice. JCI Insight.
2023 Sep 8;8(17):e162632.
Isotani Y, Amiya E, Hatano M, Kiriyama H,
Uehara M, Ishida J, Tsuji M, Bujo C, Narita K,
Ishii S, Kakuda N, Minatsuki S, Yagi H, Saito A,
Numata G, Yamada T, Kurihara T, Suzuki T,
Komuro I.A new assessment method for rightventricular diastolic function using right heart
catheterization by pressure-volume loop.Physiol
Rep. 2023 Jul;11(13):e15751.
Minatsuki S, Hatano M, Tanikawa I, Hirose K,
Saito A, Yagi H, Takeda N, Komuro I.
Verification of Optimal Balloon Size in Balloon
Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension. Cardiovasc
Intervent Radiol. 2023 Jul;46(7):967-969.
Kiriyama H, Kiyosue A, Minatsuki S, Kawahara T,
Katsushika S, Kamon T, Hirose K, Shinohara H,
Miura M, Saito A, Kikuchi H, Kodera S, Hatano
M, Ando J, Myojo M, Itoh N, Yamamoto K,
Ikenouchi H, Takeda N, Komuro I. Potential
value of saline-induced Pd/Pa ratio in patientswith coronary artery stenosis. Front CardiovascMed. 2023 Jan 6;9:1001833.
Ishii S, Hatano M, Maki H, Minatsuki S, Saito A,
Yagi H, Shimbo M, Soma K, Numata G, Fujiwara
T, Takeda N, Komuro I. Prognostic value offollow-up vasoreactivity test in pulmonary arterial
hypertension. J Cardiol. 2023 Jul;82(1):69-75.
Yamada T, Nomura S, Amiya E, Katoh M, Inoue
S, Hatsuse S, Fujita K, Ito M, Fujita T, Bujo C,
Tsuji M, Ishida J, Ko T, Yamada S, Katagiri M,
Sassa T, Kinoshita O, Nawata K, Tobita T, Satoh
M, Ishiwata J, Daimon M, Tatsuno K, Fukuda S,
Kashimura T, Minamino T, Hatano M, Ono M,
Aburatani H, Komuro I. LMNA Mutations andRight Heart Failure in Patients With
Cardiomyopathy and With Left Ventricular Assist
Devices. J Card Fail. 2023 May;29(5):855-857.
Atsukawa M, Tsubota A, Kondo C, Koyano KS,
Ishikawa T, Toyoda H, Takaguchi K, Watanabe T,
Matsuura K, Ogawa C, Hiraoka A, Okubo H,
Tateyama M, Uojima H, Nozaki A, Chuma M,

Kato K, Mikami S, Tani J, Morishita A, Kawata K,
Tada T, Furuichi Y, Okubo T, Kawano T, Arai T,
Kawabe N, Kawamura N, Ikegami T, Nakamuta M,
Shigefuku R, Iwasa M, Tanaka Y, Hatano M,
Iwakiri K. Risk factors for portopulmonary
hypertension in patients with cirrhosis: aprospective, multicenter study. Hepatol Int. 2023
Feb;17(1):139-149.
8. Dai Z, Ko T, Fujita K, Nomura S, Uemura Y,
Onoue K, Hamano M, Katoh M, Yamada S,
Katagiri M, Zhang B, Hatsuse S, Yamada T, Inoue
S, Kubota M, Sawami K, Heryed T, Ito M, Amiya
E, Hatano M, Takeda N, Morita H, Yamanishi Y,
Saito Y, Komuro I. Myocardial DNA Damage
Predicts Heart Failure Outcome in Various
Underlying Diseases. JACC Heart Fail. 2023
Oct 28:S2213-1779(23)00680-7.
9. Hosokawa K, Abe K, Funakoshi K, Tamura Y,
Nakashima N, Todaka K, Taniguchi Y, Inami T,
Adachi S, Tsujino I, Yamashita J, Minatsuki S,
Ikeda N, Shimokawahara H, Kawakami T, Ogo T,
Hatano M, Ogino H, Fukumoto Y, Tanabe N,
Matsubara H, Fukuda K, Tatsumi K, Tsutsui H.
Long-term outcome of chronic thromboembolic
pulmonary hypertension using direct oral
anticoagulants and warfarin: a Japanese prospective cohort study. J Thromb Haemost. 2023
Aug;21(8):2151-2162.
10. Purevsuren M, Uehara M, Ishizuka M, Suzuki Y,
Shimbo M, Kakuda N, Ishii S, Sumida H,
Miyazaki M, Yamashita T, Yoshizaki A, Asano Y,
Sato S, Hatano M, Komuro I.
Native T1
mapping in early diffuse and limited systemicsclerosis, and its association with diastolic
function. J Cardiol. 2023 Aug;82(2):100-107.
11. Ishii S, Minatsuki S, Hatano M, Saito A, Yagi H,
Shimbo M, Soma K, Fujiwara T, Itoh H, Konoeda
C, Sato M, Takeda N, Daimon M, Nakajima J,
Komuro I. The ratio of TAPSE to PASP predicts
prognosis in lung transplant candidates withpulmonary arterial hypertension. Sci Rep. 2023
Mar 7;13(1):3758.
12. Ishii S, Fujiwara T, Yagi H, Takeda N, Ando M,
Yamauchi H, Inuzuka R, Taniguchi Y, Hatano M,
Komuro I.A novel pathogenic variant located just
upstream of the C-terminal Ser423-X-Ser425
phosphorylation motif in SMAD3 causing Loeys-

487

13.

14.

15.

16.

17.

18.

Dietz syndrome. Mol Genet Genomic Med.
2023 Dec;11(12):e2257.
Yagi H, Amiya E, Uehara M, Minatsuki S, Hatano
M, Takeda N, Akazawa H, Komuro I. Coronary
Periarteritis and Pericardial Thickening Could Be
Predictors for Coronary Artery Events
Complicated by IgG4-Related Disease.
CJC
Open. 2023 Mar 17;5(6):480-489.
Tsuji M, Kakuda N, Bujo C, Saito A, Ishida J,
Amiya E, Hatano M, Shimada A, Imai H, Kimura
M, Ando M, Kinoshita O, Yamauchi H, Komuro I,
Ono M. Prophylactic negative pressure woundtherapy is not effective for preventing driveline
infection following left ventricular assist device
implantation. Artif Organs. 2023 Mar;47(3):566-573.
Inoue S, Ko T, Nomura S, Yamada T, Zhang B, Dai
Z, Jimba T, Katoh M, Ishida J, Amiya E, Hatano
M, Takeda N, Morita H, Ono M, Komuro I.
Compound Heterozygous Truncating Variants in
the BAG5 Gene As a Cause of Early-Onset Dilated
Cardiomyopathy. Circ Genom Precis Med. 2023
Dec;16(6):e004282.
Kakuda N, Amiya E, Hatano M, Ishida J, Tsuji M,
Bujo C, Yagi H, Fujita K, Ishii S, Isotani Y,
Kurihara T, Numata G, Gyoten T, Shimada S,
Ando M, Ono M, Komuro I Effect of renal
function under left ventricular assist device
support on the cardiac function and clinical events
after heart transplantation.
Clin Transplant.
2023 Dec;37(12):e15107.
Hosokawa K, Watanabe H, Taniguchi Y, Ikeda N,
Inami T, Yasuda S, Murohara T, Hatano M,
Tamura Y, Yamashita J, Tatsumi K, Tsujino I,
Kobayakawa Y, Adachi S, Yaoita N, Minatsuki S,
Todaka K, Fukuda K, Tsutsui H, Abe K;
KABUKI Investigators. A Multicenter, SingleBlind, Randomized, Warfarin-Controlled Trial of
Edoxaban in Patients With Chronic Thromboembolic Pulmonary Hypertension: KABUKI Trial.
Circulation. 2023 Nov 13.
Gyoten T, Amiya E, Kinoshita O, Tsuji M, Kimura
M, Hatano M, Ono M. Clinical outcomes ofcontinuous flow left ventricular assist device
therapy as bridge to transplant strategy inmuscular dystrophy: a single-center study. Gen
Thorac Cardiovasc Surg. 2023 Jun;71(6):347-353.

19. Yanase T, Hatano M, Bujo C, Tsuji M, Ishida J,
Amiya E, Okamoto K, Ando M, Shimada S,
Kinoshita O, Fukushi S, Yamada S, Ono M,
Komuro I. Successful Treatment with Letermovirin a Heart Transplant Recipient with UL97
Mutation Ganciclovir-Resistant Cytomegalovirus
Colitis and Viremia. Int Heart J. 2023 Mar 31;
64(1):95-99.
20. Hirose K, Minatsuki S, Saito A, Yagi H, Takeda N,
Hatano M, Komuro I. Impact of psychiatricdisorders on the hemodynamic and quality of life
outcome of balloon pulmonary angioplasty inpatients with chronic thromboembolic pulmonary
hypertension: a retrospective study. Respir Res.
2023 Nov 11;24(1):274.
21. Sawano S, Miura M, Higashikuni Y, Saigusa H,
Kodera S, Takeda N, Hatano M, Ando J, Ono M,
Komuro I.Clinical valve thrombosis and arterial
embolism in a cancer patient after transcatheter
aortic valve replacement. Oxf Med Case Reports.
2023 Nov 28; 2023(11):omad125. doi: 10.1093/
omcr/omad125.
22. Shindo A, Ueda K, Minatsuki S, Nakayama Y,
Hatsuse S, Fujita K, Nomura S, Hatano M, Takeda
N, Akazawa H, Komuro I. Novel AGL variants
in a patient with glycogen storage disease type IIIb
and pulmonary hypertension caused by pulmonaryveno-occlusive disease: A case report. Front
Genet. 2023 Mar 23;14:1148067.
23. Kurihara T, Amiya E, Hatano M, Ishida J,
Minatsuki S, Inoue S, Nomura S, Morita H,
Komuro I. Multivessel Coronary Artery
Dissection in a Patient with Co-Occurrence ofAortic Dissection and Dilated Cardiomyopathy in
the Postpartum Period. Diseases. 2023 Dec 10;
11(4):178.

488

Department of Clinical Genomics
Director & Professor
Katsutoshi Oda, M.D., Ph.D.

Project Associate Professor
Hidenori Kage, M.D., Ph.D.

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

Organization
The Department of Clinical Genomics started as a
special unit providing clinical genomics services in
2003. The department functions as the core unit toprovide genetic counseling services to support anappropriate and efficient application of genetic testing,as well as genomic medicine in cancer. The department also provides a training program for physicians
preparing for board-certified clinical geneticists.
Many medical staffs with diverse specialties including
pediatricians, obstetricians, neurologists, cardiologists diabetologists and surgeons participate in theactivities of the Department.

Activities
Genetic Counseling
The room (Room 200) is specifically allocated in
the outpatient clinic. Genetic counseling is performed
by a team of board-certified clinical geneticist andcertified genetic counselors in cooperation with otherclinical departments. All cases are reviewed anddiscussed at the conference which is held once every
month. We also provide support to clinicaldepartments for establishing genetic diagnosis invarious types of diseases, including neurologicaldisorder, pediatric and perinatal disorders, Marfan’sSyndrome and Hereditary Breast and Ovarian Cancer.
Genomic Medicine in Cancer
We provide cancer genomic profiling (clinicalsequencing) for incurable malignant solid tumors with12 collaborative hospitals, as a “Cancer Genome Core
Hospital”. Two types of cancer genomic profiling(OncoGuideTM NCC Oncopanel System, Foundation
One® CDx Cancer Genomic Profililng) wereapproved by PMDA in June, 2019. FoundationOne®
Liquid CDx Cancer Genomic Profililng was also
approved in 2021. As well, we provide an original
multiplex genome sequencing, named "Todai
OncoPanel”, which is composed of DNA panel andRNA panel. The Todai Oncopanel was approved as aname of “GenMineTOP” for manufacturing andmarketing from the Ministry of Health, Labour andWelfare in 2022. The room (Room 202) is specificallyallocated in the outpatient clinic for genomic
medicine in cancer (twice weekly).

Publications
1.

2.

Tanaka M, Shinozaki-Ushiku A, Kunita A,
Yasunaga Y, Akamatsu N, Hasegawa K, Ushiku
T: High-grade transformation of pancreatic
neuroendocrine tumor associated with TP53
mutations: A diagnostic pitfall mimicking
neuroendocrine carcinoma. Pathol Int. 2022
Aug;72(8):411-418.
Kage H, Kohsaka S, Tatsuno K, Ueno T, Ikegami
M, Zokumasu K, Shinozaki-Ushiku A, Nagai S,
Aburatani H, Mano H, Oda K: Tumor mutationalburden measurement using comprehensive
genomic profiling assay. Jpn J Clin Oncol. 2022
Aug 5;52(8):925-929.

489

3.

4.

5.

6.

7.

8.

Taguchi A, Rokutan H, Oda K, Tanikawa M,
Tanimoto S, Sone K, Mori M, Tsuruga T,
Kohsaka S, Tatsuno K, Shinozaki-Ushiku A,
Miyagawa K, Mano H, Aburatani H, Ushiku T,
Osuga Y: Genetic diagnosis of pseudomyxoma
peritonei originating from mucinous borderline
tumor inside an ovarian teratoma. BMC Med
Genomics. 2022 Mar 7;15(1):51.
Ando T, Kage H, Shinozaki-Ushiku A, Tatsuno
K, Tsutsumi S, Nagayama K, Nakajima J,
Kohsaka S, Miyagawa K, Aburatani H, Mano H,
Nagase T: Composite Clonal Analysis Reveals
Transition of NSCLC Subtypes ThroughAccumulation of Gene Mutations: A Case Report.
JTO Clin Res Rep. 2022 Jan 10;3(2):100277.
Naito Y, Sunami K, Kage H, Komine K, Amano
T, Imai M, Koyama T, Ennishi D, Kanai M,
Kenmotsu H, Maeda T, Morita S, Sakai D,
Watanabe K, Shirota H, Kinoshita I, Yoshioka M,
Mamesaya N, Ito M, Kohsaka S, Saigusa Y,
Yamamoto K, Hirata M, Tsuchihara K, Yoshino
T: Concordance Between Recommendations
From Multidisciplinary Molecular Tumor Boards
and Central Consensus for Cancer Treatment inJapan. JAMA Netw Open. 2022 Dec 1;5(12):e2245081.
Sunami K, Naito Y, Komine K, Amano T,
Ennishi D, Imai M, Kage H, Kanai M, Kenmotsu
H, Koyama T, Maeda T, Morita S, Sakai D,
Kohsaka S, Tsuchihara K, Saigusa Y, Yoshino T:
Chronological improvement in precisiononcology implementation in Japan. Cancer Sci.
2022 Nov;113(11):3995-4000.
Imai M, Nakamura Y, Sunami K, Kage H,
Komine K, Koyama T, Amano T, Ennishi D,
Kanai M, Kenmotsu H, Maeda T, Morita S, Sakai
D, Bando H, Makiyama A, Suzuki T, Hirata M,
Kohsaka S, Tsuchihara K, Naito Y, Yoshino T:
Expert panel consensus recommendations on theuse of circulating tumor DNA assays for patientswith advanced solid tumors. Cancer Sci. 2022
Nov;113(11):3646-3656.
Amano Y, Kage H, Tanaka G, Sato Y, Tanaka M,
Nagase T: Multiple Brain Metastases in a Patient
with
ROS1
Fusion-Positive
Lung
Adenocarcinoma as a Disease Flare due to
Crizotinib Cessation Caused by DisseminatedAseptic
Inflammation
from
CrizotinibAssociated Renal Cysts: A Case Report. Case
Rep Oncol. 2022 Mar 30;15(1):338-344.
9. Yamamoto K, Chang H, Fukushima A: Pregnant
women's experiences of non-invasive prenatal
testing (NIPT) in Japan: A qualitative study. J
Genet Couns. 2022 Apr;31(2):338-355.
10. Itamiya T, Komai T, Kanda H, Nagafuchi Y,
Chang H, Shibata S, Ishiura H, Shoda H, Toda T,
Fujio K: Efficacy of canakinumab on AA
amyloidosis in late-onset NLRP3-associatedautoinflammatory disease with an I574F somatic
mosaic mutation. Clin Rheumatol. 2022 Jul;
41(7):2233-2237..
11. Yagi H, Takeda N, Amiya E, Akiyama N, Chang
H, Ishiura H, Sato J, Akazawa H, Morita H,
Komuro I: PNonsyndromic arteriopathy andaortopathy and vascular Ehlers-Danlos syndrome
causing COL3A1 variants. Am J Med Genet A.
2022 Sep;188(9):2777-2782.
12. Ebihara T, Nagatomo T, Sugiyama Y, Tsuruoka
T, Osone Y, Shimura M, Tajika M, Ichimoto K,
Naruke Y, Akiyama N, Lim SC, Yatsuka Y, Nitta
KR, Kishita Y, Fushimi T, Okazaki A, Ohtake A,
Okazaki Y, Murayama K: Severe spinal cord
hypoplasia due to a novel ATAD3A compound
heterozygous deletion. Mol Genet Metab Rep.
2022 Aug 24;33:100912.
13. Ando T, Kage H, Shinozaki-Ushiku A, Tatsuno K,
Tsutsumi S, Nagayama K, Nakajima J, Kohsaka
S, Miyagawa K, Aburatani H, Mano H, Nagase T.
Composite Clonal Analysis Reveals Transition of
NSCLC Subtypes Through Accumulation ofGene Mutations: A Case Report. JTO Clin Res
Rep. 2022 Jan 10;3(2):100277.

490

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

Homepage

http://kokoro.umin.jp/

Introduction and Organization
The Department of Child Psychiatry wasestablished in April 2005 as the clinical counterpart to
the Clinical Education Center of Mental Development,
both of which are funded by the special grant forfaculty development. The major aim of the Clinical
Education Center is to train mental health specialists
in various fields with a fundamental grounding inchild psychiatry and neurosciences. Much of theservices provided are based on the 39 years ofexperience in intervention and treatment for developmentally disabled children established in the former
child psychiatry division of Department of Neuropsychiatry. Our department uses a multidisciplinary
approach by working in collaboration not only with
the Department of Neuropsychiatry, Department ofPediatrics and Graduate School of Education in the
University of Tokyo but also several other educational
and/or clinical facilities on mental development ordevelopmental disorders. The Department of Child
Psychiatry complemented the Clinical Education
Center by providing fieldwork for clinical training andoffered clinical services to patients with various
development problems also.
The Clinical Education Center of Mental Development was closed in March 2010 because of time limitof the fund, and Department of Child Neuropsychiatry,
Graduate School of Medicine was established in April
2010. The Department of Child Psychiatry, as theclinical counterpart to the department in graduate
school, focuses on clinical activity related to research
as well as quality practice of child psychiatry andeducation of leading child psychiatrists and allied
professionals. In addition to professors of the graduate
school, 2 psychiatrists and 3 psychologists (2 full-timeones for a definite term and 1 part-time one) areofficially assigned to the Department of Child
Psychiatry. One psychiatric social worker works
mainly for the Department of Child Psychiatry since2013 also.

Clinical activities
In the year 2022, 9 psychiatrists and 4 psychologists(full-time and part-time) and 1 psychiatric social
worker are in charge of treatment at the Department ofChild Psychiatry. Although patients with various
disorders are seen, the focus of the department ismainly on patients with developmental disorders. We
offer services to patients with a broad range ofdevelopmental disorders including Autism Spectrum
Disorder (ASD), Attention-Deficit/Hyperactivity Disorder (ADHD), Learning Disabilities (LD), Intellectual
Disability (ID), tic disorders, and child & adolescentObsessive-Compulsive Disorders (OCD).
Number of new patients in 2022 was 217, which is
not as high as in 2019 before the COVID-19 pandemic,
but compared to 173 in 2020, the number of newpatients is on a recovery track. Out of 217 patients,
children of elementary school age were 80, andchildren of junior high school age were 30. In otherwords, children of elementary or junior high school
age were more than half of the patients. Number ofpreschool children was 86, suggesting our response toongoing needs for early 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

491

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.
Furthermore,asacross-department
andcross-divisional activity, Children, AYA and Family
centered Mental Care Center was established in
January 2022, and we are playing a central role in its
practice.

Education
Undergraduates of the University of Tokyo haveopportunities to participate in an assessment anddiagnosis session at the general first visit outpatient
clinic and intervention for preschool children.
Graduate students in clinical psychology course fromthe University of Tokyo participate in intervention forpreschoolers also.
One month training course is offered to juniorresidents especially in pediatric specialty course. This
course includes intake interview of first visit patients,
attendance for assessment and treatment for follow-up
patients, intervention for preschoolers, and theparent-training. Eighteen residents participated inthis course. For general psychiatrists including seniorresidents of the Department of Neuropsychiatry, an
inpatient program of assessment about developmental
disorders is provided as opportunity to get knowledge
and experience of developmental disorders.

Research
We participate in investigation of etiology anddevelopment of effective treatment on ASD and
ADHD, which are organized in collaboration with the
Department of Neuropsychiatry and other research,educational and clinical facilities. In addition, research
related specifically to the clinical activities in the
Department of Child Psychiatry is currently being
investigated.
Clinical evaluation and treatment
Effectiveness study of early intervention for autisticpreschoolers is being undertaken. We focused oninvestigating early intervention including treatment
for children and parent support.
We are also considering support for transition fromkindergarten/nursery school to elementary school forchildren with ASD.
Effectiveness of a program of group cognitive

492

behavior therapy for adults with high-functioning
ASD is investigated in a randomized control trial.
We are also analyzing the data obtained from
“inpatient assessment on developmental disorders”
program.
In order to develop predictor of parent training for
ADHD, we are collecting and analyzing data.
The possible relations among clinical characteristics
such as tics and obsessive-compulsive symptoms in
Tourette syndrome (chronic tic disorder with multiple
motor tics and one or more vocal tics) and child &adolescent OCD are being evaluated.
Comprehensive Behavioral Intervention for Tics
(CBIT) is provided for children and adolescents with
Tourette syndrome, and investigation of its
effectiveness is undertaken. We have developed
internet-based psychoeducational materials that willlead to CBIT, and have begun investigating theireffectiveness. We are also trying to develop an
objective assessment of tics.
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.
We are also continuing to analyze the findings ofour survey of tics and related behaviors in community
preschoolers.
Neuropsychological research
Neuropsychological data on ASD, ADHD andTourette syndrome are being collected. Analysis of therelations among neuropsychological findings and theclinical evaluation are being conducted.
Neuroimaging
Studies include structural MRI, Near-Infrared Spectroscopy (NIRS) and functional MRI with exploring
the pathogenesis of developmental disorders such as
ASD and ADHD.

References1.

Kuroda M, Kawakubo Y, Kamio Y, Yamasue H,
Kono T, Nonaka M, Matsuda N, Kataoka M,
Wakabayashi A, Yokoyama K, Kano Y,
Kuwabara H. Preliminary efficacy of cognitive-

2.

3.

4.

5.

behavioral therapy on emotion regulation in
adults with autism spectrum disorder, A pilot
randomized waitlist-controlled study. PLoS One,17(11): e0277398, 2022.
Tanaka M, Kanehara A, Morishima R, Yousuke
Kumakura Y, Okouchi N, Nakajima N, Hamada J,
Ogawa T, Tamune H, Nakahara M, Jinde S, Kano
Y, Kasai K. Educational challenges for 22q11.2
deletion syndrome in Japan: Findings from amixed methods survey. J Appl Res Intellect
Disabil, 36(3): 558-570, 2023.
Ishikawa N, Ishizuka Y, Kano Y, Iida J,
Yamamoto J. Exploring factors of successfultransition to elementary school among children
with autism spectrum disorder in Japan: a focus
group
study,
International
JournalofDevelopmental Disabilities, 1-10, 2022.
Nogami W, Nakagawa A, Katayama N, Kudo Y,
Amano M, Ihara S, Kurata T, Kobayashi Y,
Sasaki Y, Ishikawa N, Sato T, Mimura M. Effectof Personality Traits on Sustained Remission
Among Patients with Major Depression: A
12-Month Prospective Study. Neuropsychiatr Dis
Treat, 18: 2771-2781, 2022.
Suzuki A, Yamaguchi R, Kim L, Kawahara T,
Ishii-Takahashi A. Effectiveness of mockscanners and preparation programs for successful
magnetic resonance imaging: a systematic review
and meta-analysis. Pediatr Radiol, 53(1): 142-158,
2023.

493

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494collaborate 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.

495･ 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.

2.

3.

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.

Abe H, Sumitani M, Matsui H, Inoue R, Konishi
M, Fushimi K, Uchida K, Yasunaga H.
Gabapentinoid use is associated with reduced
incidence of hyperactive delirium in elderly
cancer patients undergoing chemotherapy: a

4.

5.

6.

7.

nationwide retrospective cohort study in Japan.
Anesthesia & Analgeisa 2022; 135: 362-9
Mietani K, Hasegawa-Moriyama M, Yagi K,
Inoue R, Ogata T, Kurano M, Shimojo N, Seto Y,
Sumitani M, Uchida K. Preoperative detection ofserum phosphorylated neurofilament heavy chain
subunit predicts postoperative delirium: A
prospective observational study. J Gerontol
Geriatr 2022; 70: 169-77
Ando M, Sumitani M, Fuyuki M, Abe H, Shinoda
Y, Matsubayashi Y, Oshima Y, Inoue R, TsuchidaR, Uchida K. Imaging features inferring symptom
onset due to spinal metastasis progression: A
preliminary study. Ann Palliat Med 2022; 11:2247-56
Abe H, Sumitani M, Matsui H, Inoue R, Fushimi
K, Uchida K, Yasunaga H. Use of naldemedine isassociated with reduced incidence of hyperactive
delirium in cancer patients with opioid-induced
constipation: a nationwide retrospective cohort
study in Japan. Pharmacotherapy: Journal of
Human Phramacology and Drug Therapy 2022;
42: 241-9
Inoue R, Sumitani M, Otake Y, Ohya R, Tsuchida
R, Konishi M, Abe H, Uchida K. Augmented
reality-supported exercise therapy system
improves physical frailty and musculoskeletal
pain: a preliminary feasibility study. J Muscle
Health 2022; 4: 1013
Kurisu K, Inada S, Maeda I, Ogawa A, Iwase S,
Akechi T, Morita T, Imai K, Nakahara R,
Kaneishi K, Nakajima N, Sumitani M, Yoshiuchi
K. Decision tree prediction model for outcome ofpharmacological treatment of delirium inadvanced cancer patients: Pharmacological adultstudy of safety and efficacy in real world(Phase-R). Palliat Support Care 2022; 20: 153-8
Saita K, Sumitani M, Nishizawa D, Tamura T,
Ikeda K, Wakai K, Sudo Y, Abe H, Otonari J,
Takeuchi K, Hishida A, Tanaka K, Shimanoe C,
Takezaki T, Ibusuki R, Oze I, Ito H, Ozaki E,
Matsui D, Nakamura Y, Kusakabe M, Suzuki S,
Nakagawa-Senda
H,
Arisawa
K,
Katsuura-Kamano S, Kuriki K, Kita Y. Genetic
polymorphism of pleiotrophin is associated withpain experience in Japanese adults: case-control
study. Medince (Baltimore) 2022; 101: e30580

496

8.

Mietani K, Hasegawa-Moriyama M, Inoue R,
Ogata T, Shimojo N, Kurano M, Yatomi Y,
Uchida K, Sumitani M. Serum levels of
apolipoprotein A-1 and E are associated withpostoperative delirium: A post-hoc analysis.
Medince (Baltimore) 2022; 101: e29906
9. Hao X, Zhou Y, Ling Y, Feng Z, Miyoshi H,
Sumitani M, Chan KY, Park HJ, Rao Y. Effects ofhigh-dose opioid analgesia on survival, pain
relief, quality of life and adverse drug reactions
in cancer and neuropathic pain patients: aretrospective cohort study in real-world clinicalpractice. Ann Transl Med 2022; 10: 998
10. Edamura T, Sumitani M, Hayakawa K, Inoue R,
Abe H, Tsuchida R, Chikuda H, Ogata T, Kurano
M, Aoki J, Yatomi Y, Uchida K. Different profilesof the triad of lysophosphatidylcholine,
lysophosphatidic acid and autotaxin in patientswith neuropathic pain diseases: a preliminary
observational study. Pain and Therapy 2022; 11:1439-49
11. Mietani M, Hasegawa-Moriyama M, Yagi K,
Inoue R, Ogata T, Shimojo N, Seto Y, Uchida K,
Sumitani M. Elevation of serum plasminogenactivator inhibitor-1 predicts postoperativedelirium independent of neural damage: A
sequential analysis. Scientific Reports 2022; 12:17091
12. Abe H, Inoue R, Tsuchida R, Ando M, Saita K,
Konishi M, Edamura T, Ogawa A, Matsuoka Y,
Sumitani M. Efficacy of treatments for pain andnumbness in cancer survivors: a systematic
review and meta-analysis. Ann Palliat Med 2022;
11: 1439-49（And, 9 Japanese articles）

University Hospital
Central Clinical Services

498

Department of Pharmacy
Professor
Tappei Takada, Ph.D.

Lecturer
Yoshihide Yamanashi, Ph.D.,

Masashi Honma, Ph.D.

Research Associate
Takahiro Amemiya, Ph.D.,

Yuki Ikebuchi, Ph.D.,

Hiroshi Miyata, Ph.D.,

Atsushi Tokuda, M.Sc.,

Yusuke Nagae, M.Sc.

Homepage

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

Introduction and Organization
We have 8 faculty members, 84 pharmacy staffs,
and 8 graduate students and 9 undergraduate students
from the faculty of pharmaceutical sciences (as ofMarch 1st, 2023).

Clinical activities
Department of Pharmacy consists of the following
six sections:1) Drug information 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) for all of the administrationin the hospital. In order to support advanced
medical care, they develop and check
formulations (characterization of the uniformity,
stability and so on) of the medicine that 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 (2,724
items), out-patient medicines, anesthetics, muscle
relaxation drugs, psychotropic drugs, poison

499

medicines.
5) 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 2022)
Number of items on in-hospital formulary: 2,724
Number of prescriptions (ps.) filled or preparation(pp.) (annual)out-patients:
333,593 ps.
(outside :303,334 ps.)(inside :30,259 ps.)out-patient chemotherapy:
19,940 ps.
in-patients :233,796 ps.
injection drugs:
194,504 ps.
IVH:
4,529 pp.
chemotherapy:
12,053 pp.
TDM consultations (annual) :22,000 pp.
Numbers of hospital pharmaceutical cares (annual):
24,027 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

500

this system, the clinical training by pharmacists at thehospital is one of the most important curriculums. In
2021, we accepted clinical training students from The
University of Tokyo, Tokyo University of Pharmacy
and Life Sciences, Showa Pharmaceutical University,
Hoshi University, and Musashino University, Tokyo
University of Science, Keio University and educatedthem for 2.5 months. In addition, we have had an
original one-year post-graduate training course forpharmacists since long time before starting the 6-year
course education system. They learned various
practical knowledge and techniques necessary for
hospital pharmacists. Such education style is still
continuing by shortening the period to half a year. In
2022, 10 pharmacists finished this course.
In addition, we are promoting life-long education ofpharmacists in the local area by holding regular
technical workshops and seminars.

(2)

(3)

(4)

(5)

Research
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) Chang SJ, Toyoda Y, Kawamura Y, Nakamura T,
Nakatochi M, Nakayama A, Liao WT, Shimizu S,
Takada T, Takeuchi K, Wakai K, Shi Y, Shinomiya
N, Chen CJ, Li C, Okada Y, Ichida K, Matsuo H,
for Japan Gout Genomics C. A meta-analysis of
genome-wide association studies using Japanese

(6)

(7)

(8)

(9)

and Taiwanese has revealed novel loci associatedwith gout susceptibility. Hum Cell. 2022;35:76770.
Fujii E, Takata T, Yamano H, Honma M,
Shimokawa M, Sasaki H, Shikano M. Study on
horizon scanning by citation network analysis andtext mining: A focus on drug development related to
T cell immune response. Ther Innov Regul Sci.
2022;56:230-43.
Kariya Y, Honma M, Tokuda K, Konagaya A,
Suzuki H. Utility of constraints reflecting systemstability on analyses for biological models. PLoS
Comput Biol. 2022;18:e1010441.
Miyata H, Toyoda Y, Takada T, Hiragi T, Kubota Y,
Shigesawa R, Koyama R, Ikegaya Y, Suzuki H.
Identification of an exporter that regulates vitamin
C supply from blood to the brain. iScience. 2022;
25:103642.
Nakayama A, Kawamura Y, Toyoda Y, Shimizu S,
Kawaguchi M, Aoki Y, Takeuchi K, Okada R, Kubo
Y, Imakiire T, Iwasawa S, Nakashima H, Tsunoda
M, Ito K, Kumagai H, Takada T, Ichida K,
Shinomiya N, Matsuo H. Genetic epidemiologicalanalysis of hypouricaemia from 4993 Japanese on
non-functional variants of URAT1/SLC22A12 gene.
Rheumatology (Oxford). 2022;61:1276-81.
Takata T, Sasaki H, Yamano H, Honma M, Shikano
M. Study on horizon scanning with a focus on thedevelopment of AI-based medical products:
Citation network analysis. Ther Innov Regul Sci.
2022;56:263-75.
Tomabechi R, Kishimoto H, Sato T, Saito N,
Kiyomiya K, Takada T, Higuchi K, Shirasaka Y,
Inoue K. SLC46A3 is a lysosomal proton-coupledsteroid conjugate and bile acid transporter involvedin transport of active catabolites of T-DM1. PNAS
Nexus. 2022;1:pgac063.
Toyoda Y, Cho SK, Tasic V, Pavelcova K, Bohata J,
Suzuki H, David VA, Yoon J, Pallaiova A, Saligova
J, Nousome D, Cachau R, Winkler CA, Takada T,
Stiburkova B. Identification of a dysfunctional
exon-skipping splice variant in GLUT9/SLC2A9
causal for renal hypouricemia type 2. Front Genet.
2022;13:1048330.
Toyoda Y, Kawamura Y, Nakayama A, Morimoto K,
Shimizu S, Tanahashi Y, Tamura T, Kondo T, Kato
Y, Ichida K, Suzuki H, Shinomiya N, Kobayashi Y,

501

Takada T, Matsuo H. OAT10/SLC22A13 acts as arenal urate re-absorber: Clinico-genetic andfunctional analyses with pharmacological impacts.
Front Pharmacol. 2022;13:842717.
(10) Toyoda Y, Takada T, Saito H, Hirata H,
Ota-Kontani A, Tsuchiya Y, Suzuki H.
Identification of inhibitory activities of dietaryflavonoids against URAT1, a renal urate
re-absorber: In vitro screening and fractional
approach focused on Rooibos leaves. Nutrients.
2022;14:575.
(11) Yamanashi Y, Takada T, Tanaka Y, Ogata Y, Toyoda
Y, Ito SM, Kitani M, Oshida N, Okada K, Shoda J,
Suzuki H. Hepatic Niemann-Pick C1-like 1
exacerbates non-alcoholic fatty liver disease by
re-absorbing specific biliary oxysterols. Biomed
Pharmacother. 2022;156:113877.

502

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 2022, 223,213 outpatient blood
sampling were performed in this section. Furthermore,
271,757 urine samples were examined.
The 2nd Section
This section deals with clinical biochemistry andimmuno-serology tests. In 2022, 5,550,003 serum

enzyme tests (such as AST and ALT), and 566,479
immunological tests were performed.
The 3rd Section
This section deals with laboratory hematology anddiabetes-related tests, and gene analysis tests. In
2022, 1,180,677 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 2022, 44,781 ECG, 19,252
pulmonary function tests, and 12,064 EEG were
performed.
The 5th Section
This section deals with ultrasonography. In 2022,
7,163 echocardiography tests, 14,148 abdominal
echography tests, and 13,362 other ultrasonography
tests were performed.

503

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. As educational facilities
for certified clinical laboratory physicians, we havebeen training up many physicians.

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) cancer genomic medicine
using
next
generation
sequencing,iv)
echocardiographic studies of the pathophysiology of
valvular heart disease and the hemodynamics, v)
neuroscience research using magnetoencephalography
and non-invasive brain stimulation, and vi) promotionof medical-engineering cooperation.

References
Original article:
1. Addetia, K., Miyoshi, T., Amuthan, V., Citro, R.,
Daimon, M., Fajardo, P.G., Kasliwal, R.R.,
Kirkpatrick, J.N., Monaghan, M.J., Muraru, D.,
Ogunyankin, K.O., Park, S.W., Ronderos, R.E.,

5.

6.

Sadeghpour, A., Scalia, G.M., Takeuchi, M., Tsang,W., Tucay, E.S., Tude Rodrigues, A.C., Zhang, Y.,
Hitschrich, N., Blankenhagen, M., Degel, M.,
Schreckenberg, M., Mor-Avi, V., Asch, F.M., andLang, R.M. Normal values of left ventricular sizeand function on 3D echocardiography: Results of
the
World
AllianceofSocietiesof
Echocardiography
Study.
J.
Am.
Soc.
Echocardiogr. 35: 449-459, 2022.
Bujo, S., Amiya, E., Hashimoto Maeda, M., Ishida,J., Hatano, M., Ishizuka, M., Uehara, M., Oshima,T., Kojima, T., Nakanishi, K., Daimon, M.,
Shimizu, J., Toda, T., and Komuro, I. The effect of
immunosuppressive therapy on cardiac involvements in anti-mitochondrial antibody-positive
myositis. ESC Heart Fail. 9: 4112-4119, 2022.
Chaichuum, S., Chiang, S.J., Daimon, M., Chang,
S.C., Chan, C.L., Hsu, C.Y., Chen, H.H., and Tseng,
C.L. Segmental tissue speckle tracking predicts the
stenosis severity in patients with coronary arterydisease. Front. Cardiovasc. Med. 8: 832096, 2022.
Edamura, T., Sumitani, M., Hayakawa, K., Inoue,
R., Abe, H., Tsuchida, R., Chikuda, H., Ogata, T.,
Kurano, M., Aoki, J., Yatomi, Y., and Uchida, K.
Different
Profiles
of
the
Triad
of
Lysophosphatidylcholine, Lysophosphatidic Acid,and Autotaxin in Patients with Neuropathic Pain
Diseases: a Preliminary Observational Study. Pain
Ther. 11: 1439-1449, 2022.
Fujikura, Y., Kimura, K., Yamanouchi, K.,
Sugihara, H., Hatakeyama, M., Zhuang, H.,
Daimon, M., Morita, H., Komuro, I., and Oishi, K.
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507

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

Deputy Director
Masako Ikemura, M.D., Ph.D. (Lecturer, Office for “Promotion of CPC Education andGeneral Integrative Medicine”)
Aya Shinozaki-Ushiku, M.D., Ph.D. (Associate Professor, Division of Integrative Genomics)

Project Professor
Takeshi Sasaki, M.D., Ph.D. (Next-Generation Pathology Information Networking)Lecturer
Mariko Tanaka, M.D., Ph.D.
Hiroyuki Abe, M.D., Ph.D. (Department of Pathology and Diagnostic Pathology)

Research Associate
Ryohei Kuroda, M.D., Ph.D., Hirofumi Rokutan, M.D., Ph.D., Masaki Suzuki, Munetoshi
Hinata, M.D., Ph.D., Noritaka Kudo (~ Jun 30)
Akiko Iwasaki, M.D., Ph.D., Mayu Hakozaki, M.D., Ph.D., Atsushi Kondo, M.D., Ph.D.
(Department of Pathology and Diagnostic Pathology)
Yoichi Yasunaga, M.D., Ph.D. (~Jul 31 Department of Pathology and Diagnostic Pathology,
Aug 1~)

Homepage

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

Introduction and Organization
Department of Pathology and Diagnostic Pathology
and Department of Pathology of the University ofTokyo Hospital have been organized to function as aunit to perform pathology practice (autopsy, surgicalpathology, cytology, molecular testing, etc.) at the
University of Tokyo Hospital as well as education andresearch on human pathology.
We set up Telepathology & Remote Diagnosis
Promotion Center (TRDP Center) in 2013. We also
started Outpatient Clinic of Pathology to provide
detailed information and explanation about pathologic
diagnosis to the patients with breast cancer.
In February 2018, the University of Tokyo

Hospital was selected as one of the core hospitals to
promote cancer genomic medicine in Japan. From
August 2018 to December 2019, the advanced medicalcare (category B) named ‘Trial of a multiplex genomic
testing by "Todai OncoPanel" for Geneprofiling of
malignant solid tumors’ was conducted which enrolled
200 patients. In addition, cancer panel testing coveredby public health insurance (NCC Oncopanel andFoundationOne CDx) started in November 2019. We
serve as members of expert panel to contribute to thepromotion of genomic medicine.

Clinical activities(diagnostic pathology and autopsy)

The annual statistics of the pathology practice in 2022

508

fiscal year consisted of 17,566 surgical cases, 15,273
cytology, 862 intraoperative histologic diagnosis, 393
intraoperative cytology, 33 autopsy cases (autopsy rate,8.5%). The numbers of surgical and cytology cases
returned to those before COVID-19 pandemic, while
the numbers of intraoperative diagnosis and autopsy
cases remained small due to the pandemic. Fortunately,
there was no need to limit activity in our department.
The following surgical pathology conferences are
regularly held; thoracic organs (Drs. ShinozakiUshiku, Suzuki and Hinata in charge), liver andpancreato-biliary tract (Drs. 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 Yasunaga), kidney (Drs. Abe
and Hinata), and skin (Dr. Tanaka).
We provide FFPE specimens suitable formultiplex genomic testing. We also join clinicopathologic and genomic conference which is held
every week to present histology of the cases and join
the discussion. Conventional companion diagnoses
using immunohistochemistry and FISH/DISH are also
provided.
Our mission is to provide the correct diagnosis assoon as possible. We also perform double check byreviewing the reports and slides of all cases to assure
the quality of pathologic diagnosis. Whole slide
imaging system have been installed, which enabled us
to deposit and review all the biopsy specimens as
digital information in daily practice.
We hold autopsy case conferences every Monday.
Hospital clinico-pathologic conferences (CPC) arealso held every month, in which two cases are
discussed. The contents are provided as CPC Digest
through the hospital internet.

Teaching activities
The lectures and exercise course of systemic
pathology are for the 2nd grade medical students.
Clinical Clerkship (CC) courses of autopsy andsurgical pathology are for the 3rd and 4th grade medical
students. We accepted several medical students inElective Clerkship course as well as Free Quarter
program.
We instructed all clinical residents (junior course)

to submit a report of CPC case as an obligatory
requirement of their medical training. We have madeout the digest version of CPC slides open in thehospital and started e-learning program for interns tosolve the problems in CPC by themselves, thereby
facilitating their understanding.
The Department of Pathology accepted fourjunior residents (total 8 months) in 2022 for their firstand second-year program.

Research activities
We are working on the pathologic research projects ofneoplastic diseases based on observation obtained
from pathologic diagnosis as well as discussion withclinicians at surgical pathology conferences.
To develop AI-based pathology diagnosis system,some projects are currently in progress. Dr. Abe
focuses on gastrointestinal tract biopsy diagnosis
using machine learning. Dr. Hinata has developed an
automatic system to detect immunotherapy-sensitive
subtype in gastric cancer using histologic image-based
deep learning.
The development of automatic grossing andsectioning system using AI-equipped robot is also inprogress as collaborative research with engineering
faculty-of the University of Tokyo (Prof. Mamoru
Mitsuishi).
We continue the study to investigate the usefulness of post-mortem CT images for hospital autopsy
in collaboration with the department of radiology. We
obtain post-mortem images with a CT apparatus in the
autopsy-assisting CT room and compare the resultswith those of autopsy to better understand thepatients’ pathophysiology.
In addition, a lot of collaborative research
projects are also being conducted with various
departments and laboratories.

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15(6):1078-1082.
Sato D, Takayanagi S, Takami H, Iwamoto T,
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Hong SM, Kumarasinghe P, Lam AK, Lauwers G,
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Ishigami D, Hongo H, Dofuku S, Takami H,
Mitsui J, Ikemura M, Komura D, Katoh H,
Ushiku T, Ishikawa S, Shin M, Nakatomi H,
Saito N. Clinical significance of NF2 alteration ingrade I meningiomas revisited; prognostic impact
integrated with extent of resection, tumour
location, and Ki-67 index. Acta Neuropathol
Commun. 2022;10:76.

511

Radiology Center
Professor (Director)
Osamu Abe, M.D., Ph.D.

Lecturer (Vice Director)
Wataru Gonoi, M.D., Ph.D.

Assistant Professor
Go Shirota, M.D., Ph.D.

Chief Technologist (Vice Director)
Hideyuki Iwanaga, R.T.

Homepagehttps://www.h.u-tokyo.ac.jp/patient/depts/houshasenbu/

Introduction and Organization
Radiology Center was established in August 1964
as a part of the Central Clinical Services. Currently,
the Department consists of three divisions: Diagnostic
Radiology (imaging and intervention), Nuclear
Medicine, and Radiotherapy, in addition to Radiation
Safety Control Center. The center engages inradiology services such as various imaging
examinations, radiotherapy, and radiation safety
management.
The members are as follows: Professor Osamu Abe(Director, since Oct. 2016), Wataru Gonoi (ViceDirector/Lecturer), Go Shirota (Assistant Professor),
77 radiology technologists, including Chief
Technologist Hideyuki Iwanaga, and one technicalspecialist in charge of radiation control. In addition to
the above, Radiology Center is operated in corporation
with the staff radiologists, graduate students, andresidents of the Department of Radiology, as well as
physicians from other departments, nurses, andclinical engineering technicians of the Department ofClinical Laboratory. In recent years, the number ofradiological services has increased, and we are trying
to cope with this trend by improving work efficiency,
optimizing staffing, and introducing new equipment.
The development of technologies for advancing andimproving radiological practice is a cooperative effort

between physicians and radiologists. In addition to thefields of imaging and radiation therapy, theconstruction of image management systems, image
processing, and image transfer systems have become
essential themes in recent years. The radiology
information system (RIS) and diagnostic reporting
systems were digitalized in 1994. And a picturearchiving and communication system (PACS, thefilm-less imaging system) was introduced in thehospital in May 2003. To reduce and equalize theburden of radiologists, we started preparing for thetrial introduction of a new high-performance
diagnostic interpreting system in 2012 and launched a
new PACS system with deep learning-based software
in 2023. In the field of radiation safety control,
stimulated by the need to evaluate the individualaccumulated exposure dose by medical radiation, we
have started a working group to solve this problem.
We provide the individualized accumulated exposure
dose data on RIS. We also work for research on new
radiology techniques such as image-guided radiation
therapy, CT, MRI, PET, flat panel detector,
postmortem imaging, artificial intelligence, etc.

Clinical activities
1) Diagnostic Radiology Section:
The diagnostic radiology section is responsible for512

simple radiography (bone, chest, abdomen, head,
pediatric, breast, pelvic measurement), various
radiography with contrast mediums (gastrointestinal
tract, urinary tract), radiography in the operatingrooms, radiography in the emergency rooms,
outpatient radiography, portable radiography in
hospital wards, dental and oral radiography, bonemineral content determination, CT, MRI, angiography
and interventional radiology (IVR), image processing
and analysis (3D image reconstruction and analysis).
Most examinations are performed in the diagnostic
radiology section on the 1st floor of the Central
Clinical Services Building 1. Some are performed in
the MRI rooms, Surgical Center, Critical Care andEmergency Medical Center/ER, and some otherdepartments in the Central Clinical Services Building
2. The number of examinations, especially CT and
MRI, is dramatically increasing. Six multi-slice CT
machines (2 x 320-row, 1 x 256-row, 1 x 64-row CT, 2
x 80-row), 7 MRI machines (5 x 3T MRI, 2 x 1.5T
MRI), 6 angiography systems (including one hybrid
angiography system in the Surgical Center) are in use.
From April 2023, Interventional Radiology Computed
Tomography (IR-CT) is in operation, enabling toprovide more advanced IR procedures.
2) Nuclear Medicine Section:
The nuclear medicine section is responsible forvarious nuclear medicine examinations (gamma
camera, single-photon emission computerized
tomography (SPECT), positron emission tomography(PET)), radiopharmaceutical management, productionof PET nuclides using accelerators, label synthesis,
qualityverification,
radioactive
contaminant
management, and internal isotope irradiation therapy.
The nuclear medicine section in Central Clinical
Services Building 1 performs various medical services
using unsealed radionuclides. Nuclear medicine
examinations include conventional scintigraphy (bone,tumor, kidney, thyroid), myocardial SPECT, and brain
SPECT. Functional and statistical images using tracer
methods are also available. In recent years, thedemand for PET examinations has been increasing,
especially for 18F-fluorodeoxyglucose-PET (FDGPET) in cases with malignant tumors. PET
examinations using tracers labeled with positron
nuclides produced by a small cyclotron are used toevaluate blood flow and metabolism, receptor imaging,and the presence of amyloid accumulation in the brain.
With the opening of the Central Clinical Service
Building 2, a PET-CT scanner and a cyclotron were
installed. In 2009, we started internal radioisotope
therapy for castration-resistant prostate cancer withbone metastasis and radioimmunotherapy formalignant lymphoma.
3) Radiation Oncology Section:
The radiation oncology section is responsible forhigh-energy radiotherapy, gamma-knife therapy,
brachytherapy, and radioisotope (RI) internal therapy.
The radiation oncology section is on the thirdbasement floor of Central Clinical Services Building 2
and has dedicated rooms for RI internal therapy on the
9th floor of the Inpatient Building A.
The radiation oncology section has three linear
accelerators (LINAC), an iridium brachytherapy
machine, a gamma-knife for stereotactic irradiation of
the head, and a CT scanner for treatment planning. A
treatment planning system is used to perform radiation
therapy. All linear accelerators are equipped with a CT
imaging function for position matching, enablinghighly accurate image-guided radiation therapy. In
2014, one of the linear accelerators was upgraded, anda tomotherapy was introduced. Tomotherapy is ahelical intensity-modulated machine dedicated tohigh-precision radiotherapy for brain and head andneck tumors, whole-body irradiation, and whole-bodyskin irradiation. The Radiology Information System(RIS), introduced in 2012 from the viewpoint of
medical safety, is now in operation to construct acomprehensive management system for cancer
treatment. Recently, the gamma-knife system was
updated in February 2019, and image-guided
radiotherapy is now available in the gamma-knife
system.
4) Others:
The radiation control office handles the hospital's
management of X-ray generators, radioactive
contaminants, radiation education, and healthmanagement (glass badge management, etc.). In
addition, it conducts management and operation under
the Medical Service Law and the Law Concerning
Prevention of Radiation Hazards Act on the513

Prevention of Hazards to Persons with Disabilities.

Conclusion
In 2002, the diagnostic imaging equipment was fully
digitalized, and in the following year, a filmlesssystem was realized by distributing images anddiagnostic reports via the hospital information system.
The Critical Care and Emergency Medical Center/ER,
MRI rooms, and the radiation oncology section wererelocated to the Central Clinical Service Building 2(completed in 2006), and the latest equipment was
introduced. In January 2018, when Inpatient Building
B started operation, a portable radiography system
was established.
As a result of the development of digital technology,
diagnostic equipment, image processing technology,
diagnostic imaging, and radiotherapy technology havebecome more sophisticated. Radiology Center willcontinue to contribute to improving the level of
medical care at the University of Tokyo Hospitalthrough improved services to other departments.

Publications
See the corresponding part of the Department ofRadiology.

Number of examinations in 2022.4
to 2023.3
Inpatient

Outpatient

Total

Radiography(plain)79,57275,165

154,737

Radiography(enhanced)

4,869

1,089

5,958

Angiography

3,447

23

3,470

Computed
tomography

13,57837,35850,936

Magnetic
resonance
imaging

4,678

16,744

24,422

Nuclearmedicine

1,312

3,355

4,667

Radiotherapy

3,732

8,078

11,810Bone mineraldensitometry

186

2,808

2,994

514

Rehabilitation Center
Professor
Toru Ogata, M.D.

Lecturer
Sayaka Fujiwara, M.D.

Research Associate
Haruhi Inokuchi, M.D., Kentaro Morita, M.D.,
Ryoko Sawada, M.D.
※The following information is the same as that of the previous year for certain reasons.

Homepage

http://todaireh.umin.ne.jp

Introduction and Organization
The physical therapy service started in 1963 at the
University of Tokyo Hospital, and then expanded toinclude occupational therapy and social work section.
In 1966 this service was converted to the central
rehabilitation service department as a part of theCentral Diagnostic and Therapeutic Service Department. The Central Rehabilitation Service became an
independent unit in 1970. After the reorganization of
the University of Tokyo Hospital according to majororganic classification in 1998, outpatient clinic asrehabilitation medicine was installed. The formal titleof our unit was changed from the Physical Therapy
Department to the Rehabilitation Department by thebudget measures in the fiscal year 2001, and we
integrated the related personnel categories, which
belonged to the orthopedic surgery department and thephysical medicine department.
At present our department consists of four sections.
Rehabilitation physicians’ section includes five fulltime doctors and two other part-time doctors. They
work chiefly for clinical practice in medical
rehabilitation service, but also have to engage inteaching activities for medical students. Nineteen
physical therapists are working in the physical therapy
section. In the occupational therapy section, six

occupational therapists work for the generalrehabilitation service and the other four therapists workfor the psychiatric rehabilitation. Four acupuncture
therapists perform acupuncture and moxbustion. In the
Day-care Unit, clinical psychologists and nurses also
work. In 2006, speech therapists who had belonged toother departments in the University of Tokyo Hospitalwere included in our department. From 2009, a speechtherapist added to our department, and now threetherapists perform therapy for patients with aphasia,
dysarthria, and dysphagia.

Clinical activities
The professor serves as a director of Rehabilitation
Center, the University of Tokyo Hospital. The Rehabilitation Center and the Department of Rehabilitation
Medicine are united and engage in clinical practice. We
have at present no charged ward, and treat about 4,700
new referrals annually from almost all the departmentsof the university hospital. We always take charge of
250-300 patients corresponding about 25-30% of thewhole number of inpatients. We also see 15 people per
day at the outpatient rehabilitation setting. The
numerical ratio of outpatient is being reduced in orderto give priority to the clinical service corresponding toneeds expansion of service to inpatients.

515

Teaching activities

References

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 patientsand learn how to take a patients’ history, physicalfindings, functional evaluation, and how to plan
rehabilitation programs. We have introduced a few ofelective students for elective clinical clerkship to ourcollaborating hospitals with specialized rehabilitationward.
In addition, we have provided the training ofstudents including physical therapy, occupational
therapy, and speech therapy. Twenty students or morecome and stay at the university hospital annually as along-term clerkship from several PT/OT/ST training
schools.

1.

2.

3.

4.

5.

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

6.

7.

Kojima T, Ishikawa H, Tanaka S, Haga N, Nishida
K, Yukioka M, Hashimoto J, Miyahara H, Niki Y,
Kimura T, Oda H, Asai S, Funahashi K, Kojima M,
Ishiguro N: Validation and establishing targets forthe physician-based clinical scale for foot and ankle
surgery in patients with long-standing rheumatoid
arthritis based on patient-reported outcomes:
Results from a multicenter prospective
observational cohort study to evaluate the efficacy
of joint surgery in the treat-to-target era. Mod
Rheumatol, Online ahead of print
Mano H, Fujiwara S, Haga N: Body knowledge inchildren with congenital upper limb deficiency.
Brain Nerve 72(4): 445-451, 2020
Mano H, Fujiwara S, Haga N: Effect of prostheseson children with congenital lower limb deficiencies.
Pediatr Int 62: 1039-1043, 2020
Mano H, Fujiwara S, Takamura K, Kitoh H,
Takayama S, Ogata T, Haga N: Treatment
approaches for congenital transverse limb
deficiency: Data analysis from an epidemiologicalnation survey in Japan. J Orthop Sci, Online aheadof print
Matsuoka M, Tsukamoto S, Orihara Y, Kawamura
R, Kuratani M, Haga N, Ikebuchi K, Katagiri T:
Design of primers for direct sequencing of nine
coding exons in the human ACVR1 gene. Bone138: 115469, 2020
Matsushita M, Mishima K, Yamashita S, Haga N,
Fujiwara S, Ozono K, Kubota T, Kitaoka T,
Ishiguro N, Kitoh H: Impact of fracture
characteristics and disease-specific complications
on health-related quality of life in osteogenesis
imperfecta. J Bone Miner Metabol 38(1): 109-116,
2020
Pignolo RJ, Cheung K, Kile S, Fitzpatrick MA, De
Cunto C, Al Mukaddam M, Hsiao EC, Baujat G,
Delai P, Eekhoff EMW, Di Rocco M, Grunwald Z,
Haga N, Keen R, Levi B, Morhart R, Scott C,
Sherman A, Zhang K, Kaplan FS: Self-reported
baseline phenotypes from the International
Fibrodysplasia Ossificans Progressiva (FOP)
Association Global Registry. Bone 134: 115274,
2020

516

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11.

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Sawada R, Yamana H, Shinoda Y*, Tsuda Y, Matsui
H, Fushimi K, Kobayashi H, Matsubayashi Y,
Yasunaga H, Tanaka S, Haga N: Predictive factorsof 30-day mortality after surgery for spinal
metastasis: Analysis of a nationwide database. J
Orthop Sci S0949-2658(20)30208-6, 2020, Online
ahead of print
Shinoda Y, Sawada R, Ishibashi Y, Akiyama T,
Zhang L, Hirai T, Oka H, Ohki T, Ikegami M,
Okajima K, Okuma T, Kobayashi H, Goto T, Haga
N, Tanaka S: Prediction of pathological fracture inpatients with lower limb bone metastasis using
computed tomography imaging. Clin Exp
Metastasis 37(5): 607-616, 2020
Takeda J, Nanatsue K, Yamagishi R, Ito M, Haga N,
Hirata H, Ogi T, Ohno K: InMeRF: Prediction ofpathogenicity of missense variants by individualmodeling for each amino acid substitution. NAR
Genom Bioinform 2(2):lqaa038,2020
Taya M, Hatano M, Saito A, Nitta D, Maki H,
Hosoya Y, Minatsuki S, Tsuji M, Sato T, Murakami
H, Narita K, Konishi Y, Watanabe S, Yokota K,
Haga N, Komuro I: Clinical importance of
respiratory muscle fatigue in patients withcardiovasculardisease.
Medicine(Baltimore)
99(34): e21794, 2020
Umezaki S, Shinoda Y, Mukasa A, Tanaka S,
Takayanagi S, Oka H, Tagawa H, Haga N, Yoshino
M: Factors associated with health-related quality oflife in patients with malignant glioma: Impact ofsymptoms and implications for rehabilitation. Jap J
Clin Oncol 50(9): 990-998, 2020
Haga N, Nakashima Y, Kitoh H, Kamizono J,
Katagiri T, Saijo H, Tsukamoto S, Shinoda Y,
Sawada R, Nakahara Y: Fibrodysplasia ossificans
progressiva: review and research activities in Japan.
Pediatr Int 62: 3-13, 2020

517

Surgical Center
Professor (Director)
Kazuhiko Fukatsu M.D., Ph.D.

Lecturer
Satoshi Murakoshi, M.D., Ph.D.
Yuhei Saito, Ph.D.
Yuki Taniguchi, M.D., Ph.D
Ryoji Fukushima, M.D., Ph.D.

Assistant Professor
Ryota Yamagami. M.D.
※The following information is the same as that of the previous year for certain reasons.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/syujutsu/index.html

Introduction and Organization
Uniform management of operating rooms (OR) firstbegan at the University of Tokyo Hospital in July 1955.
The office, so called the surgical center, was located at
the Old Central Building until December 1987. The
center moved to the new Central Clinical Service
Building 1 in January 1988, where there are 12 ORs
including one bio-clean room. The surgical center
became to provide managerial services of the OR to 18
surgical departments after moving into the new officebuilding. The total number of operations remained tobe below 6,300 a year between 1999 and 2000 becauseof the limitation of number of ORs and nurses.
In July 2001, the branch hospital in Mejiro area wasmerged with the University of Tokyo Hospital in
Hongo area, which opened a new Ward A Building in
October 2001. After the merger, the number of elective
operations markedly increased and became over 7,300.
Two additional ORs began to be used tentatively toaccommodate an enormous increase in the number ofelective operations. The one OR was set up on the
ICU/CCU/HCU floor in the new Ward A Building andthe other was in the Outpatient Clinic Building. The
outpatient OR for orthopedic outpatients was diverted

for the general OR, which was used for the short-stayand day surgery.
Until September 2001, the elective operations had
been performed in 9.5 ORs/day on average. After
October 2001, 12 ORs/day began to be used. In 2006,
the Central Clinical Service Building 2, which had 11
ORs, was completed to solve the shortage of thenumber of ORs. As a result, the total number of ORs
became 23, and then the number of operations has
tremendously increased. More recently, “On call PM
block time” has been introduced to improve OR
utilization. In April 2014, one of the ORs in the Central
Clinical Service Building 2 was renovated into a hybrid
OR which is equipped with advanced interventional
imaging system for the patients undergoinginterventional surgical treatment. In August 2020, Day
Surgery room was built at ICU-2 area for ophthalmic
operation.
A total of 8,485, 9,550, 9921, 9,944, 10,394, 10,170,
10,752, 11,235, 11,150, 10,960, 11,161, 11,014, 11,124,
11,323, 9,945 (under the circumstance of Covid-19
pandemic) and 11,047 operations were performed in
2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014,2015, 2016, 2017, 2018, 2019, 2020 and 2021 fiscal

518

year, respectively. The number of operations in 2021
fiscal year counts for approximately 1.8 times
comparing to that in 2001.
These days more and more patients undergo
endoscopic surgery such as laparoscopy/thoracoscopy
assisted operation. There is also an apparent increase in
the number of patients who are at high risk with criticalmorbidity or carrier of the particular types of pathogens
such as tuberculosis, MRSA, pseudomonas aeruginosa,
HBV, HCV and HIV.

Clinical Activities
All operations of in-patients are performed in 23
ORs and Day Surgery room at the surgical center.
Computer system has been utilized to handle theinformation on operation. In May 1999, the on-line
system was introduced to order the elective andurgent/emergent operations through the computer
terminal in the wards. The input of postoperative
patient information started from March 2000. Thissystem also enabled the medical staff to know theavailability of the ORs of the next day. From November
in 2000, the medical staff can see the operation
schedule through the hospital computer network.
The present status of the operation process began to
be seen through the computer monitor from May 1997.
The photographs of surgical sites, resected organs andlive video image began to be delivered to the clinicaldepartments from February 1997.
Hospital logistics system were totally replaced to
improve material flow of hospital in October 2001,
when supply processing and distribution (SPD)department was established and started its practice. In
the surgical center, this SPD system has been available
since September in 2002.
Recently, the number of complicated and long
surgical procedures using advanced technology has
dramatically increased. In addition, more and morepatients tend to undergo surgery using artificial implant,
joint prosthesis or intraocular lenses. Those operations
include organ transplantation, microvascular surgery,cardiovascular surgery, minimally invasive surgery andnavigation-guided orthopedic/neurosurgical surgery
and stent grafting for the abdominal or thoracic aortic
aneurysms. Organ transplantation and intraoperative
three-dimensional echo-guided surgery are alsofrequently performed. Minimally invasive surgery is
another recent trend of the operation. Those include
endovascular treatment for heart anomalies such as
ASD and VSD. More recently, the robotic surgery has
started at the surgical center.
Healthcare-Associated infections (HAIs) are criticalissues in the surgical center. It is essential to educate
staffs how to prevent HAIs and occupational infections.
As the number of operations associated with emerging
or re-emerging infectious diseases such as HIV andtuberculosis has increased, all healthcare staff are
required to adhere to the principles of standard and/ortransmission-based precautions also in the surgicalcenter.

Teaching Activities
The following lectures or seminar are given to theundergraduate and postgraduate medical students:
aseptic techniques, sterilization/disinfection methods,
prevention of perioperative infections, humoral andcellular responses to trauma and shock, training ofscrubbing and gown techniques. The curriculum is
updated each year. Introductory course for disinfection,sterilization and preservation of surgical instruments
and medical devices was added in the training courses
in 1998, which gained more interest and popularity
among many students.
In the surgical center, the innovative surgicalinstruments and medical devices are introduced toperform highly advanced operations such as in thenavigation
surgery,transplantation
surgery,
cardiovascular surgery and robotic surgery. As a result,the education related to the assist for those surgicalprocedure has become most important activities in thesurgical center. The lectures of advanced technologies
are in the curriculum for the surgeons, the nursing staff
and clinical engineers so that they can understand how
to use them in a proper way.
Lectures for the nursing staff consist of a freshmancourse and an advanced course. The freshman course isa basic training course for scrub nurses and circulating
nurses. It consists of lectures of aseptic techniques, decontamination/sterilization methods, prevention of
perioperative infections, and on-site training ofscrubbing and gown techniques as well as aseptic
preparation of surgical instruments in the OR. An

519

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, openheart surgery neurosurgery and robotic surgery.
There is also a training course to medical engineers
and students of biomedical engineers. This training
course consists of introduction on the medical devices
and electronic instruments, precautions of accidental
troubles in handling surgical instruments/medical
devices, development of new surgical instruments/
medical devices, cardiopulmonary bypass techniques
and illumination techniques in the operating fields. The
contents of this course are summarized in the manual
for the nursing staff and contribute to decrease thefrequency of incident associated with surgicalinstruments and medical devices.
The on-the-job training are given to the non-nursing
staff including technical officials and part-time
employees since they start their careers at the surgicalcenter. They are given lectures on aseptic techniques,
sterilization/disinfection methods, prevention of
perioperative infections, and maintenance of reusable
surgical instruments such as forceps, scissors andclamps. These subjects are stated and summarized in
the manual. Lectures are also given to the seniortechnical officers and part-time employees to promote
their technical knowledge and skills.

Research Activities
1) Safe surgery and risk management in the OR2) Improvement of cost-effectiveness in the surgicaltreatment
3) Development of central monitoring system using
IT technology
4) Introduction of robotic surgery5) Efficient use of human resources6) Introduction of advanced surgical procedureincluding microscopy surgery and laparoscopy
7) Management of equipment of endoscopy-assisted
surgery8) Centralization of the live video images of thesurgical field
9) Management of surgical instruments using uniquedevice identification (UDI)

10) Perioperative infection control and prevention
related to the sterilization
11) Maintenance of the surgical environment in the OR12) Maintenance and management of surgicalequipment13) Nutritional management of perioperative patients
14) Others

520

Central Supply Service
Professor
Kazuhiko Fukatsu, M.D., Ph.D.
Lecturer
Satoshi Murakoshi, M.D., Ph.D.

Assistant Professor
Hiroshi Ookawa※The following information is the same as that of the previous year for certain reasons.

Homepage

http://www.cc.h.u-tokyo.ac.jp/mulins/zairyobu/

Introduction

Activities

Central supply service is an integrated place in thehospital for cleaning and sterilization of previously
used devices. All re-usable devices are transported toour division via automated guided vehicle system fromsurgical center, ward and outpatient clinics. The used
instruments are cleaned using standard precautionary
procedures, disinfected, reassembled, packaged, andsterilized. The sterilized instruments are then placed at
designated sites for use.
One professor and one assistant professor, one
nurse, one 8 staff members, and 26 members fromexternal staff sources are the main members of thisdivision.

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.

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.

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 surgical521

insult is another theme of our division. The research isimportant for improving outcome of surgical patientsand our data have been published as original articles

522

Department of Endoscopy andEndoscopic Surgery
Associate Professor
Yousuke Nakai, M.D., Ph.D.

Assistant Professor
Naomi Kakushima, M.D., Ph.D.

Homepagehttps://www.h.u-tokyo.ac.jp/patient/depts/kougaku/

Introduction and Organization
Department of Endoscopy and Endoscopic Surgery
was 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 2022, 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.

523

Table1

2013

2014

2015

2016

2017

EGD*

11840

11740

11874

11944

11490

Colonoscopy

6000

6043

6394

6814

5921

Bronchoscopy

169

218

228

362

ERCP

912

1035

946

763

766

Enteroscopy

375

Laryngoscopy

2018

2019

11699

11226

（2177） （2501）

2020

2021

2022

8.906

10232

10239

4,548

5619

5445

5530

5675

（109）

（329）

350

316

395

300

312

305

1206

1137

1057

1314

1302

1166

1326

882

1084

1023

923

1059

711

847

993

396

310

86

304

138

151

74

23

83

128

102

105

125

114

92

102

42

39

99

Colposcopy

404

327

295

417

430

414

392

333

364

451

Total

20591

20627

21034

22038

20769

20169

20314

16226

18602

18941

EUS

**

†

*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.

References
1.

2.

3.

4.

Sato T, Yasuda I, Nakai Y; WONDERFUL study
group in Japan. The second shot to walled-off
necrosis: The sooner the better versus sooner orlater DEN Open 2022;3:e182.
Nakai Y, Shiomi H, Hamada T, Ota S, Takenaka
M, Iwashita T, Sato T, Saito T, Masuda A,
Matsubara S, Iwata K, Mukai T, Isayama H,
Yasuda I; WONDERFUL study group in Japan.
Early versus delayed interventions fornecrotizing pancreatitis: A systematic review andmeta-analysis. DEN Open 2022;3:e171.
Hakuta R, Nakai Y, Oyama H, Noguchi K, Kanai
S, Nomura Y, Suzuki T, Ishigaki K, Saito K,
Saito T, Hamada T, Takahara N, Mizuno S,
Kogure H, Moriya K, Fujishiro M. Increased riskof biliary infection after biliary stent placementin users of proton pump inhibitors. DEN Open
2022;3:e129.
Sato T, Saito T, Nakai Y, Fujishiro M.
To-and-fro balloon technique for deployment of alumen-apposing metal stent in highly solid
walled-off necrosis of the pancreas. Endoscopy
2022;54:E750-1.
5. Hamada T, Saito T, Noguchi K, Nakai Y,
Fujishiro M. The "funitel" technique forendoscopic target biopsy at a biliary bifurcation.
Endoscopy 2022;54:E637-8.
6. Fukuda K, Nakai Y, Mizuno S, Sato T, Noguchi
K, Kanai S, Suzuki T, Hakuta R, Ishigaki K,
Saito K, Saito T, Takahara N, Hamada T, Kogure
H, Fujishiro M. Endoscopic Bridge-and-Seal of
Bile
Leaks
Using
a
Fully
CoveredSelf-Expandable Metallic Stent above the Papilla.
J Clin Med. 2022;11:6019.
7. Sato T, Nakai Y, Fujishiro M. Current
endoscopic approaches to biliary strictures. Curr
Opin Gastroenterol 2022;38:450-60.
8. Kogure H, Nakai Y, Fujishiro M. How should
needle tract seeding be addressed in endoscopic
ultrasound-guided fine-needle aspiration? Dig
Endosc 2022;34:958-9.
9. Yamashita Y, Tachikawa A, Shimokawa T,
Yamazaki H, Itonaga M, Sakai Y, Sugiyama H,
Nakai Y, Tanaka K, Isayama H, Kitano M.
Covered versus uncovered metal stent forendoscopic drainage of a malignant distal biliary
obstruction: Meta-analysis. Dig Endosc 2022;34:
938-51.
10. Hamada T, Kogure H, Hakuta R, Nakai Y, Koike
K. The "zipline" technique for double-balloon
enteroscopy-assisted removal of a migrated stent

524

11.

12.

13.

14.

15.

in a peripheral bile duct. Endoscopy 2022;54:
E353-4.
Iwashita T, Ogura T, Ishiwatari H, Nakai Y,
Iwata K, Mukai T, Shimizu M, Isayama H,
Yasuda I, Itoi T. Utility of dedicated bougie
dilator for a 0.018-inch guidewire during
EUS-guided biliary drainage: A multi-center
retrospective cohort study. J Hepatobiliary
Pancreat Sci. 2022;29:810-6.
Kato S, Kuwatani M, Onodera M, Kudo T, Sano
I, Katanuma A, Uebayashi M, Eto K, Fukasawa
M, Hashigo S, Iwashita T, Yoshida M, Taya Y,
Kawakami H, Kato H, Nakai Y, Kobashigawa K,
Kawahata S, Shinoura S, Ito K, Kubo K, Yamato
H, Hara K, Maetani I, Mukai T, Shibukawa G,
Itoi T. Risk of Pancreatitis Following Biliary
Stenting
With/Without
Endoscopic
Sphincterotomy: A Randomized Controlled Trial.
Clin Gastroenterol Hepatol 2022;20:1394-1403.
Kitano M, Yoshida M, Ashida R, Kita E,
Katanuma A, Itoi T, Mikata R, Nishikawa K,
Matsubayashi H, Takayama Y, Kato H, Takenaka
M, Ueki T, Kawashima Y, Nakai Y, Hashimoto
S, Shigekawa M, Nebiki H, Tsumura H, Okabe
Y, Ryozawa S, Harada Y, Mitoro A, Sasaki T,
Yasuda H, Miura N, Ikemoto T, Ozawa E, Shioji
K, Yamaguchi A, Okuzono T, Moriyama I, Hisai
H, Fujita K, Goto T, Shirahata N, Iwata Y, Okabe
Y, Hara K, Hashimoto Y, Kuwatani M, Isayama
H, Fujimori N, Masamune A, Hatamaru K,
Shimokawa T, Okazaki K, Takeyama Y, Yamaue
H; Committee of Clinical Research, Japan
Pancreas Society. Needle tract seeding afterendoscopic ultrasound-guided tissue acquisitionof pancreatic tumors: A nationwide survey inJapan. Dig Endosc 2022 May3. Online ahead ofprint.
Hisada H, Tsuji Y, Obata M, Cho R, Nagao S,
Miura Y, Mizutani H, Ohki D, Yakabi S,
Takahashi Y, Sakaguchi Y, Kakushima N,
Yamamichi N, Fujishiro M. The impact ofsarcopenia on short- and long-term outcomes ofendoscopic submucosal dissection for earlygastric cancer. J Gastroenterol 2022;57:952-61.
Kakushima N, Hinata M, Ushiku T. White
opaque substance in a non-neoplastic duodenal
lesion. Dig Endosc 2022;34:1495.

16. Hisada H, Sakaguchi Y, Oshio K, Mizutani S,
Nakagawa H, Sato J, Kubota D, Obata M, Cho R,
Nagao S, Miura Y, Mizutani H, Ohki D, Yakabi
S, Takahashi Y, Kakushima N, Tsuji Y,
Yamamichi N, Fujishiro M. Endoscopic
Treatment of Superficial Gastric Cancer: Present
Status and Future. Curr Oncol. 2022;29:4678-88.

525

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.

3.
4.

5.

6.

7.
8.

Teaching activities
1.
2.

Clinical activities
1.
2.

Start of maintenance hemodialysis therapy forend-stage kidney disease (ESKD).
Regular hemodialysis therapy for hospitalized

ESKD patients. Please note that our center does
not accept holiday dialysis.
Emergency hemodialysis and hemodiafiltration
for ICU patients.
PAD screening using skin reperfusion pressure
examination during hemodialysis treatment, andintradialytic exercise to ameliorate frailty andsarcopenia.
Plasmapheresis for neurodegenerative diseases,
myasthenia gravis, dermatological disorders,waldenstrom
macroglobulinemia,
collagendiseases, TMA (TTP), and pre/post solid organtransplant patients.
Granulocyte and Monocyte Apheresis for
inflammatory bowel diseases such as ulcerative
colitis.
Cell-free and concentrated ascites reinfusion
therapy (CART) for refractory ascites.
Induction and maintenance of peritoneal dialysis
for ESKD.

3.

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
are summarized in Japanese handbook in 2010
[Apheresis Pocket Manual] and 2011 [CRRTPocket Manual]. English and Chinese version of

526

4.

“Apheresis Pocket Manual” is available for
global experts of Apheresis therapy.
Critical Care Nephrology Course for educating
young clinical researchers and fellows incollaboration with Department of Emergency andCritical Care Medicine.

Doi K, Nangaku M. Clinical frailty assessment
might be associated with mortality in incident
dialysis patients. Sci Rep. 2022 Oct 21;12(1):17651.
4.

Nangaku M. Screening and Management for
Intracranial Aneurysms in Japanese Patients With

Research activities
1.
2.

3.

4.

5.
6.
7.
8.

Prognostic analysis for post-liver transplantpatients received plasma exchange therapy.
Identification of prognostic factors including
biomarkers in AKI/CKRT patients admitting to
ICU/CCU.
Associations between factors at the initiation of
kidney replacement therapy and prognosis in
ESKD 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.

Matsuura R, Komaru Y, Miyamoto Y, Yoshida T,
Yoshimoto K, Yamashita T, Hamasaki Y, Noiri E,
Nangaku M, Doi K. HMGB1 Is a Prognostic
Factor for Mortality in Acute Kidney Injury
Requiring Renal Replacement Therapy. Blood
Purif. 2023 Jun 19:1-8.

2.

Komaru Y, Isshiki R, Matsuura R, Hamasaki Y,
Nangaku M, Doi K. Application of urinary
biomarkers for diagnosing acute kidney injury in
critically ill patients without baseline renal
function data. J Crit Care. 2023 Oct;77:154312.

3.

Oki R, Hamasaki Y, Tsuji S, Suzuki K, Tsuneishi S,
Imafuku M, Komaru Y, Miyamoto Y, Matsuura R,

Matsuura R, Honda K, Oki R, Hamasaki Y, Doi K,

ADPKD. Kidney Int Rep. 2022 Jun 1;7(8):18931896.
5.

Miyamoto Y, Iwagami M, Aso S, Uda K, Fushimi
K, Hamasaki Y, Nangaku M, Yasunaga H, Doi K.
Postoperative outcomes of cancer surgery inpatients with and without kidney failure withdialysis therapy: a matched-pair cohort study. Clin

Kidney J. 2022 Jan 13;15(6):1137-1143.
Oki R, Hamasaki Y, Komaru Y, Miyamoto Y,
Matsuura R, Akari S, Nakamura T, Murase T, Doi
K, Nangaku M. Plasma xanthine oxidoreductase isassociated with carotid atherosclerosis in stable
kidneytransplant
recipients.
Nephrology(Carlton). 2022 Apr;27(4):363-370. Epub 2021
Oct 14.
7. Komai T, Iwasaki Y, Tsuchida Y, Hanata N,
Tsuchiya H, Harada H, Hamasaki Y, Nangaku M,
Shoda H, Fujio K. Efficacy and safety of plasma
exchange in interstitial lung diseases with
anti-melanoma differentiation-associated 5 gene
antibody positive clinically amyopathic dermatomyositis. Scand J Rheumatol. 2021 Dec 13:1-7.
8. 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.
9. 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.
10. Kotani A, Oda Y, Hirakawa Y, Nakamura M,
Hamasaki Y, Nangaku M. Peritoneal Dialysisrelated Peritonitis Caused by Streptococcus oralis.
Intern Med. 2021 May 22.
11. Oki R, Tsuji S, Hamasaki Y, Komaru Y, Miyamoto
Y, Matsuura R, Yamada D, Doi K, Kume H,

6.

527

12.

13.

14.

15.

16.

17.

18.

19.

20.

Nangaku M. Time until treatment initiation isassociated with catheter survival in peritoneal
dialysis-related peritonitis. Sci Rep. 2021 Mar 22;
11(1):6547.
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.
Matsuura R, Doi K, Hamasaki Y, Nangaku M.
RRT Selection for AKI Patients With Critical
Illness. Semin Nephrol. 2020 Sep;40(5):498-505.
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.
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.
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.
Komaru Y, Yoshida T, Hamasaki Y, Nangaku M,
Doi K. Hierarchical Clustering Analysis for
Predicting 1-Year Mortality After Starting
Hemodialysis. Kidney Int Rep. 2020 May 23;5(8):1188-1195.
Miyamoto Y, Aso S, Iwagami M, Yasunaga H,
Matsui H, Fushimi K, Hamasaki Y, Nangaku M,
Doi K. Association Between IV Thiamine andMortality in Patients With Septic Shock: A
Nationwide Observational Study. Crit Care Med.
2020 Aug;48(8):1135-1139.
Matsuura R, Komaru Y, Miyamoto Y, Yoshida T,
Yoshimoto K, Hamasaki Y, Nangaku M, Doi K.
Different Biomarker Kinetics in Critically Ill
Patients with High Lactate Levels. Diagnostics(Basel). 2020 Jul 4;10(7):454.
Matsuura R, Iwagami M, Moriya H, Ohtake T,
Hamasaki Y, Nangaku M, Doi K, Kobayashi S,

21.

22.

23.

24.

25.

26.

27.

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.
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.
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.
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.

528

Immune-Mediated Diseases
Therapy Center
Professor
Associate Professor
Hiroko Kanda, M.D., Ph.D.

Lecturer
Associate

Homepage

http://www.m.u-tokyo.ac.jp/patients/depts./menekishikkan/

Introduction and Organization
In many immune diseases, some immune cells andresponses are out of control. “Biologics” have beendeveloped as agents that control the cytokines and cellsurface molecules. In Japan, TNF inhibitors wereintroduced for the first time as "biologics" forrheumatoid arthritis (RA) in 2003. The effect of thesedrugs has been tremendous and has brought about aparadigm shift in RA practice, not only in terms oftreatment goals, but also in terms of treatment
algorithms, revised classification criteria for diagnosis,
and so on. Now, "small-molecule inhibitors" that target
specific molecules of intracellular signal transduction
events have been added, and these drugs, called"molecular targeted therapies," are being developed
one after another. Currently, “Biologics” include 9 TNF
inhibitors, 3 IL-6 inhibitors, 1 CTLA4-Ig, 4 IL-17
inhibitors, 1 IL-12/23 inhibitor, 2 IL-23 inhibitors, 2alpha 4 integrin inhibitors, 2 IL-5 inhibitors, 1 IL-4/13
inhibitor, 1 anti-IgE antibody, 1 IL-1 inhibitor, 2 B-cell
activation inhibitors, 1 typeI IFN inhibitor, 2complement activation inhibitors and 1 nFcR inhibitor,and "small-molecule inhibitors" include 5 JAK
inhibitors, 1 TYK2 inhibitor and 1 PDE4 inhibitor,
have been approved. Target diseases include not only

immunological diseases such as RA, juvenile
idiopathic arthritis, systemic lupus erythematosus,
scleroderma, adult-onset Still's disease, vasculitis,
spondyloarthritis, psoriasis and psoriatic arthritis,
inflammatory bowel disease, multiple sclerosis,
neuromyelitis
optica,nocturnal
paroxysmal
hemochromaturia, Castleman's disease, but also
autoinflammatory diseases, atopic Dermatitis.
Molecularly targeted therapies have shown highefficacy against these diseases and are expected to
avoid long-term administration of corticosteroids.
In 2017, with the expansion of molecular targeted
agents, the “Immune-mediated Diseases Therapy
Center Outpatient Department” was established in theoutpatient consultation division. Due to further
increases in the number of drugs and indications, theCenter was approved as a department of the Graduate
School of Medicine of the University of Tokyo in April
2020. At the same time, the "Immune-mediatedDiseases Therapy Center" was established on the 12th
floor of Inpatient Unit B as an outpatient center toprovide intravenous molecular targeted therapy for all
patients with immune-mediated diseases in theuniversity of Tokyo hospital. There are eight
departments: Allergy and Rheumatology, Dermatology,

529

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 molecular targeted therapy. In addition, once
every two months, the immune-mediated diseases
therapy center meeting is held as a forum for
information sharing, where new drug regimens are
discussed and problems are remedied.
The current number of prescriptions for molecularly
targeted agents has more than doubled from 550 in2017 to 1,300 in 2021, with 65% subcutaneous, 30%
intravenous, and 5% oral. As a cross-sectional center,
we would like to deepen our cooperation and aim forsafer operations in the future.

Clinical activities
We have an outpatient clinic at the “ImmuneMediated Therapy Center” every Monday morning,where we provide consultation services for diagnosis
and treatment of immune-mediated diseases, especiallythose related to molecular targeted therapy. The actual
treatment is provided by the attending physician ofeach department, but as mentioned above, intravenous
treatment is centralized at our center.

Teaching activities
As for education for outpatient staff, lectures on eachdisease are held once a year. When a new drug isintroduced, additional lectures related to that drug are
given. Medical students are educated through BSL.

Research activities
We aim to conduct research on the efficacy andsafety of molecular targeted agents for each immunemediated disease by searching for biomarkers andanalyzing medical information, which will lead to theestablishment of precision medicine.

References
1.

Saeko Yamada S, Kanda H, Abe H, Domoto YS,
Yoshida R, Harada H, Kubo K, Ushiku T, Fujio K.
Predominant mesangial IgM, C3, and λ light chain
depositions and interstitial nephritis in a patient

2.

3.

4.

5.

6.

with overlap syndrome and positivity for antimitochondrial M2 antibody: a case report. Mod
Rheumatol Case Rep. 6: 124-7, 2022
Itamiya T, Komai T, Kanda H, Nagafuchi Y,
Chang H, Shibata S, Ishiura H, Shoda H, Toda T,
Fujio K. Efficacy of canakinumab on AA
amyloidosis in late-onset NLRP3-associatedautoinflammatory disease with an I574F somatic
mosaic mutation. Clin Rheumatol 41: 2233-7,
2022
Kanda H. Association between bone mineraldensity and anti-citrullinated protein antibodies inpatients with rheumatoid arthritis. Rheumatology.
2022; 68: 118-22
Kanda
H.
Cryopyrin-associatedperiodic
syndrome. Clinical Immunology & Allergology.
2022; 77: 694-8
Kanda H. Vascular diseases associated withrheumatoid
arthritis(including
vasculitis
syndrome and hypersensitivity vasculitis). Nippon
Rinsho. 2022; 80:603-7
Kanda H. How to take physical findings ofpsoriatic arthritis. Journal of the Japanese
Dermatological association. 2022; 132: 27-34

530

Tissue Bank
Director and Associate Professor
Sumihito Tamura, M.D., Ph.D. FACS

Homepage https://www.h.u-tokyo.ac.jp/english/centers-services/centralclinical-facilities/tissue-bank/index.html
Introduction and Organization

Target Diseases

The tissue bank handles cardiac arrest and brain death
donor information on a 24-7-365 basis, and is
responsible for the retrieval and cryo-preservation
management of homograft cardiac valve and bloodvessels. We provide these cryo-preserved vascular
tissues to medical organizations nationwide forpatients that require vascular tissue transplantation.
Additionally, we initiated allograft bone banking
program limited to in-house retrieval and suppy since
2018. Dissemination and educational activities for theadvancement of tissue transplantation and transplantation medicine is our important mission. In thisline of effort, starting 2020, our staff now function as
in-house organ donor coordinator.

Cardiac valve transplantation:
Infectious endocarditis, prosthetic valve infection,aortic valve periannular abscess, some cases ofcongenital cardiovascular diseases (hypoplastic left
heart syndrome, pulmonary artery/aorta reconstruction,etc.), etc.
Vascular transplantationvascular prosthesis infection, infected aortic aneurysm,
hepatobiliary tract and pancreas diseases, some casesof congenital cardiac diseases.

Activities
Tissue retrieval is carried out by a team of surgeons
after a transplantation coordinator certified by theJapan Society of Tissue Transplantation (JSTT)
explains tissue donation to the donor’s family, andobtains their consent. The donated tissue undergoes
preservation work in the cleanroom located within theCentral Clinical Facilities and is stored under strict
round-the-clock online management, so that it may betransplanted to a patient (recipient) who is deemed tonecessitate a tissue transplantation. As a rare tissuebank that handles homograft cardiac valves andvascular tissues in Japan, the department is certified
by the JSTT and has the largest number of stored
tissues in Japan.

Characteristics
Excellent resistance to infections: Homograft tissues
are cryopreserved in a state in which the cells are alive,
and provide higher resistance to infections by bacteria
than artificial cardiac valves and vessels.
No need for anticoagulation: It is not always
necessary to use coagulants throughout one’s life, as
in the case of post-replacement of artificial cardiac
valves and blood vessels, and it is particularly usefulfor people who are engaged with strenuous exercise,young children, or women who have a desire to givebirth.
Durability: As long as 15 to 20 years. However, re-do
operations may be necessary in some cases.
Banking system: In collaboration with other tissuebanking facilities in Japan, responds to recovery cases
mainly in the Kanto region. Certified cardiac and liver
surgeons consists the donor response team. Shipment
area covers entire nation.
Honoring the donor: Importance is non-comparable toartificial grafts. Human tissues are recovered fromdeceased donors. Since donation is rare in Japan, graft

531

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.

532

Department of Corneal
Transplantation
Professor
Makoto Aihara, M.D., Ph.D.

Lecturer
Takashi Miyai, M.D., Ph.D.
※The following information is the same as that of the previous year for certain reasons.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/kakumaku.html

Introduction and Organization
The department of corneal transplantation wasestablished in 1976 as one of clinical sections in the
University of Tokyo Hospital. The purpose of theestablishment of this section is to carry out and promotecorneal transplantation and to perform clinical andbasic research in the corneal diseases and corneal
transplantation. The section is composed of two
members (Professor Makoto Aihara, Lecturer Takashi
Miyai).

Clinical activities
The clinical activities of this section include corneal
transplantation and outpatient clinics for various
corneal diseases as a consulting corneal service. The
members are responsible not only for corneal transplantation but also for general ophthalmologicalpractice as a senior staff member of Department ofOphthalmology, University of Tokyo. The corneal
service for special cases is held every Monday (PM),Wednesday (AM), Thursday (AM), and Friday (AM).
Keratoconus clinic for providing corneal crosslinking
surgery, which is a brand-new treatment to halt
keratoconus progression, were held in the afternoon ofThursday. Special contact lens clinic for keratoconus
and post-keratoplasty eyes were in the afternoon of thesecond and fourth Thursday. At the corneal service, we

determine indication for corneal transplantation andfollow up patients after the surgery. Total 71 corneal
surgeries including keratoplasty were performed in
2021. In addition to the full-thickness corneal
transplantation (penetrating keratoplasty), we havesuccessfully performed corneal endothelial transplantation for patients with bullous keratopathy, themost common disease of corneal transplantation.
Generally, corneal transplantation is performed as
emergency operation, because we need to transplant
corneas as soon as possible.
The other important activities of the section include
mediation of donor eyes to other university hospitals
and medical institutes that need donor eyes for corneal
transplantation with cooperation of Eyebank. We arealso performing corneal transplantation using corneas
from American Eyebank as needed.
Followings are our main clinical themes to be
pursued to improve the safety and prognosis of corneal
transplantation.
1) Positive proof that donors were free of such
infectious diseases as viral hepatitis, syphilis,
AIDS and acute T-cell leukemia to prevent
transmission to recipient patients through grafting.
2) Postoperative clinical outcomes are evaluated inregenerative medicine for ocular surface
reconstruction, such as cultured corneal limbal,
oral mucosal and conjunctival epithelial sheet

533

transplantation 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 corneal
operation technique.

4:

Teaching activities
We give lectures on corneal diseases and corneal
transplantation to medical students and practitioners. In
addition, we are engaged in practical training for young
ophthalmologists on ophthalmological examinations at
the outpatient clinic.

5:

Research activities
We are conducting clinical research of postoperative
results of DSAEK, clinical results of corneal
crosslinking, and clinical research of corneal biometryby using anterior segment OCT.
In addition, we are investigating genetic analysis andgenome editing research for corneal dystrophy. And weare also conducting research to elucidate the pathology
using corneal transplant specimens.

6:

References
1:

2:

3:

Yamamoto R, Ono T, Toyono T, Shirakawa R,
Noda M, Yoshida J, Miyai T. Assessment ofLong-Term Anterior and Posterior Topographic
Changes in the Cornea After Ptosis Surgery Using
Fourier Harmonic Analysis. Cornea. 2021 Apr;
40(4):440-444. doi:10.1097/ICO.000000000000
2429. PMID: 33881809.
Nakagawa S, Ishii H, Takamoto M, Kaburaki T,
Ishii K, Miyai T. Diagnosis of cytomegalovirus
corneal endotheliitis using surgically removed
Descemet's membrane and endothelium despite
negative results with aqueous humor PCR: a casereport. BMC Ophthalmol. 2021 May 1;21(1):194.
doi: 10.1186/s12886-021-01962-y. PMID: 33933
006; PMCID: PMC8088667.
Ueda K, Ono T, Toyono T, Yoshida J, Kaburaki T,
Miyai T. Descemet stripping endothelial keratoplasty after cytomegalovirus corneal endotheliitis
and immunosuppression for Mooren's ulcer. Am J

7:

8:

9:

Ophthalmol Case Rep. 2021 Apr 14;22:101088.
doi:10.1016/j.ajoc.2021.101088. PMID:33937582;
PMCID: PMC8079431.
Omoto T, Agata C, Akiyama R, Kitamoto K,
Toyono T, Yoshida J, Yamagami S, Usui T, Miyai
T. Iridotrabecular and Iridocorneal Contact
Changes after Cataract Surgery and Endothelial
Keratoplasty in Bilateral Iridoschisis. Case Rep
Ophthalmol. 2021 Apr 12;12(1):198-203. doi:
10.1159/000513793. PMID: 33976682; PMCID:
PMC8077475.
Takahashi S, Ono T, Abe K, Mori Y, Nejima R,
Iwasaki T, Miyai T, Miyata K. Prognosis andetiology of traumatic and non-traumatic corneal
perforations in a tertiary referral hospital: a 30year retrospective study. Graefes Arch Clin Exp
Ophthalmol. 2022 Feb;260(2):629-635. doi:
10.1007/s00417-021-05389-5. Epub 2021 Sep 1.
PMID: 34468830.
Ono T, Mori Y, Nejima R, Iwasaki T, Miyai T,
Aihara M, Miyata K. Comparison of Corneal
Irregularity After Recurrent and Primary
Pterygium Surgery Using Fourier Harmonic
Analysis. Transl Vis Sci Technol. 2021 Sep 1;10(11):13. doi: 10.1167/tvst.10.11.13. PMID:
34515760; PMCID: PMC8444459.
Ono T, Mori Y, Nejima R, Iwasaki T, Miyai T,
Miyata K. Corneal endothelial cell density andmorphology in ophthalmologically healthy young
individuals in Japan: An observational study of16842 eyes. Sci Rep. 2021 Sep 14;11(1):18224.
doi:
10.1038/s41598-021-97776-5.
PMID:
34521951; PMCID: PMC8440503.
Kamiya K, Ayatsuka Y, Kato Y, Shoji N, Miyai T,
Ishii H, Mori Y, Miyata K. Prediction of
keratoconus progression using deep learning ofanterior segment optical coherence tomography
maps. Ann Transl Med. 2021 Aug;9(16):1287.
doi: 10.21037/atm-21-1772. PMID: 34532424;
PMCID: PMC8422102.
Ono T, Mori Y, Nejima R, Iwasaki T, Miyai T,
Ohtani S, Miyata K. Corneal Edema with Anterior
Uveitis after Exposure to the Sap of Euphorbia
trigona: A Case Report. Case Rep Ophthalmol.
2021 Aug 6;12(2):699-705. doi: 10.1159/

534

10:

11:

12:

13:

14:

000517742. PMID: 34594207; PMCID: PMC
8436689.
Miyoshi Y, Ono T, Seki S, Toyono T, Kitamoto K,
Hayashi T, Usui T, Aihara M, Miyai T. Corneal
Graft Rejection after Descemet's Membrane
Endothelial Keratoplasty with Peripheral Anterior
Synechiae. Case Rep Ophthalmol. 2022 Jan
31;13(1):17-22. doi: 10.1159/000520877. PMID:
35221975; PMCID: PMC8832220.
Ishii H, Yoshida J, Toyono T, Yamagami S, Usui
T, Miyai T. Three-year results of accelerated
transepithelial cross-linking (30 mW/cm2 × 3min) for keratoconus: a prospective study. BMJ
Open Ophthalmol. 2022 Feb 8;7(1):e000827. doi:
10.1136/bmjophth-2021-000827. PMID: 35224204;
PMCID: PMC8830257.
Inamochi A, Miyai T, Usui T, Aihara M,
Yamagami S. Effects of corneal epithelial
superficial keratectomy in patients with focal
limbal stem cell disease. Am J Ophthalmol Case
Rep. 2021 Dec 7;25:101239. doi: 10.1016/j.ajoc.
2021.101239. PMID: 34917856; PMCID: PMC
8666511.
Ono T, Takahashi S, Mori Y, Nejima R, Iwasaki
T, Kataoka Y, Miyai T, Miyata K. Severe
fishhook-related ocular injury: A case series.
Trauma Case Rep. 2021 Dec 8;37:100574. doi:
10.1016/j.tcr.2021.100574. PMID: 34917740;
PMCID: PMC8666537.
Abe K, Miyai T, Toyono T, Aixinjueluo W, Inoue
T, Asano S, Ishii H, Yoshida J, Shirakawa R, Usui
T. Comparison of efficacy and safety ofaccelerated trans- epithelial crosslinking for
keratoconus patients with corneas thicker andthinner than 380μm. Curr Eye Res. 2022 Apr;
47(4):511-516. doi: 10.1080/02713683.2021.
2018466. Epub 2021 Dec 27. PMID: 34898348.

535

Department of Cell Therapy andTransplantation Medicine
Professor
Mineo Kurokawa, M.D., Ph.D. (Hematology-Oncology)

Assistant Professor
Moe Hidaka, M.D., Ph.D. (Pediatrics/Hematology-Oncology)
Junji Tokushige, M.D., Ph.D. (Hematology-Oncology)

Homepage

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

Approximately 1,000 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-mismatched donors,
and donor lymphocyte infusion are available. In 2022,
17 patients (including 2 children) received autologous
HSCT and 23 patients (including 5 children) allogeneic
HSCT. We cooperate with the members of Department
of Hematology and Oncology, Hematology/Oncology
group in the Department of Pediatrics, and Departmentof Transfusion Medicine.

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 development of
new methods of transplantation management, such as
immunosuppression, it has become possible to safely
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.

Allogeneic hematopoietic stem cell transplantation:
Bone marrow cells are operatively harvested andinfused without preservation. For peripheral blood

High-dose chemotherapy with or without autologous
stem cell support: High-dose chemotherapy isadministered according to the malignant disease. For

Introduction and Organization
The Department of Cell Therapy and Transplantation
Medicine was institutionally established in 1995, andwas formally organized in 1996. At present, the staff
consists of the above-mentioned medical doctors.
Clinical facilities include 8 single-patient rooms withhigh- efficiency particulate air filtration and other highstandards. Patients who are eligible for the treatment
with high-grade infectious prophylaxis are admitted to
the facilities.

Clinical activities

536

the autologous stem cell support, peripheral blood stem
cell is usually selected as a source of stem cells. Similar
procedures used in the allogeneic stem cell harvest are
performed for leukapheresis and preservation of
autologous stem cell. Malignant lymphomas arisingfrom the central nervous system (brain and spinal cord)
are known to be refractory to treatment and have a poor
prognosis.
Recently,
chemotherapy
includingautologous HSCT has been used to treat this disease
with good efficacy. In our department, we are striving
to improve the prognosis of patients with CNS
malignant lymphoma by providing treatment including
autologous transplantation.
CAR-T Cell Therapy: CAR-T cell therapies arecustomized for each individual patient. They are madeby collecting T cells from the patient and reengineering them in the laboratory to produce proteinson their surface called chimeric antigen receptors, or
CARs. The CARs recognize and bind to specificproteins, or antigens, on the surface of tumor cells, andallow T cells to exert their ability to kill these tumor
cells. By collaborating with the Department of
Hematology and Oncology, the Department ofPediatrics (Hematology/Oncology), and the Cell
Processing Center, we are performing this mostadvanced and promising cancer treatment for patientswith hematologic malignancies, and actively recruiting
patients.
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.

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 junior andsenior medical doctors and learn medical practices andpatient management, through playing a role as a juniormember of the team, as well as through discussions andpresentations. We
also provide
educational
opportunities to continuously develop future specialistson HSCT – Board-certified physicians, hematopoietic
cell transplant coordinators, and long-term follow up
nurses by the Japan Society for Hematopoietic Cell
Transplantation.

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 thestudies on molecular mechanisms of pediatricmalignancies
suchasneuroblastoma,
rhabdomyosarcoma, and infant leukemia.

References
1.

2.

3.

4.

Oyama T, Matsuda K, Honda A, Maki H,
Masamoto Y, Murakami D, Toya T, Sakurai M,
Kataoka K, Doki N, Kurokawa M. Clinicalcharacteristics
ofsteroid-responsive
butdependent chronic graft-versus-host disease: amulticenter retrospective analysis. Int J Hematol.
2023 Feb;117(2):260-268.
Fukui Y, Honda A, Takano H, Obo T, Mizuno H,
Masamoto Y, Kurokawa M. Severe autoimmune
pancytopenia after autologous hematopoietic stem
cell transplantation for Hodgkin lymphoma. J Clin
Exp Hematop. 2022 Dec 28;62(4):217-221.
Kato K, Yabe H, Shimozawa N, Adachi S,
Kurokawa M, Hashii Y, Sato A, Yoshida N, Kaga
M, Onodera O, Kato S, Atsuta Y, Morio T. Stemcell transplantation for pediatric patients withadrenoleukodystrophy:
Anationwide
retrospective analysis in Japan. Pediatr Transplant.
2022 Feb;26(1):e14125.
Mizuta S, Ugai T, Kato H, Doki N, Ota S,
Kawakita T, Katayama Y, Kurokawa M, Nakamae
H, Yano S, Nawa Y, Kanda Y, Fukuda T, Atsuta Y,

537

5.

6.

7.

Kako S. Propensity score matching/reweighting
analysis comparing autologous and allogeneic
stem cell transplantation for B-lineage acutelymphoblastic leukemia. Int J Hematol. 2022 Sep;
116(3):393-400.
Ito Y, Honda A, Kurokawa M. Impact of vitaminD level at diagnosis and transplantation on the
prognosis of hematological malignancy: a metaanalysis. Blood Adv. 2022 Mar 8;6(5):1499-1511.
Sato M, Honda A, Maki H, Toyama K, Yamaguchi
R, Ikeda M, Moriya K, Kurokawa M. Successfultreatment of pneumonia caused by multidrugresistant Pseudomonas aeruginosa after allogeneic
hematopoietic stem cell transplantation withcolistin and amikacin inhalation therapy. J InfectChemother. 2022 Jan;28(1):91-94.
Kato S, Nakano Y, Okamoto K, Takasugi N,
Hidaka M, Sekiguchi M, Hiwatari M, Kurono M,
Kato M. COVID-19 in an adolescent with aplastic
anemia undergoing immunosuppressive therapy:
A case report and details of antibody testing for
SARS-CoV-2. Pediatric Blood Cancer. 2022 Feb,
69(2):e29332.doi

538

Clinical Nutrition Center
Head of the Center
Kazuhiko Fukatsu (Professor)

Assistant Head of the Center
Naoto Kubota (Associate Professor) Department of Clinical Nutrition Therapy
Hideaki Ijichi (Lecturer) Division of Dietary Treatment and Nutritional Care
※The following information is the same as that of the previous year for certain reasons.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/eiyou/

Introduction and Organization
In 1922, a stall in the outpatient department of thehospital and hospital ward shop sold milk, baked goods,
cider and ice cream. In 1925, a service contract between
the hospital and the Kojinkai Foundation resulted in thestart of a patient food service. In 1936, a “special
therapeutic diet” approach for newborn infants,
diabetes, nephropathy in which a physician prescribed
the food composition individually for each patient was
instituted for the first time in Japan. In 1950, a nationalhospital complete food service system was announced,
and the nutrient content provided was standardized.
The nutrient content provision for patient meals at thetime was 2400 kcal/day. In 1952, the inpatient meal
service was officially outsourced to a foundation.
In 1957, the first nationwide meeting of nationaluniversity-hospital head dietitians was held at the
University of Tokyo with the aim of improving patients’
diets.
In 1958, the complete food service was abolished.
Implementation of a standard food service and staffing
with a dietitian became required conditions, and thefood service section was staffed by a part-time section
chief and a dietitian. In 1962, a request from thenationwide meeting of national-university-hospitalhead dietitians, which primarily conducted its activities
at the University of Tokyo, was realized, and the
managerial dietitian system was established by a partial
revision of the Nutritionists Act. In 1972, nutritional

guidance was actively provided to inpatients andoutpatients with the aim of obtaining approval tocharge fees, and in 1978 a medical diet charge andnutrition guidance charge were established. In 1988, atimely tray service achieved by using hot and cold
food-tray carts was instituted in order to dispel the “tooearly, cold, unappetizing” reputation of hospital meals.
In 1991, the name of the food service section waschanged to the “Department of Nutrition Management”,
a change that had a long been sought by nationwide
national-university-hospital managerial dietitian staff
members. At the same time, the nutrition sections of themain hospital and branch hospital were consolidated,
and the head of the Department of Nutrition
Management, who was a managerial dietitian, assumed
the section manager post to form a system composed of
5 managerial dietitians at the main hospital and 3
managerial dietitians at the branch hospital.
In 1994, as a result of a partial revision of the
National Health Insurance Act, a diet therapy
notification system on admission was set up. An onadmission nutrition guidance fee was also established.
In 1998, the first Diet Therapy Exhibit organized by
the Department of Nutrition Management was
conducted as part of the diabetes week events by the
Tokyo Diabetes Association. Since then, Diet Therapy
Exibit has been conducted every year for over 20 years.
In 2001, integration of the branch hospital with themain hospital resulted in an 8-managerial- dietitiansystem. In 2004, the Department of Nutrition

539

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.
During the pandemic of COVID-19, the hospital
closed the special admission room and the Grand Menu

540

was stopped in 2021.

Clinical Activities
The Center is proactively conducting nutritional
guidance in regard to metabolic diseases, including
diabetes, chronic kidney disease, dyslipidemia, andobesity, perioperative guidance, including in regard to
postgastrectomy diets, hepatobiliary and pancreaticdisease diets, and cardiac disease diets, etc.
In 2021, nutritional guidance of inpatients andoutpatients increased upto3648 instances for inpatientsand 6916 instances for outpatients. Nutritional
guidance for malignant tumor patients was performedfor 822 instances.
The Center is also proactively cooperating withseveral departments in the hospital. In 2021,
perioperative guidance was 91 instances, diabetes anddialysis prevention guidance for outpatients was 141
instances, dietary management with palliative care was
339 instances, nutritional guidance for outpatientchemotherapy was 161 instances, nutritional guidanceat the preventive medicine center was 60 instances. In
addition, the provision of inpatient nutrition
information was 61 instances.
In April 2014, the department started calculating
charges for NST and counted 1261 instances in the firstfiscal year. In April 2016, dentists joined the NST
round and started to calculate the additional charge.
After 2020, due to the COVID-19 pandemic, theinstances decreased. 260 rounds were performed and204 instances were calculated in 2021.
In November 2014, a procedure manual ofnutritional management was revised and an original
two-step nutritional screening by physicians,
managerial dietitians, nurses and pharmacists wasintroduced. In this system, the high-risk patients ofmalnutrition were weekly screened through thecommon criteria in our hospital and referred to the NSTof each floor (ward NST). In April 2015, alternative
initial screening criteria specific for pediatric andpregnant patients were added to the procedure manualof nutritional management, respectively. By 2019,
almost all the floor started the ward NST, whichindicated raised awareness of nutritional care as a team
medicine in our hospital. Then, in 2020, instead of thecommon screening criteria, each floor started more

specific screening for the ward NST, based on thecharacteristics of the patients and treatment department.
In 2018, related with the start of surgery for severe
obesity patients (sleeve gastrectomy), sleeve diet was
newly introduced. In January 2019, ketogenic diet wasalso introduced in cooperation with Epilepsy Center.
In 2019, in addition to the Tokyo Food Hygiene
Meister and Elite Institution of Food Hygiene by
Bunkyo-ku, the safe and assured food service in our
hospital was evaluated “S” rank (the highest) by thehospital function evaluation.

Educational Activities
The department has accepted managerial dietitian
clinical trainees. In 2019, the department accepted 45
trainees from 7 training schools: Ochanomizu
University, Tokyo Kasei University, Otsuma Women’s
University, Kagawa Education Institute of Nutrition,
Jissen Women’s Educational Institute, Japan Women’s
University, and Wayo Women’s University.
In 2011, the department began accepting NST
trainees. From 1 to 4 or 5 terms are conducted a year (5days/ week/ term). Participants are mainly managerial
dietitians, pharmacists, nurses, medical technologists,and physical therapists, and candidates are trainees
whose aim is acquiring the qualifications certified byacademic societies or to become a full-time employee
to calculate the billing charges for the NST. There were18 participants in 2019. Due to the COVID-19
pandemic, these programs accepting external trainee
were cancelled in 2020-2021.
In 2017, the department was involved in the
curriculum of Clinical Clerkship 2, the medical education program of the Faculty of Medicine, the Universityof Tokyo. 106 medical students at M4 grade
participated in the two-day practice course in 2021.
To disseminate NST activities fully in the hospital,
the department has organized two NST-related
seminars throughout the year: Basic Series for
Nutrition Therapy and Clinical Nutrition Seminar. The
department has also organized NST Conference andJoint Conference of Team Medicine (JCTM) for casediscussions to facilitate cooperation with each floor
NST and other medical teams. In 2020, due to the
COVID-19 pandemic, all the seminars and JCTM wereconducted online and the NST Conference was541adjourned. In 2021, the Center combined the twoseminars and restarted with a hybrid style, on-site andonline, with total 546 attendee.
In 2015, the department started “Nutritional
Management e-learning” for all employee to learn basic
knowledge of nutritional management procedure.
In 2016, “The Manual of The Department of ClinicalNutrition Therapy 2015-2016” was published. After
that, “The Pocket Manual of The Department ofClinical Nutrition Therapy 2016-2017”, “The Manualof The Department of Clinical Nutrition Therapy 20172019”, “Records of the Kitchen Renovation 20162018”, “The Pocket Manual of The Department ofClinical Nutrition Therapy 2018-2021”, “Illustrated
Tools of Nutritional Guidance 2018-2022” and “New
Cook Chill Manual 2018-2022” were published byMarch 2020.

Research・Research topic: “Retrospective study using databaseof patients records who have undergone nutritional
guidance”
・Research topic: “Surveillance of nutritional status
and its change in pancreatic cancer patients receiving
chemotherapy”
・ Research topic: “Surveillance of change in bodycomposition by using visceral fat measuring device”
・Research topic: “Roles of microbiome in lifestylerelated diseases” (Joint research)
・ Research topic: “Exploratory research in theassociation of plasma amino acids and the nutrition
status of patients with diabetes mellitus and thecomorbidities”
・Research topic: “Exploratory research of biomarkers
in the blood and body fluid for diabetes mellitus”
・Research topic: “Impact of periodical measurementof serum glycoalbumin on the patients with diabetes
mellitus”
・Research topic: “Impact of periodical measurementof diabetes mellitus-related biomarkers in tear fluid”
・Research topic: “Association of food diversity andobesity in patients with diabetes mellitus”
・Research topic: “Evaluation of nutritional guidanceon the treatment-naïve patients with high LDLcholesterolemia”
・ Research topic: “Association of initial nutritional

condition and prognosis in elderly patients at NST
round”
・ Research topic: “Assessment of dietary intake of
inpatients with diabetes mellitus”
・Research topics: “Correlation research of biomarkers
in the blood and body fluid and diabetes mellitus”
・Research topic: “Association of diet and nutritional
factors and control of blood sugar and lipid inpatients with diabetes mellitus”
・Research topic: “Association of diet and nutritional
factors and sarcopenia and frail in elderly patientswith diabetes mellitus”
・Research topic: “Association of dietary intake andbackground dietary habit in inpatients with diabetes
mellitus”
・Research topic: “Assessment of dietary intake andbodily characteristics in patients with eating disorder”
・Research topic: “Association of change of dietaryintake and weight loss effect in highly obese patients
after bariatric surgery”
・Research topic: “Surveillance of nutritional status
and its change in patients with severe heart failure”
・ Research topic: “Surveillance of nutritional
assessment and guidance at the perioperative clinic”

References<Publications (English)>
1. Nakatsuka T, Tateishi K, Kato H, Fujiwara H,
Yamamoto K, Kudo Y, Nakagawa H, Tanaka Y,
Ijichi H, Ikenoue T, Ishizawa T, Hasegawa K,
Tachibana M, Shinkai Y, Koike K. Inhibition ofhistone methyltransferase G9a attenuates livercancer initiation by sensitizing DNA-damaged
hepatocytes to p53-induced apoptosis. Cell Death
Dis. 12:99, 2021.
2. Yamazaki T, Inada S, Sawada M, Sekine R,
Kubota N, Fukatsu K, Yoshiuchi K. Diets withhigh carbohydrate contents were associated withrefeeding hypophosphatemia: A retrospective
study in Japanese inpatients with anorexia nervosa.
Int J Eat Disord. 54:88-94, 2021.
3. Tanaka Y, Shimanaka Y, Caddeo A, Kubo T, Mao
Y, Kubota T, Kubota N, Yamauchi T, Mancina RM,
Baselli G, Luukkonen P, Pihlajamäki J, YkiJärvinen H, Valenti L, Arai H, Romeo S, Kono N.
LPIAT1/MBOAT7
depletion
increases

542

triglyceride synthesis fueled by high phosphatidylinositol turnover. Gut. 70:180-193, 2021.
4. Aihara M, Kubota N, Minami T, Shirakawa R,
Sakurai Y, Hayashi T, Iwamoto M, Takamoto I,
Kubota T, Suzuki R, Usami S, Jinnouchi H, Aihara
M, Yamauchi T, Sakata T, Kadowaki T.
Association between tear and blood glucose
concentrations: Random intercept model adjustedwith confounders in tear samples negative foroccult blood. J Diabetes Investig. 12:266-276,
2021.
5. Saito K, Nakai Y, Takahara N, Ishigaki K, Suzuki
Y, Inokuma A, Noguchi K, Kanai S, Sato T,
Hakuta R, Saito T, Hamada T, Mizuno S, Kogure
H, Ijichi H, Tateishi K, Koike K. A retrospective
comparative study of S-IROX and modified
FOLFIRINOX for patients with advanced
pancreatic cancer refractory to gemcitabine plus
nab-paclitaxel. Invest New Drugs. 39:605-613,
2021.
6. Sakurai Y, Kubota N, Yamauchi T, Kadowaki T.
Role of Insulin Resistance in MAFLD. Int J Mol
Sci. 22:4156, 2021.
7. Hamada T, Oyama H, Nakai Y, Tada M, Koh H,
Tateishi K, Arita J, Hakuta R, Ijichi H, Ishigaki K,
Kawaguchi Y, Kogure H, Mizuno S, Morikawa T,
Saito K, Saito T, Sato T, Takagi K, Takahara N,
Takahashi R, Tanaka A, Tanaka M, Ushiku T,
Hasegawa K, Koike K. ABO Blood Group and
Risk of Pancreatic Carcinogenesis in Intraductal
Papillary
Mucinous
Neoplasms.
CancerEpidemiol Biomarkers Prev. 30:1020-1028, 2021.
8. Kubota N, Kubota T, Kadowaki T. Midlobularzone 2 hepatocytes: A gatekeeper of liver
homeostasis. Cell Metab. 33:855-856, 2021.
9. Watanabe D, Murakami H, Ohno H, Tanisawa K,
Konishi K, Todoroki-Mori K, Tsunematsu Y, Sato
M, Ogata Y, Miyoshi N, Kubota N, Kunisawa J,
Wakabayashi K, Kubota T, Watanabe K, Miyachi
M. Stool pattern is associated with not only theprevalence of tumorigenic bacteria isolated fromfecal matter but also plasma and fecal fatty acids
in healthy Japanese adults. BMC Microbiol. 21:
196, 2021.
10. Hasegawa Y, Ijichi H, Saito K, Ishigaki K, Takami
M, Sekine R, Usami S, Nakai Y, Koike K, Kubota
N. Protein intake after the initiation of

11.

12.

13.

14.

15.

16.

chemotherapy is an independent prognostic factor
for overall survival in patients with unresectablepancreatic cancer: A prospective cohort study.
Clin Nutr. 40:4792-4798, 2021.
Watkins A, Fukatsu K, Higashizono K, Watanabe
T, Noguchi M, Tominaga E, Murakoshi S,
Yasuhara H. Influence of a Low-Carbohydrate
High-Fat Diet on Peritoneal Inflammation,
Cancer-Associated Lymphocytes, and Survival ina Murine Carcinomatous Peritonitis Model. JPENJ Parenter Enteral Nutr. 45:1293-1301, 2021.
Hayashi T, Kubota T, Mariko I, Takamoto I,
Aihara M, Sakurai Y, Wada N, Miki T, Yamauchi
T, Kubota N, Kadowaki T. Lack of Brain Insulin
Receptor Substrate-1 Causes Growth Retardation,
With Decreased Expression of Growth HormoneReleasing Hormone in the Hypothalamus.
Diabetes. 70:1640-1653, 2021.
Furuzono S, Kubota T, Taura J, Konishi M, Naito
A, Tsutsui M, Karasawa H, Kubota N, Kadowaki
T. A xanthene derivative, DS20060511, attenuates
glucose intolerance by inducing skeletal musclespecific GLUT4 translocation in mice. Commun
Biol. 4:994, 2021.
Sano M, Takahashi R, Ijichi H, Ishigaki K,
Yamada T, Miyabayashi K, Kimura G, Mizuno S,
Kato H, Fujiwara H, Nakatsuka T, Tanaka Y, Kim
J, Masugi Y, Morishita Y, Tanaka M, Ushiku T,
Nakai Y, Tateishi K, Ishii Y, Isayama H, Moses HL,
Koike K. Blocking VCAM-1 inhibits pancreatictumour progression and cancer-associatedthrombosis/thromboembolism. Gut. 70:17131723, 2021.
Ochiai T, Sano T, Nagayama T, Kubota N,
Kadowaki T, Wakabayashi T, Iwatsubo T.
Differential involvement of insulin receptor
substrate (IRS)-1 and IRS-2 in brain insulin
signaling is associated with the effects on amyloid
pathology in a mouse model of Alzheimer's
disease. Neurobiol Dis. 159:105510, 2021.
Ishihama S, Yoshida S, Yoshida T, Mori Y, Ouchi
N, Eguchi S, Sakaguchi T, Tsuda T, Kato K,
Shimizu Y, Ohashi K, Okumura T, Bando YK,
Yagyu H, Wettschureck N, Kubota N, Offermanns
S, Kadowaki T, Murohara T, Takefuji M.
LPL/AQP7/GPD2 promotes glycerol metabolism

543

under hypoxia and prevents cardiac dysfunction
during ischemia. FASEB J. 35:e22048, 2021.
17. Jinnouchi T, Sakurai Y, Miyoshi K, Koizumi C,
Waki H, Kubota N, Yamauchi T. Chronic
Intestinal Pseudo-obstruction with Mitochondrial
Diseases. Intern Med. 61:469-474, 2021.
18. Kato H, Tateishi K, Fujiwara H, Nakatsuka T,
Yamamoto K, Kudo Y, Hayakawa Y, Nakagawa H,
Tanaka Y, Ijichi H, Otsuka M, Iwadate D, Oyama
H, Kanai S, Noguchi K, Suzuki T, Sato T, Hakuta
R, Ishigaki K, Saito K, Saito T, Takahara N,
Kishikawa T, Hamada T, Takahashi R,
Miyabayashi K, Mizuno S, Kogure H, Nakai Y,
Hirata Y, Toyoda A, Ichikawa K, Qu W, Morishita
S, Arita J, Tanaka M, Ushiku T, Hasegawa K,
Fujishiro M, Koike K. MNX1-HNF1B Axis Is
Indispensable for Intraductal Papillary Mucinous
Neoplasm Lineages. Gastroenterology. Epub 2021
Dec 22.

544

Swallowing Center
Director/Associate Professor
Rumi Ueha, M.D., Ph.D.

Vice Director
Haruhi Inokuchi, M.D., Ph.D. (Department of Rehabilitation Medicine)
Asako Kaneoka, SLP., Ph.D. (Rehabilitation Center)

Homepage

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

Introduction and Organization
A condition in which there is a problem withswallowing food or drink is called swallowing disorder.
In recent years, advances in medical technology haveincreased the lifesaving rate and aging of society,resulting in an increase in the number of patients withdysphagia among a wide range of age groups caused bycongenital diseases, stroke, intractable diseases,
malignant tumors, and aging. Since 2009, we have been
providing medical care for patients with dysphagia at
the University of Tokyo Hospital by organizing the "Swallowing Support Team" with specialists in the fieldof swallowing. To provide a more specialized andmultifaceted treatment for dysphagia in 2021, theSwallowing Center was established.
At the Swallowing Center, the departments of
Otolaryngology and Head and Neck Surgery,
Rehabilitation Medicine, Oral-Maxillofacial Surgery
and Orthodontics, Geriatric Medicine, Pediatrics,
Pediatric Surgery, Neurology, Clinical Nutrition,
Nursing, and Clinical Laboratory work together as ateam of multidisciplinary specialists, including
physicians, speech pathologists, nurses, dietitians,
pharmacists, and dental hygienists, taking a
multifaceted approach to each patient.
The following is a list of departments and divisions thatcollaborate with the Swallowing Center:
1. Otolaryngology and Head and Neck Surgery
2. Rehabilitation Medicine
3. Oral-Maxillofacial Surgery and Orthodontics
4. Geriatric Medicine

5. Pediatrics
6. Pediatric Surgery
7. Neurology
8. Clinical Nutrition Center
9. Nursing Department
10. Pharmaceutical Department
We also hold a bimonthly meeting of the Swallowing
Center to share information and improve problems.

Clinical activities
We have outpatient clinics for patients with dysphagia
at the Department of Otorhinolaryngology and Headand Neck Surgery every Tuesday and Thursday
morning. For hospitalized patients, we provide more
specialized and multifaceted treatment for dysphagia
caused by a variety of factors in a wide range of age
groups, with physicians and specialists from multiple
departments working as a team. A weekly swallowing
conference is held on Tuesdays to discuss the various
cases with a multidisciplinary team.
We also actively perform surgical treatment fordysphagia (to prevent aspiration or to improveswallowing function) and provide intensive
rehabilitation after surgery to improve swallowing
function during hospitalization.
The following is a list of swallowing examinations
performed in 2022:
 Videofluorographic swallowing study: 683 cases Videoendoscopic examination of swallowing: 586
cases High-resolution swallowing manometry: 37 cases

545



Swallowing computed tomography: 13 cases

Teaching activities
The center emphasizes educational activities on
feeding and swallowing throughout the hospital, andactively organizes e-learning and training sessions.
We participate in undergraduate education as part ofsystemic lectures and bedside learning by the
Department of Otolaryngology and Head and Neck
Surgery and Rehabilitation Medicine.
Research activities
Our research field covers a variety of topics related toswallowing. Clinical and basic research activities arehighly encouraged. Clinical research is related toswallowing dynamics and physiology, laryngology,
broncho-esophagology, and rhinology, as well as caseresearch and clinical statistics.
Basic research is also encouraged to solve the essenceof clinical problems and to elucidate basic phenomena
or anatomical and cellular structures. Our research
topics are as follows:
1. Effects of aspiration prevention surgery on
patients with severe dysphagia
2. Swallowing mechanisms using pathological andelectrophysiological analysis and VR system
3. Esophageal Motility in neuromuscular disorders
4. Esophageal Motility in systemic sclerosis
5. Swallowing impairment in patients with lungtransplants
6. Evaluation of swallowing physiology withpharyngo-esophageal high-resolution manometry
7. Regeneration of vocal fold structure and its
molecular mechanism
8. Gene expression analysis of recurrent respiratory
papillomatosis
9. Research on preventive rehabilitation for
dysphagia due to chemoradiotherapy for head andneck cancer
10. Pathophysiology of dysphagia after esophageal
cancer surgery
11. Statistical analysis of dysphagia patients using big
data
12. Research on the effect of cervical spine surgery on
swallowing function

References
1.

2.

3.

4.

5.

6.

7.

8.

Sugaya T, Ueha R, Sato T, Goto T, Yamauchi A,
Yamasoba T. Safety of surgical tracheostomy
under continued antithrombotic therapy. Clin
Otolaryngol. 47(1):88-93. 2022.
Masuda H, Ueha R, Sato T, Goto T, Yamauchi A,
Kaneoka A, Suzuki S, Yamasoba T. Risk factors
for aspiration pneumonia after receiving liquid
thickening recommendations. Otolaryngol Head
Neck Surg. 67(1):125-132. 2022.
Ueha R, Ito T, Furukawa R, Kitabatake M, OujiSageshima N, Ueha S, Koyama M, Uranaka T,
Kondo K, Yamasoba T. Oral SARS-CoV-2
inoculation causes nasal viral infection leading toolfactory bulb infection: an experimental study.
Front Cell Infect Microbiol. 12:924725. 2022.
Ueha R, Ito T, Ueha S, Furukawa R, Kitabatake M,
Ouji- Sageshima N, Tanaka H, Uranaka T, Kondo
K, Yamasoba T. Evidence for the Spread of SARSCoV-2 and Olfactory Cell Lineage Impairment in
Close-Contact Infection Syrian Hamster Models.
Front Cell Infect Microbiol. 12: 1019723. 2022.
Sugito R, Yamauchi A, Sato T, Goto T, Ueha R,
Nito T, Yamasoba T. Sex- and age-based
etiological analysis of 2901 patients withdysphonia in a Japanese tertiary medical institute.
J Voice. S0892-1997(22)00236-3. doi: 10.1016/j.
jvoice.2022.08.003. 2022
Kaneoka A, Ueha R, Nagatomo M, Matsunaga A,
Umezaki S, Inokuchi H, Ogata T. Esophageal
speech for a patient with Amyotrophic Lateral
Sclerosis who underwent a central-partlaryngectomy to prevent aspiration: a case report.
Progress in Rehabilitation Medicine. 7:20220064.
doi: 10.2490/prm.20220064. 2022.
Koyama S, Mori E, Ueha R. Insight into themechanisms of olfactory dysfunction by COVID19. Auris Nasus Larynx. doi: 10.1016/j.anl.2022.
12.002. 2022.
Inooka Y, Yamana H, Shinoda Y, Inokuchi H,
Matsui H, Fushimi K, Yasunaga H, Haga N.
Predictive factors for oral intake recovery after
acute stroke: analysis of a Japanese nationwide
inpatient database．Dysphagia. 37(6):1623-1632.
2022.

546

International 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.

547

Center for Epidemiology andPreventive Medicine
Director & Associate Professor
Nobutake Yamamichi, M.D., Ph.D.

Deputy Director & Assistant Professor
Lumine Matsumoto, M.D., Ph.D.

Associates
Keiko Niimi, M.D., Ph.D., Yukari Masuda, M.D., Ph.D.
Hirotaka Matsuzaki, M.D., Ph.D., Eriko Hasumi, M.D., Ph.D., Chie Bujyo, M.D., Ph.D.,
Takako Nishikawa, M.D., Ph.D., Nobuyuki Sakuma, M.D., Ph.D.,

Homepage:https://www.todai-yobouigaku-dock.jp/
https://www.h.u-tokyo.ac.jp/patient/depts/yobouigaku/

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, 20 in April 2019, 22 in January 2021, and 25 in
October 2022. Most of the examinations except for
MRI and CT scan can be performed within our floor,
which increased the convenience and comfort for theexaminees.
In the administrative organization of the Center for
Epidemiology and Preventive Medicine, the Director
directly under the head of the hospital is responsible forthe entire organization. Examinations in the
Department are administered in collaboration withthree Central Clinical Facilities (Clinical Laboratory
Center, Radiological Center, and Department ofEndoscopy and Endoscopic Surgery) and four Clinical548

Divisions (Gastroenterology, Breast and Endocrine
Surgery, Gynecologic Surgery and Ophthalmology and
Vision Collection).
The staff of the Center for Epidemiology andPreventive Medicine is composed of nine physicians.
Three of the regular physicians also perform uppergastrointestinal endoscopy and colonoscopy. Our
department also has 11 nurses, six assistant clerks, andthree medical clerk.

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.

Clinical activities

Past activities

In addition to basic examinations, we provide ten
optional examinations: 1) comprehensive cardiovascular examinations, 2) comprehensive cerebrovascularexaminations, 3) checkup for dementia, 4) colorectal
cancer screening, 5) uterine cancer screening, 6) breast
cancer screening, 7) lung cancer screening, 8) tumor
marker diagnosis, 9) estimation of gastric cancer risk,and 10) pancreatic cancer screening. While meeting theneeds of examinees, we have increased the number ofthe optional examinations.
The physicians of our department are responsible foranalyzing the results of examinations and performing
overall evaluations. We take plenty of time to perform
comprehensive medical examinations and instantly
write a referral letter to each department in the
University of Tokyo Hospital when we find any
abnormality through the examinations. Formally, theexaminee is notified in writing within approximately
three weeks after the examination. We also offer eachexaminee a free consultation so that we can help
him/her understand the results or decide whether tohave further detailed examination.

The total number of examinees (who had basic
examinations and optional examinations) in the FY
2022 was 9400 including 3249 in basic examinations,
596 in complete cardiovascular examinations, 751 incomplete cerebrovascular examinations, 111 in checkup for dementia, 434 in colorectal cancer screening,
700 in uterine cancer screening, 842 in breast cancer
screening, 763 in lung cancer screening, 1373 in tumor
marker diagnosis, 343 in estimation of gastric cancer
risk, 238 in pancreatic cancer screening, and 10 inupper gastrointestinal endoscopy (later). Respiratory
function test has been cancelled from March 31,2020
due to coronavirus.
One of the important roles of our center is to provide
the appropriate medicine to the examinees when any
abnormal finding was detected. We provide referral
letters to the department within/outside of our hospitalfor detailed examination or treatment, according to therequest by the examinees. Prompt reference to the
medical department in the University of Tokyo
Hospital is one of the most contributable factors for thesatisfaction of the examinees. In the FY 2022, weissued 1513 letters of referral to other departments in
our hospital and 69 to other hospitals.
We have expanded our public relations efforts. We
renewed brochures and 15,000 brochures weredelivered during the FY 2021.
We have updated our original website(https://www.todai-yobouigaku-dock.jp/) and offer upto-date information to the examinees. We also renewed
brochure, distributing 15,000 copies within our hospitaland on and off campus of the University of Tokyo as
well. We have established preferential treatment system
for graduates, faculty and staff to acquire new
examinees.

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

549

The University of Tokyo Hospital established theCenter for International Preventive Medicine in April
2020 and started to provide public services in July 2022.
We offer full cooperation to the Center for International
Preventive Medicine management.

References
Academic Papers in English
1. Takeuchi C, Yamamichi N, Liu YY, Ito M, Furuta
T, Nakajima S, Sakaguchi Y, Takahashi Y, Tsuji Y,
Niimi K, Tomida S, Fujishiro M, Yamamichi N,
Ushijima T. Autoimmune gastritis inducesaberrant DNA methylation reflecting its
carcinogenic potential. J Gastroenterol. 2022
Mar;57(3):144-155.
2. Hisada H, Sakaguchi Y, Oshio K, Mizutani S,
Nakagawa H, Sato J, Kubota D, Obata M, Cho R,
Nagao S, Miura Y, Mizutani H, Ohki D, Yakabi S,
Takahashi Y, Kakushima N, Tsuji Y, Yamamichi
N, Fujishiro M. Endoscopic Treatment ofSuperficial Gastric Cancer: Present Status andFuture. CurrOncol. 2022 Jul;29(7):46784688.
3. Hisada H, Tamura N, Tsuji Y, Nagao S, Fukagawa
K, Miura Y, Mizutani H, Ohki D, Yakabi S,
Minatsuki C, Takahashi Y, Sakaguchi Y,
Yamamichi N, Fujishiro M. The impact ofsarcopenia on adverse events associated withgastric endoscopic submucosal dissection. Surg
Endosc. 2022 Sep;36(9):6387-6395.
4. Ohki D, Tsuji Y, Shinozaki T, Sakaguchi Y,
Mizutani H, Nagao S, Miura Y, Fukagawa K,
Tamura N, Yakabi S, Yamamichi N, Fujishiro M.
Long-term prognosis after endoscopic resection of
T1a-MM/T1b-SM1 esophageal squamous cell
carcinoma. Medicine (Baltimore). 2022 Dec;
101(49): e32115.
5. Arai J, Suzuki N, Niikura R, Ooki D, Kawahara T,
Honda T, Hasatani K, Yoshida N, Nishida T,
Sumiyoshi T, Kiyotoki S, Ikeya T, Arai M,
Ishibashi R, Aoki T, Tsuji Y, Yamamichi N,
Hayakawa Y, Fujishiro M. Chemoprevention for
Colorectal Cancers: Are Chemopreventive Effects
Different Between Left and Right Sided
Colorectal Cancers? Dig Dis Sci. 2022 Nov;
67(11):5227-5238.

Saito K, Shimamoto T, Takahashi Y, Okushin K,
Takahashi M, Masuda Y, Nishikawa T, Kakushima
N, Wada R, Yamamichi N. Gender-specificfactors contributing to visceral obesity including
the sleep-obesity relationship: a large-scale crosssectional study from East Asia. Sci Rep. 2022 Nov
24;12(1):20318.
7. Takahashi Y, Yamamichi N, Kubota D,
Shimamoto T, Nagao S, Sakuma N, Sakaguchi Y,
Yakabi S, Tsuji Y, Wada R, Mitsushima T, Ichinose
M, Fujishiro M. Risk factors for gastric cancer inJapan in the 2010s: a large, long-term
observational study. Gastric Cancer. 2022 May;25(3):481-489.
8. Ohki D, Yamamichi N, Sakaguchi Y, Takahashi Y,
Kageyama-Yahara N, Yamamichi M, Takeuchi C,
Tsuji Y, Sakai Y, Sakurai K, Tomida S, Koike K,
Fujishiro M. Transcriptome of sessile serrated
adenoma/polyps is associated with MSI-highcolorectal cancer and decreased expression of
CDX2. Cancer Med. 2022 Dec;11(24):5066-5078.
9. Tamura N, Sakaguchi Y, Furutani W, Matsui M,
Nagao S, Sakuma N, Fukagawa K, Miura Y,
Mizutani H, Ohki D, Kataoka Y, Saito I, Ono M,
Minatsuki C, Tsuji Y, Ono S, Kodashima S, Abe H,
Ushiku T, Yamamichi N, Koike K, Fujishiro M.
Magnifying endoscopy with narrow-band imaging
is useful in differentiating gastric cancer frommatched adenoma in white light imaging. Sci Rep.
2022 May 19;12(1):8349.
10. Yamamichi N, Shimamoto T, Takahashi Y,
Takahashi M, Takeuchi C, Wada R, Fujishiro M.
Trends in proton pump inhibitor use, reflux
esophagitis, and various upper gastrointestinal
symptoms from 2010 to 2019 in Japan. PLoS One.
2022 Jun 17;17(6):e0270252.
11. Hisada H, Tsuji Y, Obata M, Cho R, Nagao S,
Miura Y, Mizutani H, Ohki D, Yakabi S, Takahashi
Y, Sakaguchi Y, Kakushima N, Yamamichi N,
Fujishiro M. The impact of sarcopenia on shortand long-term outcomes of endoscopic
submucosal dissection for early gastric cancer. J
Gastroenterol. 2022 Dec;57(12):952-961.
12. Yamamichi N, Shimamoto T, Okushin K,
Nishikawa T, Matsuzaki H, Yakabi S, Takahashi
M, Wada R, Koike K, Fujishiro M. Fibrosis-4
index efficiently predicts chronic hepatitis and
6.

550

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liver cirrhosis development based on a large-scaledata of general population in Japan. Sci Rep. 2022
Nov 27;12(1):20357.
Kubota D, Takahashi Y, Yamamichi N, Matsui M,
Shimamoto T, Minatsuki C, Nakagawa H,
Mizutani S, Tsuji Y, Sakaguchi Y, Tamura N,
Yakabi S, Ohki D, Mizutani H, Niimi K, Wada R,
Fujishiro M. Analysis of Barrett's Esophagus and
Its Risk Factors: A Cross-Sectional Study of
10,122 Subjects at a Japanese Health Examination
Center. Digestion. 2022;103(6):411-420.
Ohki D, Yamamichi N, Sakaguchi Y, Takahashi Y,
Kageyama-Yahara N, Yamamichi M, Takeuchi C,
Tsuji Y, Sakai Y, Sakurai K, Tomida S, Koike K,
Fujishiro M. Transcriptome of sessile serrated
adenoma/polyps is associated with MSI-highcolorectal cancer and decreased expression of
CDX2. Cancer Med. 2022 May 10.
Matsubara TJ, Fujiu K, Kodera S, Kani K, Goto K,
Shimizu Y, Oguri G, Hasumi E, Kojima T,
Komuro I.
Prediction of Atrial Fibrillation
Being Asymptomatic at First Onset by Cardiac
Pacing Int Heart J. 2022;63(3):486-491.
Takumi J Matsubara, Katsuhito Fujiu, Eriko
Hasumi, Issei Komuro et al. Prediction of Atrial
Fibrillation Being Asymptomatic at First Onset by
Cardiac Pacing. International heart journal 63 (3)486-491 2022
Late-onset right ventricular failure after
continuous-flow left ventricular assist device
implantation: case presentation and review of theliterature. J Cardiol. 2022;80 (2):110-115.
A Cold-Blooded Tiptoer: Nonresolving Cellulitis
in an Immunocompromised Patient. Open Forum
Infect Dis. 2022;9(4): ofac074.
Determining the factors for interhospital transfer
in advanced heart failure cases. Int J Cardiol Heart
Vasc. 2022; 40:101035.
Sarcopenia and risk of infection in adult hearttransplant recipients in Japan. ESC Heart Fail.
2022;9(2):1413-1423.
Residual Pulmonary Vascular Resistance Increase
Under Left Ventricular Assist Device Support
Predicts Long-Term Cardiac Function After Heart
Transplantation. Front Cardiovasc Med. 2022;9:904350.

International conferences
1. Takako Nishikawa, Makoto Kurano, Hitoshi Ikeda,
Nobutake Yamamichi, Yutaka Yatomi, Kazuhiko
Koike, Mitsuhiro Fujishiro. Lysophosphatidylserine
may stimmulate liver fibrosis EASL scientificprogramme committee of The International Liver
Congress™ 2022 to be held in London, United
Kingdom, 22 to 26 June 2022

551

Medical Community Network andDischarge Planning Center
Associate Professor
Masahiko Sumitani, M.D., Ph.D. (concurrently)

Assistant Profeesor

Homepage https://www.h.u-tokyo.ac.jp/english/centers-services/central-clinicalfacilities/medical-community-network-and-discharge-planning/index.html
Introduction and Organization
In April 1997, plans for the Department of Medical
Social Service and Welfare were initiated by the
University of Tokyo Hospital with the aim ofsupporting inpatients upon discharge. The Department
was officially authorized in April 2000, the firstamong national universities. In April 2005, theDepartment began providing assistance to outpatientsreferred from other hospitals and was renamed theDepartment of Medical Community Network andDischarge Planning. Further, in 2019, the departmentchanged the name to Medical Community Network
and Discharge Planning Center. The Center provides
assistance to outpatients referred from local medical
institutions, to inpatients being discharged to theirhomes, and to inpatients being transferred to local
medical institutions.

Clinical activities
Assistance to patients receiving 9 medica I treatment:
The Department provides assistance to outpatientsreferred from local medical institutions. Our staff
helps patients make appointments and follow procedures to receive medical treatment. The Department
assists new outpatients in arranging general consultations, helps outpatients schedule spedalized treatment,
and provides assistance to patients who have beenreferred to a specific physician.
Assistance to inpatients upon discharge: The
Department provides assistance to patients for whomtransfer to a local medical institution or discharge tohome if need arises.
Many of such patients are highly dependent on
medical care due to the severity of their condition. For
those receiving medical care at home, our department
staff arranges home visits by primary care doctors andnurses. For patients being transferred to local
institutions, our staff provides assistance both togeneral hospitals and hospice care units.
Home Care Support (Home Care Support clinic): Our
Home Care Support Clinic, which offers home care
support to our outpatients, has been running since
Janualy 2003. The clinic supports the implementationand coordination of home care services, and refers
outpatients requesting hospital admission to otherhospitals or facilities.
Consultation by Social Worker (Consultation on
Recuperation): Our consultation service provided bysocial workers has been running since 2012. Oursocial workers mainly consult enquiries regarding
patient recuperation.
Transferring out patients to local institutes: Aiming todefining the distinction of the medical role between
the University Hospital and local institutes andfacilitate transferring our outpatients to them, theproportion of such transferring patients to first-visit
patients keeps more than 80%.

Teaching activities
We educate undergraduate students of the Medical
Social Working and Welfare of other university.

552

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.

553

Department of Cancer Resource
CenterChief
Sachiyo Nomura, M.D., Ph.D.

Associate chief
Mayuyo Mori, M.D., Ph.D.

Counseling staff
Kunie Wakao, RN., Yuko Irisawa, RN., Takako Wakeda, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/gansoudan/

Introduction and Organization
As part of national efforts to address cancer, thegovernment has been establishing a network of“cancer care hub hospitals.” In response to its being
designated as a regional cancer care hub hospital in2008, the University of Tokyo Hospital established theCancer Patient Support Center to provide consultations to cancer patients and their families as well as
residents in neighboring communities with the aim ofleading them to appropriate departments and facilities.

Medical Services
Provision of information if patient contracts cancer
If a person gets cancer, the first thing they need to
do is collect information on cancer. The Cancer
Counseling and Support Center provides information
and booklets on different types of cancer.
Furthermore, the person needs to accurately
understand the doctors’ explanations to select the besttreatment for oneself from the various options
presented by doctors. At the Cancer Counseling andSupport Center, we explain difficult medical terms in
simple language, and we help patients understand theirdoctors’ advice.

Various kinds of advice related to the medical careof cancer
If a person contracts cancer, besides the medical
problem of what kind of treatment to undergo andwhere, there are also issues related to medical carewhen receiving treatment, such as medical expenses,
how to get along after being discharged from hospital,
job, and nursing services. The Cancer Counseling andSupport Center provides patients with advice andsupport so that they can resolve such social worries.
Provision of information on second opinions
The Center provides information on how to get asecond opinion and on facilities that provide second
opinions.
Various kinds of advice related to the appearancechanges caused by cancer treatment
Cancer treatment often causes appearance changes
such as hair loss and skin pigmentation. The center
provides patients with practical advice and support
about wig and cover make-up.
Provision of general information and advice on
cancer
The Center sends out and provides information topeople who do not have cancer but who want to find554

out about cancer, for instance the treatment andscreening for it.

Open hours
If you have any queries, please contact us on
03-5800-9061 between 9am-12noon, 1pm-4pm
weekdays.

Research activities
Our research field covers the relation between
appearance changes caused by cancer therapy andPatients’ quality of life.

555

Clinical Research Promotion
CenterProfessor, Director
Takashi Moritoyo M.D., Ph.D.

Associate Professor, Vice Director
Tatsuya Maruyama, M.D., Ph.D.

Project Associate Professor,
Ruri Kaneda, M.D., Ph.D.

Project Lecturer
Kosuke Kashiwabara, Ph.D.

Assistant Professor
Takuya Kawahara, Ph.D., Mihoko Shibuya, M.D., Ph.D., Mariko Inoue, M.D. , Ph.D.

Project Assistant Professor
Miki Ohta, M.D., Ph.D., Ryo Matsuoka, M.D., Ph.D.

Homepagehttps://www.h.u-tokyo.ac.jp/english/centers-services/clinicalresearch-division/clinical-research-promotion-center/index.html

History and Organization
The Clinical Research Promotion Center was
established in 2019. It originated from Clinical Trial
Managing Center, which was established in 1998, andsubsequently the former Clinical Research Center,
which was established in 2001. Currently, it belongs to
the Clinical Research Services of the hospital andprovides supports not only for clinical trials but also forinvestigator-initiated (independent) clinical studies.
However, given the increasing diversity and volume ofclinical research conducted in the University of Tokyo
Hospital, demand mounted for the structural
framework to provide support for multi-centercollaborative studies, research on new technology inevidence-based medicine and translational research etc.
In response to such diversified demands, the former
Clinical Research Center was reorganized in April 2010
into the Clinical Research Support Center, enablingstrengthened support and expeditious promotion ofclinical research.
The Center at the beginning consisted of Site
Coordinating Unit, roughly equivalent to the former
Clinical Research Center, and Central Coordinating
Unit, which provides coordinating functions forresearch such as multicenter trials.
Site Coordinating Unit is comprised of the[Institutional Review Board (IRB) Secretariat
Division] [Investigational Drug/Information Control
Division] and [Clinical Research Coordinator
Division], each charged with IRB secretarial affairs,
management of drugs used in the conduct of clinicalresearch and provide assistance with safety information
reporting, and clinical research coordination activities.
In addition to the existing Consultation Division, newdivisions such as Operation Division, Biostatistics
Division, Data Management Division, Monitoring
Division and Safety Information Division and556

Operation Division have been added to the Central
Coordinating Unit.
In 2011, the Center was selected as an Ministry of
Health, Labour and Welfare (MHLW)-funded Center of
Excellence for early stage and exploratory clinical
trials of drugs for psychiatric and neurological diseases,
enabling the Center to reinforce the staff and to beequipped 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 to ensuretransparency of clinical research. IRB for reviewing
industry-initiated and investigator-initiated clinical
trials was newly established in the hospital. With
respect to the IRB’s secretarial and administrative
duties, the Center will continue to take responsibilities.
Moreover, an Specific Clinical Research Steering
Committee was established under the hospital director
and external audit committee to seek external
evaluation. In addition, we integrated clinical research
management system by strengthening management ofconflicts of interest, created educational environment
for clinical research personnel, formed collaboration
with the Clinical Evaluation and Safety Division tostrengthen safety management system. As a result, theUniversity of Tokyo Hospital received accreditation asa clinical research core 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
Drug Management Division. Furthermore, Consultation Division was relocated outside the unit. In 2017,
The Regulatory Strategy Division was also establishedwithin the Central Coordinating Unit. In order tocomply with the Clinical Trials Act that was enforced
in April 2018, we established Clinical Research Site
Secretariat, enacted general and individual rules to
respond to the act and started operation.
Furthermore, in order to clarify that it is anorganization that promotes clinical research, the Center
was renamed as Clinical Research Promotion Center in
December 2019. The Center was reorganized into 8
departments.
<Investigator-Initiated Clinical Trials Promotion
Department>
The department is responsible for: (1) secretariat
duties for investigator-initiated clinical trials, advanced
medical treatment, patient-proposed healthcare
services and regenerative medicine; (2) Providing
advice and support regarding development strategy,
trial design, pharmaceutical affairs, funding, intellectual property, industry-academia collaboration, etc.;(3) Providing support (study management, monitoring,safety information support, data management,
biostatistics, etc.) to promote investigator-initiatedtrials.

557<Industry-Initiated Clinical Trials Promotion
Department>
The department is responsible for: (1) Supporting thesafe and smooth implementation of industry-initiatedclinical trials; (2) CRC operations, study drug
management, and clinical psychological examinations.
<IRB Office>The office is responsible for: (1) Managing theInstitutional Review Board (IRB) and coordinatingwith related departments; (2) Providing support forinvestigators 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 Management Department>
The department is responsible for Management ofsafety reports and collection and reporting of safety
information. (In March 2023, the Personal Information
Management Office was abolished and its name waschanged to the Medical Safety Management
Department.)<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 investigators who wish to conduct clinical research;(5) Management, education and training of clinicalresearch trainers; (6) Management of the progress ofclinical research conducted at the University of Tokyo
Hospital.
<Network Promotion Department>
The department is responsible for: (1) Secretariat
duties for the National University Hospital ClinicalResearch Promotion Initiative joined by 44 hospitals of
42 national universities; (2) Secretariat duties for the
University of Tokyo Hospital related to the University
Hospital Clinical Trial Alliance which is a regional
network of national university hospitals involved inclinical research (consisting of 8 universities and 9
hospitals in the Kanto-Koshinetsu region).

<Clinical Trials Patient Counseling Department>
The department is responsible for providing
consultation services for patients and citizens who
would like to use advanced medical care and public
relation activities.

Clinical Research Promotion
Activities
The Clinical Research Promotion Center provides
wide range of support from pre-application
consultation, secretariat for the IRB to supporting theimplementation and reporting of clinical trials. In 2002,
during the time of the Clinical Trials Department, theCenter began providing assistance for investigatorinitiated clinical trials evaluating therapeutic drugs andstudies involving unapproved drugs in addition toconventional clinical trials (from 2015 use ofunapproved drugs in clinical research was transferred
to Research Ethics Committee of Graduate School of
Medicine and School of Medicine, and from 2018, it
was moved to Evaluation Committee on Unapproved
News Drugs). To further improve the quality of these
supports we decided to adopt ICH-GCP guidance andcomplied with the guidelines, procedure manuals,
styles and guidance etc. From 2009, we have been
providing support for all invasive and interventional
clinical research.
For industry-initiated clinical trials, we hold apreliminary hearing session (called “protocolpresentation”) in order to shorten the period fromapplication to approval and enhance the content ofreview. As a result, we could avoid re-review by the
IRB due to lack of information.
Since 2002, Clinical research coordinators (CRC) of
the Center have been supporting all clinical trials forapproval and post marketing trials. We started tosupport in part investigator-initiated research from2004. We started providing CRC support toinvestigator-initiated research on a beneficiary-paysbasis from 2005 and clinical pharmacology studies inhealthy volunteers from 2012. CRCs exclusively
involved in investigator-initiated research, have been
employed as needed. CRC support for Advanced
Medical Care Program B which University of Tokyo
Hospital participated as a head investigational site wasinitiated in 2017.

558

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
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.
Regarding the exploratory studies, monitoring and data
management were to be carried out by each clinicaldepartment, the Center undertook responsibility forsupervision of the quality control (QC). The Center
manages SAE (severe adverse event) reporting andsupports various safety reporting in order to ensure thatclinical studies are conducted safely. One of the majorachievements is the investigator-initiated clinical trialof the pediatric ventricular assist device; the trial was
initiated in February 2012, applied for regulatory
approval in November 2014, and marketing approval
was received in June 18, 2015.
Since its establishment in May 2012, the Phase 1 Unit
(P1 Unit) has undertaken various preparations to
respond to early phase clinical research, such as
development of SOP program, procedure manuals,
establishment of in-house collaboration system, on-the
job training for staff and the system for recruiting
health volunteers. P1 Unit conducted its very firstclinical study in October 2012. In September 2018 theunit was relocated as a new ward with augmented 21
beds exclusively aimed for clinical 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.
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, the University of Tokyo took thelead in establishing the 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.

559

Education/Training
The Center has been accepting M3/M4 students fortraining course in ‘Clinical Clerkship’ since it become
mandatory in 2013. From 2017, we have been offeringsystematic lectures on “Clinical Research” for M2
medical students. In addition, we have been accepting
junior resident physicians for training as a part of the
M.D. residency-training program.
Education and Training Division was established in2015 and since then it has been providing education andtraining for students and researchers. In particular, wehave developed curriculum called CREDITS(Continuous Systematic Education & Training
Curriculum for Clinical Researchers and Specialists)
jointly with UHCT Alliance.
Clinical instructor system was established in 2015, in
which physicians recommended by each clinicaldepartment hold an additional position at the ClinicalResearch Promotion Center concurrently with theirdepartment, centrally manage information on clinicalresearch conducted in their own departments and holdregular training sessions to disseminate information on
education and training programs.
The University of Tokyo Hospital has conductedannual CRC training program for national, public andprivate university hospitals since 2010, commissionedby the Ministry of Education, Culture, Sports, Scienceand Technology. As a part of the Japan Agency for
Medical Research and Development (AMED) project,training workshop for clinical research personnel has
been held since 2017, sponsored by the University ofTokyo.
Furthermore, in response to the shortage ofbiostatisticians, biostatistics and bioinformatics course
was established by AMED, at the university hospital.
In 2018, master’s course was also established within
the Graduate School of Interdisciplinary Information
Studies and the Clinical Research Promotion Centerhas established a system to conduct practical training
for course participants.

Research Activities
In April 2007, with the cooperation of the Biostatistics
Department, the Center launched the Clinical Trial
Data Management course (endowed course).
As of fiscal 2020, the Center was involved inscientific meetings, which include The Japan Societyof Clinical Pharmacology and Therapeutics,
Conference on CRC and Clinical Trials, etc. As for
publications such as academic papers, 55 papers were
produced (42 papers in English and 3 papers inJapanese).

Publications
1)

2)

3)

4)

5)

Mitsui J, Matsukawa T, Tanaka M, Sato NS,
Nakamoto FK, Yasuda T, Naruse H, Matsukawa
MK, Ishiura H, Nagase M, Yamamoto Y,
Kuzuyama H, Wada I, Ga T, Yamazaki T,
Moritoyo T, and Shoji Tsuji. Randomized, doubleblind, placebo-controlled phase 1 study toevaluate the safety and pharmacokinetics of highdoses of ubiquinol in healthy adults. Neurol Clin
Neurosci. 10:14–24, 2022
Shinya Y, Hasegawa H, Shin M, Kawashima M,
Koizumi S, Katano A, Suzuki Y, Kashiwabara K,
Saito N. In reply: stereotactic radiosurgery
provides long-term safety for patients witharteriovenous malformations in the diencephalon
and brainstem: the optimal dose selection andlong-term outcomes. Neurosurgery. 92(2):e42–
e43, 2022
Matsubara M, Haruna M, Yonezawa K, Yokoyama
M, Tahara-Sasagawa E, Hikita N, Nakamura Y,
Mizuno Y, Sanada H, Tamai N, Abe M,
Kashiwabara K. Development and validation of an
infant facial skin assessment tool: a prospective
observational study. BMC Pediatrics. 22: 614,
2022
Ebata S, Yoshizaki A, Oba K, Kashiwabara K,
Ueda K, Uemura Y, Watadani T, Fukasawa T,
Miura S, Yoshizaki-Ogawa A, Okiyama N, Kodera
M, Hasegawa M, Shinichi S. Safety and efficacyof rituximab in systemic sclerosis (DESIRES):
open-label extension of a double-blind,
investigators-initiated, randomised, placebocontrolled trial. Lancet Rheumatology. 4(8):E546–E555, 2022
Murayama R, Oyama H, Abe-Doi M, Masamoto Y,
Kashiwabara K, Tobe H, Komiyama C, Sanada H,
Kurokawa M. Safety verification of a new
peripheral intravenous catheter placed in the upperarm vein for administration of drugs with high560

irritant potential. Drug Discoveries andTherapeutics. 16(3): 128–134, 2022
6) Shimura T, Nakagami G, Ogawa R, Ono S,
Takahashi T, Nagata M, Kashiwabara K, Sugama
J, Sanada H, Oe M. Incidence of and risk factors
for self-load-related and medical device-relatedpressure injuries in critically ill patients: aprospective observational cohort study. Wound
Repair and Regeneration. 30(4): 453–467, 2022
7) Hasegawa H, Inoue A, Helal A, Kashiwabara K,
Meyer FB. Pineal cyst: results of long-term MRI
surveillance and analysis of growth and shrinkage
rates. Journal of Neurosurgery. 138(1): 113–119,
20228) Sugawara Y, Hirakawa Y, Mise K, Kashiwabara K,
Hanai K, Yamaguchi S, Katayama A, Onishi Y,
Yoshida Y, Kashihara N, Matsuyama Y, Babazono
T, Nangaku M, Wada J. Analysis of inflammatory
cytokines and estimated glomerular filtration rate
decline in Japanese patients with diabetic kidneydisease: a pilot study. Biomarkers in Medicine.
16(10): 759–770, 2022
9) Ebata S, Oba K, Kashiwabara K, Ueda K, Uemura
Y, Watadani T, Fukasawa T, Miura S, YoshizakiOgawa A, Yoshihide A, Yoshizaki A, Sato S.
Predictors of rituximab effect on modified rodnan
skin score in systemic sclerosis: a machinelearning analysis of the DESIRES trial.
Rheumatology. 61(11): 4364–4373, 2022
10) Ishii J, Kashiwabara K, Ozaki Y, Takahashi H,
Kitagawa F, Nishimura H, Ishii H, Iimuro S,
Kawai H, Muramatsu T, Naruse H, Iwata H,
Tanizawa-Motoyama S, Ito H, Watanabe E,
Matsuyama Y, Fukumoto Y, Sakuma I, Nakagawa
Y, Hibi K, Hiro T, Hokimoto S, Miyauchi K,
Ohtsu H, Izawa H, Ogawa H, Daida H,
Shimokawa H, Saito Y, Kimura T, Matsuzaki M,
Nagai R. Small dense low-density lipoproteincholesterol and cardiovascular risk in statintreated patients with coronary artery disease.
Journal of Atherosclerosis and Thrombosis.
29(10): 1458–1474, 2022
11) Ebata S, Yoshizaki A, Fukasawa T, YoshizakiOgawa A, Asano Y, Kashiwabara K, Oba K, Sato
S. Percentage of residual B cells after 2 weeks ofrituximab treatment predicts the improvement ofsystemic sclerosis-associated interstitial lungdisease. The Journal of Dermatology. 49(1): 179–
183, 2022
12) Taira N, Kashiwabara K, Tsurutani J, Kitada M,
Takahashi M, Kato H, Kikawa Y, Sakata E, Naito
Y, Hasegawa Y, Saito T, Iwasa T, Takashima T,
Aihara T, Mukai H, Hara F. Quality of life in arandomized phase II study to determine theoptimal dose of 3-week cycle nab-paclitaxel inpatients with metastatic breast cancer. Breast
Cancer. 29(1):131–143, 2022
13) Erratum: Taira N, Kashiwabara K, Tsurutani J,
Kitada M, Takahashi M, Kato H, Kikawa Y, Sakata
E, Naito Y, Hasegawa Y, Saito T, Iwasa T,
Takashima T, Aihara T, Mukai H, Hara F.
Correction to: Quality of life in a randomized
phase II study to determine the optimal dose of 3week cycle nab-paclitaxel in patients withmetastatic breast cancer. Breast Cancer. 29(1):
186–188, 2022
14) Kawahara T, Yamada K, Terashima R, Takashima
I, Ogata T, Tanaka S, Chikuda H, Miura H,
Nakamura K, Ohe T. Practical guidance to handle
missing values in the 25-question GeriatricLocomotive Function Scale (GLFS-25): A
simulation study. BMJ Open. 12:e065607, 2022
15) Tomioka Y, Sekino M, Gu J, Kurita M, Yamashita
S, Miyamoto S, Iida T, Kanayama K, Yoshimura
K, Nakagawa M, Akawaza S, Kagaya Y, Tanaka
K, Sunaga Y, Ueda K, Kawahara T, Tahara Y,
Okazaki M. Wearable, wireless, multi-sensor
device for monitoring tissue circulation after freetissue transplantation: a multicentre clinical trial.
Scientific Reports. 12:16532, 2022
16) Kawahara T, Iwamoto T, Takashima I, Hanazawa
R, Uemura K, Uemura Y, Mukai H, Kikawa Y,
Taira N. Association of change in health-related
quality of life and treatment discontinuation inmetastatic breast cancer: a post hoc, exploratory
analysis of two randomized clinical trials.
Supportive Care in Cancer. 30:8367–8375, 2022
17) Terada J, Fujita R, Kawahara T, Hirasawa Y,
Kinoshita T, Takeshita Y, Isaka Y, Kinouchi T,
Tajima H, Tada Y, Tsushima K. Favipiravir,
camostat, and ciclesonide combination therapy inpatients with moderate COVID-19 pneumonia
with/without oxygen therapy: An open-label,

561

single-center phase 3 randomized clinical trial.
eClinicalMedicine. 49:101484, 2022
18) Kawahara T, Shiba K, Tsuchiya A. Application of
causal inference methods in the analysis ofobservational neurosurgical data: G-formula andmarginal structural model. World Neurosurgery.
161:310–315, 2022
19) Morita T, Kawahara T, Stone P, Sykes N,
Miccinesi G, Klein C, Stiel S, Hui D, Deliens L,
Heijltjes MT, Mori M, Heckel M, Robijn L,
Krishna L, Rietjens J. Intercountry andintracountry variations in opinions of palliative
care specialist physicians in Germany, Italy, Japanand UK about continuous use of sedatives: aninternational cross-sectional survey. BMJ Open.
12:e060489, 2022
20) Kimura N, Kawahara T, Uemura Y, Atsumi T,
Sumida T, Mimura T, Kawaguchi Y, Amano H,
Iwasaki Y, Kaneko Y, Matsui T, Muro Y, Imura
Y, Kanda T, Tanaka Y, Kawakami A, Jinnin M,
Ishii T, Hiromura K, Miwa Y, Nakajima H,
Muwana M, Nishioka Y, Morinobu A, Kameda H,
Kohsaka H. Branched chain amino acids in thetreatment of polymyositis and dermatomyositis: aphase II/III, multi-centre, randomized controlled
trial. Rheumatology. 61:4445-4454, 2022
21) Kawahara T, Taira N, Shiroiwa T, Hagiwara Y,
Fukuda T, Uemura Y, Mukai H. Minimal
important differences of EORTC QLQ-C30 for
metastatic breast cancer patients: Results from arandomized clinical trial. Quality of Life Research.
31:1829–1836, 2022
22) Arai J, Niiukra R, Hayakawa Y, Kawahara T,
Honda T, Hasatani K, Yoshida N, Nishida T,
Sumiyoshi T, Kiyotoki S, Ikeya T, Arai M, Suzuki
N, Tsuji Y, Yamada A, Kawai T, Koike K.
Chemoprevention of oesophageal squamous cell
carcinoma and adenocarcinoma: a multicentre
retrospective cohort study. Digestion. 103:192204, 2022
23) Niikura R, Aoki T, Shichijo S, Yamada A,
Kawahara T, Kato Y, Hirata Y, Hayakawa Y,
Suzuki N, Hirasawa T, Tada T, Koike K. Artificial
intelligence versus expert endoscopists fordiagnosis of gastric cancer in patients who
underwent upper gastrointestinal endoscopy.
Endoscopy. 54:780-784, 2022

24) Morishita-Kawahara M, Koike K, Kawahara T,
Kamibeppu K. Relationship between satisfaction
with care and quality of life among family
caregivers of terminal cancer patients in generalwards: a cross-sectional study. International
Journal of Palliative Nursing. 28:575-582, 2022
25) Morishita-Kawahara M, Tsumura A, Aiki S, Sei Y,
Iwamoto Y, Matsui H, Kawahara T. Association
between family caregivers’ satisfaction with carefor terminal cancer patients and quality of life of
the bereaved family: A prospective pre- and postloss study. Journal of Palliative Medicine. 25:8188, 2022
26) Aizawa H, Kato H, Oba K, Kawahara T, Okubo Y,
Saito T, Naito M, Urushitani M, Tamaoka A,
Nakamagoe K, Ishii K, Kanda T, Katsuno M,
Atsuta N, Maeda Y, Nagai M, Nishiyama K,
Ishiura H, Toda T, Kawata A, Abe K, Yabe I,
Takahashi-Iwata I, Sasaki H, Warita H, Aoki M,
Sobue G, Mizusawa H, Matsuyama Y, Haga T,
Kwak S. Randomized phase 2 study of
perampanel for sporadic amyotrophic lateralsclerosis. Journal of Neurology. 269:885–896,
202227) Cho S, Kurokawa R, Hagiwara A, Gonoi W, Mori
H, Kawahara T, Nakaya M, Sakamoto N, Fujita N,
Kamio S, Koyama H, Abe O. Localization of theCentral Sulcus Using the Distinctive High Signal
Intensity of the Paracentral Lobule on T1WI.
Neuroradiology. 64:289-299, 2022
28) Nakayama A, Morita H, Sato T, Kawahara T, Kato
S, Itoh H, Komuro I. Small dense low-density
lipoprotein cholesterol is a potential marker forpredicting laser treatment for retinopathy indiabetic patients. Journal of Atherosclerosis andThrombosis. 29:678-691, 2022
29) Shiroiwa T, Hagiwara Y, Taira N, Kawahara T,
Konomura K, Iwamoto T, Noto S, Fukuda T,
Shimozuma K. Randomized controlled trial of
paper-based at a hospital versus continualelectronic patient-reported outcomes at home formetastatic cancer patients: does electronic
measurement at home detect patients’ health status
in greater detail? Medical Decision Making.
42:60-67, 2022
30) Sun C, Anraku M, Kawahara T, Karasaki T,
Kitano K, Nagayama K, Sato M, Nakajima J.

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Respiratory strength and pectoralis muscle mass
as measures of sarcopenia: Relation to outcomesin resected non-small cell lung cancer. The Journalof Thoracic and Cardiovascular Surgery. 163:
779–787, 2022
31) Kokubo T, Kodera S, Sawano S, Katsushika S,
Nakamoto M, Takeuchi H, Kimura N, Shinohara
H, Matsuoka R, Nakanishi K, Nakao T,
Higashikuni Y, Takeda N, Fujiu K, Daimon M,
Akazawa H, Morita H, Matsuyama Y, Komuro I.
Automatic Detection of Left Ventricular
Dilatation and Hypertrophy from Electrocardiograms Using Deep Learning. Int Heart J.
63(5):939-947, 2022
32) Ieki H, Ito K, Saji M, Kawakami R, Nagatomo Y,
Takada K, Kariyasu T, Machida H, Koyama S,
Yoshida H, Kurosawa R, Matsunaga H, Miyazawa
K, Ozaki K, Onouchi Y, Katsushika S, Matsuoka
R, Shinohara H, Yamaguchi T, Kodera S,
Higashikuni Y, Fujiu K, Akazawa H, Iguchi N,
Isobe M, Yoshikawa T, Komuro I. Deep learningbased age estimation from chest X-rays indicatescardiovascular prognosis. Commun Med (Lond).
2(1):159, 2022

563

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., Atsuhiko Hikita, M.D., Ph.D.

Project Associate Professors
Kazumichi Yonenaga, D.D.S., M.D., Ph.D, Yasunori Omata, M.D. Ph.D.

Project Lecturer
Yukiyo Asawa, D.V.M., Ph.D. , Ono Sachiko, D.D.S., Ph.D., Asuka Terashima, Ph.D.

Research Associates
Itai Shunsuke, D.D.S., Ph.D.

Homepagehttps://www.h.u-tokyo.ac.jp/patient/depts/te/

Introduction and Organization
Division of Tissue Engineering was established as a
special medical office in The University of Tokyo
Hospital, in October 2001 and has a fully equipped 800
m2 laboratory on the 8th floor of the In-patient Ward B.
In May 2016, it moved to Molecular and Life
Innovation building. Division of Tissue Engineering
consists of Department of Bone & Cartilage
Regenerative Medicine, Department of Tissue Stemcell/Life Dentistry, Department of Eat-loss Medicine,and Department of Clinical Stem Cell Biology.
Researchers assigned to each department are
conducting research with many graduate students. The
researchers continue their studies to make the center
function as a translational research center.
Tie-up with companies, technical transfer, patenting developed technologies, producing materials fortreatment at a GMP level, safety evaluation studies andorganization for clinical trials are necessary in order torealize regenerative medicine, which is now recognized
as a national project. As foundation and operation ofventure companies as well as industry-university-

government cooperation is essential to the success, it
seems that state-level efforts are necessary. It is
expected that broad progress in tissue engineering
technologies and regenerative medicine contributes totreatment and drug discovery of all medical fields
regardless of specialties.
October, 2001 Division of Tissue Engineeringfounded as a special medical office in the University ofTokyo Hospital.
June, 2002 Department of Corneal Tissue Engineering founded by a donation from HOYA health care CO.,Ltd.
July, 2002 Department of Vascular Regeneration
founded by a donation from Daiichi PharmaceuticalCo., Ltd.
July, 2002 Department of Bone & Cartilage
Regenerative Medicine founded by a donation from
TAKEDA Chemical Industries., Ltd.
September, 2002 Department of Regeneration
Medicine for Hematopoiesis founded by a donationfrom KIRIN Brewery Co., Ltd.
November, 2002 Department of Clinical Renal

564

Regeneration founded by a donation from MOCHIDA
Pharmaceutical Co., Ltd.
November, 2002 Department of MENICON
Cartilage & Bone Regeneration founded by a donationfrom MENICON Co., Ltd.
March, 2003 The Cell Processing Center set up on
the 8th floor of the In-patient Ward B.
June, 2005 Department of Corneal Tissue Regeneration was renewed by a donation from AMNIOTEC Co., Ltd.
July, 2005 Department of Bone & Cartilage
Regenerative Medicine was renewed by a donationfrom TAKEDA Chemical Industries Co., Ltd.
September, 2005 Department of Regeneration
Medicine for Hematopoiesis was renewed by adonation from KIRIN Brewery Co., Ltd.
November, 2005 Department of Clinical Renal
Regeneration was renewed by a donation fromMOCHIDA Pharmaceutical Co., Ltd.
November, 2005 By a donation from FUJISOFTABC Co., Ltd. Department of MENICON Cartilage &Bone Regeneration was renewed to Department of Fuji
Software ABC Cartilage & Bone Regeneration.
January, 2007 Laboratory for Pediatric Regenerative Medicine was founded by department of pediatricsurgery.
July, 2007 Department of Bone & Cartilage
Regenerative Medicine was renewed by a donationfrom Eli Lilly Japan K.K.
March, 2012 Department of Advanced Nephrol- ogy
and Regenerative Medicine founded by a donationfrom Zenjinkai.
April, 2016 The Cell Processing & Banking Centerset up on the 4th floor of the Molecular & Life
Innovation Building.
November 2017 Change of the department name:
Department of Cartilage & Bone Regeneration became
Department of Cell & Tissue Engineering.
July, 2018 Department of Bone & Cartilage
Regenerative Medicine was renewed by a donationfrom Avenue Cell Clinic, Kaneka Corporation, Rohto
Pharmaceutical Co., Ltd. and Nichirei Corporation.
November, 2019 Department of Tissue Stemcell/Life Dentistry established by Dental assist Co., Ltd,
Fuke hospital, Sashiogi Hospital, Ikegami Home Clinic
and Inotec Co., Ltd.
April, 2020 Department of Eat-loss Medicine wasfounded by a donation from ITOEN ltd.
October, 2020 Department of Cell & Tissue
Engineering was terminated.
July, 2023 Department of Clinical Stem Cell Biology
was founded by founded by a donation from Kohjin Bio
Co., Ltd.
November, 2022 Department of Tissue Stemcell/Life Dentistry was renewed by SheepMedical
Co.,Ltd.

Research activities
As for the Department of Bone and Cartilage
Regeneration, we are researching and developing thetreatment of osteoarthritis using human adipose stem
cells (ASCs) from the renewal of the department in2018. To clarify the protective effects of human ASCsfor cartilage more precisely, we are planning toestablish the assay system for the knee pain of mouse.
We are also developing the culture medium by whichhighly-functional human mesenchymal cells can beamplified stably and effectively. We are also working
on basic research for (1) elucidation of molecularmechanisms underlying osteoarthritis（2）clarificationof the roles of tissue stem cells in the homeostasis of
joints and pathogenesis of osteoarthritis. In addition,
for the realization of bone regeneration, we are trying
to apply a nanosheet which can induce osteogenesis.
Now we are testing its effectiveness in large animals.
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 theself-generation by the tissue encapsulating the mold
(BIO-TUBE).
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.
In the Department of Clinical Stem Cell Biology, weare conducting research for the development of a cell

565

therapy for the peri-implantitis. In addition, to produce
regenerated cartilage and bone with high safety andusefulness, to realize production system and establish
practical quality control and to promote the applicationof regenerated cartilage and bone, we are conducting
research on development of novel scaffolds in cartilage
and bone regeneration, development of 3-D
reconstruction system for regenerated tissues,evaluation on biochemical and biophysical propertiesof regenerated tissues in vivo and clinical trials andapplication of regenerated cartilage and bones.

Clinical Studies
Of particular note is clinical studies started as a resultof basic research. In Department of Bone & Cartilage
Regenerative Medicine, a clinical study on bone
implants into non-loading parts (IRB approval number#1310) was conducted on 10 patients successfully anda large-scale clinical trial was started across the nation.
In project for cartilage regeneration, an investigatorinitiated clinical trial “A clinical trial for the validationof safety and efficacy of the implant-type tissueengineered cartilage using autologous cells” wascarried out. In addition, we have been preparing for aclinical study “a clinical study for the treatment of
osteoarthritis of temporomandibular joint byautologous adipose-derived stem cell (AUASCTKY2017)” .
As stated above, we are proceeding translational
research aiming at clinical application of tissue
engineering and regenerative medicine. Contribution to
the Hospital

References
1.

2.

3.

4.

5.

6.

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.

7.

8.

Superior stemness of a rapidly growing subgroupof isolated human auricular chondrocytes and thepotential for use in cartilage regenerative therapy.
Shimizu R, Asawa Y, Komura M, Hoshi K, Hikita
A. Regen Ther. 2022 Jan 4;19:47-57.
Hematopoietic progenitor cells specifically inducea unique immune response in dental pulp underconditions of systemic inflammation.
Osaki J, Yamazaki S, Hikita A, Hoshi K. Heliyon.
2022 Feb 5;8(2):e08904.
TGFβ selects for pro-stemness over pro-invasive
phenotypes during cancer cell epithelialmesenchymal transition.
Tsubakihara Y, Ohata Y, Okita Y, Younis S,
Eriksson J, Sellin ME, Ren J, Ten Dijke P,
Miyazono K, Hikita A, Imamura T, Kato M,
Heldin CH, Moustakas A. Mol Oncol. 2022
Jun;16(12):2330-2354.
Micro/nanostructural properties of peri-implant
jaw bones: a human cadaver study.
Koresawa K, Matsunaga S, Hikita A, Okudera H,
Yamaguchi A, Yajima Y, Abe S. Int J Implant Dent.
2022 Apr 11;8(1):17.
Hematopoietic-Mesenchymal Signals Regulate
the Properties of Mesenchymal Stem Cells.
Kanazawa S, Okada H, Riu D, Mabuchi Y,
Akazawa C, Iwata J, Hoshi K, Hikita A. Int J Mol
Sci. 2022 Jul 26;23(15):8238.
Quantitative analyses of matrices, osteoblasts, andosteoclasts during bone remodeling using an invitro system.
Oguchi S, Sakamoto T, Hoshi K, Hikita A. J Bone
Miner Metab. 2023 Jan;41(1):3-16.
Spatiotemporal
AnalysisofOsteoblast
Morphology and Wnt Signal-Induced Osteoblast
Reactivation during Bone Modeling in Vitro.
Tsuji N, Sakamoto T, Hoshi K, Hikita A. JBMR
Plus. 2022 Oct 21;6(11):e10689.
Evaluation of the improvement of laryngeal
penetration using complete lateral position
throughvideoendoscopic
evaluationofswallowing in patients with dysphagia
Tonosaki K, Yonenaga K, Itai S, Oyama S, Mizuno
T, Ono S, Watanabe R, Hoshi K.
Oral Science International 2023.

566

9.

10.

11.

12.

13.

14.

Risk of post-extraction bleeding with direct oral
anticoagulant
comparedwithwarfarin:
Retrospective cohort study using large scaleclaims data in Japan.
Ono S, Ishimaru M, Yokota I, Konishi T, Okada A,
Ono Y, Matsui H, Itai S, Yonenaga K, Tonosaki K,
Watanabe R, Hoshi K, Yasunaga H
Thrombosis Research 222 24-30 2022。
Complete lateral positioning enabled feeding in apatient with aspiration pneumonia
Tonosaki K, Yonenaga K, Itai S, Oyama S, Mizuno
T, Ono S, Watanabe R, Hoshi K
The Tokai Journal of Experimental and Clinical
Medicine 47(3) 105-108 2022
Nagata K, Hojo H, Chang SH, Okada H, Yano F,
Chijimatsu R, Omata Y, Mori D, Makii Y, Kawata
M, Kaneko T, Iwanaga Y, Nakamoto H,
Maenohara Y, Tachibana N, Ishikura H, Higuchi J,
Taniguchi Y, Ohba S, Chung UI, Tanaka S, Saito
T. Runx2 and Runx3 differentially regulate
articular chondrocytes during surgically induced
osteoarthritis development. Nat Commun. 2022
Oct 19;13(1):6187.
Tachibana N, Chijimatsu R, Okada H, Oichi T,
Taniguchi Y, Maenohara Y, Miyahara J, Ishikura
H, Iwanaga Y, Arino Y, Nagata K, Nakamoto H,
Kato S, Doi T, Matsubayashi Y, Oshima Y,
Terashima A, Omata Y, Yano F, Maeda S, Ikegawa
S, Seki M, Suzuki Y, Tanaka S, Saito T. RSPO2
defines a distinct undifferentiated progenitor in
the tendon/ligament and suppresses ectopic
ossification. Sci Adv. 2022 Aug 19;8(33):
eabn2138.
Tsukasaki M, Komatsu N, Negishi-Koga T, Huynh
NC, Muro R, Ando Y, Seki Y, Terashima A,
Pluemsakunthai W, Nitta T, Nakamura T,
Nakashima T, Ohba S, Akiyama H, Okamoto K,
Baron R, Takayanagi H.Periosteal stem cells
control growth plate stem cells during postnatalskeletal growth. Nat Commun. 2022 Jul 18;13(1):4166.
Omata Y, Okada H, Uebe S, Izawa N, Ekici AB,
Sarter K, Saito T, Schett G, Tanaka S, Zaiss MM.
Interspecies Single-Cell RNA-Seq Analysis
Reveals the Novel Trajectory of Osteoclast
Differentiation and Therapeutic Targets. JBMR
Plus. 2022 May 16;6(7):e10631.

15. Takeda R, Matsumoto T, Maenohara Y, Omata Y,
Inui H, Nagase Y, Nishikawa T, Tanaka S.
Increasing trend of radiographic features of knee
osteoarthritis in rheumatoid arthritis patients
before total knee arthroplasty. Sci Rep. 2022 Jun
21;12(1):10452.
16. Watanabe H, Okada H, Hirose J, Omata Y,
Matsumoto T, Matsumoto M, Nakamura M, Saito
T, Miyamoto T, Tanaka S. Transcription Factor
Hematopoietically Expressed Homeobox Protein(Hhex)
Negatively
Regulates
Osteoclast
Differentiation by Controlling Cyclin-Dependent
Kinase Inhibitors. JBMR Plus. 2022 Feb 14;6(4):e10608.
17. Omata Y, Frech M, Saito T, Schett G, Zaiss MM,
Tanaka S. Inflammatory Arthritis and BoneMetabolism Regulated by Type 2 Innate andAdaptive Immunity. Int J Mol Sci. 2022 Jan 20;
23(3):1104.
18. Frech M, Omata Y, Schmalzl A, Wirtz S, Taher L,
Schett G, Zaiss MM, Sarter K. Btn2a2 Regulates
ILC2-T Cell Cross Talk in Type 2 Immune
Responses. Front Immunol. 2022 Jan 25;13:757436.
19. Kaneko T, Horiuchi K, Chijimatsu R, Mori D,
Nagata K, Omata Y, Yano F, Inui H, Moro T,
Tanaka S, Saito T.Regulation of osteoarthritis
development by ADAM17/Tace in articularcartilage. J Bone Miner Metab. 2022 Mar;40(2):196-207.
20. Yokote F, Yamauchi Y, Komura H, Tanuma T,
Sakao Y, Kawamura M, Komura M. A novel
method of tracheal anastomosis healing using asingle submucosal injection of basic fibroblast
growth factor: initial report. Eur J Cardiothorac
Surg. 2022 Mar 24;61(4):917-924.
【Book】
1. Evidence of Green Tea 2022:Review Book ver.1
Itai S, Yonenaga K, Ono S, Watanabe R, Tonosaki
K, Hoshi K. DesignEgg 2022.

567

Cooperative Unit of Medicine andEngineering Research
Organization
The University of Tokyo Hospital
Cardiovascular Medicine, Nutrition and Metabolism, Surgical Oncology, Vascular Surgery,
Artificial Organ and Transplantation, Cardiac Surgery, Thoracic Surgery, Neurosurgery,
Urology, Orthopaedic Surgery, Oral and maxillofacial Surgery, Radiology, Tissue
Engineering Unit, Department of Clinical Epidemiology & Systems, Bone & Cartilage
Regenerative

Medicine,

Cartilage

of

Bone

Regeneration,

Department

ofImmunotherapeutics (Medinet), Division of Science for Joint Reconstruction

Engineering and Pharmaceutical Research
Chemical System Engineering, Mechanical Engineering, Precision Engineering, Quantum
Engineering and System Science, Nuclear Engineering and Management, Chemistry andBiotechnology, Material Engineering, Information Science and Technology, Frontier
Sciences, Pharmaceutical Sciences Laboratory of Chemistry and Biology, Center for Disease
Biology and Integrative Medicine, Center for Disease Biology and Integrative Medicine
Regenerative Medical Engineering, Center for Disease Biology and Integrative Medicine
Clinical Biotechnology, Research Center for Advanced Science and Technology, Institute ofIndustrial Science※The following information is the same as that of the previous year for certain reasons.

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

568

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. Configurationof each project in a space of 554.4m2 that is consistedof a portion of the first floor and the basement of an
administration building came to a decision by theconference.
2003 May. The construction of Cooperative Unit ofMedicine and Engineering Research was completed.
The cost of the construction was shared by theparticipation groups.
2003 May 22. The first research meeting of
Cooperative Unit of Medicine and Engineering
Research took place and research activities started.
2004 September 3. The second research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2005 September 13. The third research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2006 December 21. The fourth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2007 December 13. The fifth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2009 December 3. The sixth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2011 February 2. The seventh research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2011 December 17. The eighth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place2013 January 25. Development forum of advanced
medical seeds took place
2014 January 24. Development forum of advanced
medical seeds took place
2015 January 22. Development forum of advanced

medical seeds took place
2016 February 2. Development forum of advanced
medical seeds took place2017 February 2. Development forum of advanced
medical seeds took place2018 February 1. Development forum of advanced
medical seeds took place2018 October. Each lab was moved from the thefirst floor and the basement of an administrationbuilding, based on the decision of redistribution of
hospital facility
2019 February 18. Development forum of advanced
medical seeds took place2020 January 21. Development forum of advanced
medical seeds took place
2021 February 10. Development forum of advanced
medical seeds took place
2022 February 4. Development forum of advanced
medical seeds took place

Research activities
Development of Advanced Stereotactic Radiation
Cancer Therapy System
Department of Radiology
Nuclear Professional School, Department of Nuclear
Engineering and Management
Department of Chemical System Engineering
High Precision Stereotactic X-ray Cancer Therapy
System. Development of Advanced Compact Electron
Linear Accelerator for Cancer Inspection and Therapy
The aim of this research is to apply the in-vivo
visualization technique developed by our group in
high-precision radiation therapy and to develop the
motion prediction system for a real-time
tumor-tracking radiation therapy. For the visualizationof the treatment area during treatment, afour-dimensional cone-beam computed tomography(4D CBCT) reconstruction algorithm is developed bytaking the anatomy or tumor motion analysis into
account. In-treatment 4D CBCT requires the
projection images acquired during treatment. The
projection images are analyzed online, and comparedwith the reprojection images from the treatment
planning CT or registration CT. The time lag due tothe analysis can be compensated by the prediction
using a multi-channel singular spectrum analysis. This

569

system 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
Development of micro-neurosurgical robotic systems
and advanced microscopic image processing forautonomous surgical task recognition.
Development of Support Systems for Risk
Reduction in the Clinical Process
Chemical System Engineering
Center for Epidemiology and Preventive Medicine
Our specific targets are research and education on the
integration of biological and clinical information
including genome. In particular, we focus onestablishment of personalized medicine as translational research, selection of drug targets by proteomics,
interpretation of transcriptional regulations and drug
development by targeting transcriptional factors inmetabolic and cardiovascular diseases. Also, analysesof genomic functions, clinical safety monitoring by
clinical database and assessments of clinicalinformation systems are conducted.
Project of Neutron Capture Therapy & Innovationof DDS for Cancer
Department of Cardiothoracic Surgery, Graduate
School of Medicine
Institute of Engineering Innovation, School ofEngineering
Department of Bioengineering, School of Engineering
In order to control and eliminate human cancers, wedevelop the neutron capture therapy (NCT) using
small neutron accelerator equipped to hospital andalso aim to augment cancer therapy combined withapproaches of Drug Delivery System. We develop thetumour specific drug delivery systems entrappedboron or gadolinium compounds as neutron capture

agents (WOW emulsion, Nano-micelle, Cationic
Polyplex).
Development of adhesion barrier materials using a
new animal model of liver-peritoneal adhesion
Artificial Organ and Transplantation Division,
Department of Surgery, Graduate School of Medicine,
University of Tokyo
Hepato-Biliary-Pancreatic
Surgery
Division,
Department of Surgery, Graduate School of Medicine,
University of Tokyo
Organs and Biosystems Engineering Laboratory,
Institute of Industrial Science, The University of Tokyo
Division of Biomedical Equipment and Biomaterials,
Center for Disease Biology and Integrative Medicine,
Graduate School of Medicine, The University of Tokyo
Department of Chemical System Engineering,
Graduate School of Engineering, The University ofTokyo
Department of Bioengineering, Graduate School ofEngineering, The University of Tokyo
Adhesions between liver and other organs are an
important issue in the cases of second surgeries suchas hepatic resection. Adhesions extend operative
duration; in addition, they increase the risk ofsurgeries. Thus, it is important to avoid adhesions at afirst surgery. However, no one report both the animalmodel and adhesion barrier materials of liver adhesion.
We try to develop a new adhesion model by hepatic
resection, instead of a usual peritoneal abrasion model.
Also, we develop new materials for preventing theadhesions.
Development of gene therapy of cardiovasculartherapy by polymeric micelles.
Department of Vascular Surgery, Division of Tissue
Engineering, The University of Tokyo Hospital
Kataoka Laboratory, Department of Materials Scienceand Engineering, Graduate School of Engineering,
The University of Tokyo
To achieve effective and safe in vivo gene therapy ofcardiovascular and vascular diseases, we aredeveloping non-viral gene vectors based on
nano-scaled polymer assemblies (polymeric micelles).
Polymeric micelles, which are spontaneously formed
from block copolymers, have a core containing
packaged genes surrounded by biocompatible poly

570

(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.

7.

8.

References (in 2021)
1.

2.

3.

4.

5.

6.

Hanada K, Hoshina K, Iwakiri T, Akai T,
Miyahara K, Isaji T, Takayama T, Yamamoto S. A
comparison of subjective clinical and objective
judgement of abdominal aortic aneurysm
morphology. Int Angiol 2021;40:138-142.
Okata S, Hoshina K, Miyahara K, Matsukura M,
Akai T, Isaji T, Takayama T. High aneurysm wallenhancement values are associated with late sacshrinkage after endovascular repair of abdominal
aortic aneurysms. Medicine(Baltimore) 2021 Jan
15;100:e24133.
Hoshina K, Kato M, Ishimaru S, Michihata N,
Yasunaga H, Komori K; Japanese Committee for
Stentgraft Management (JACSM). Impact of theurgency and the landing zone on rates of inhospital death, stroke, and paraplegia following
thoracic endovascular aortic repair in Japan. J
Vasc Surg 2021; S0741-5214(21)00142-7
Matsuura S, Takayama T, Yuhn C, Oshima M,
Shirasu T, Akai T, Isaji T, Hoshina K. Carotid
stump pressure and contralateral internal carotid
stenosis ratio during carotid endarterectomies:
1D-0D hemodynamic simulation of cerebral
perfusion. Ann Vasc Dis 2021;14:39-45.
Hoshina K, Komori K, Kumamaru H, Shimizu H.
The Outcomes of endovascular aneurysm repair
in Japan in 2017: A Report from the JapaneseCommittee for Stentgraft Management. 2021;25;
14:92-98.
Sugawara M, Hoshina K, Chigira M, Suzuki H,
Daimon M, Takayama T, Ono Y, Yatomi Y.
Usefulness of duplex ultrasonography to detect

9.

10.

11.

12.

13.

collagen sponge misplacement into the arterial
lumen during the use of Angio-Seal: A casereport. SAGE Open Med Case Rep 2021;9:2050313X211004818
Matsuura S, Takayama T, Oyama TG, Oyama K,
Taguchi M, Endo T, Akai T, Isaji T, Hoshina K. A
Radiation-crosslinked gelatin hydrogel that
promotes tissue incorporation of an expanded
polytetrafluoroethylene vascular graft in rats.
Biomolecules 2021;11:1105.
Iida T, Murono K, Shiratori H, Nozawa H, Kawai
K, Sasaki K, Emoto S, Kishikawa J, Ishii H,
Yokoyama Y, Abe S, Nagai Y, Anzai H, Sonoda H,
Takayama T, Hoshina K, Ishihara S. Impact ofinferior mesenteric artery occlusion on the calibreof collateral arteries of the colon. Anticancer Res
2021;41: 5189-5193.
Hoshina K, Komori K, Kumamaru H, Shimizu H.
The outcomes of thoracic endovascular aortic
repair in Japan in 2017: A report from theJapanese Committee for Stentgraft Management.
Ann Vasc Dis 2021;14:281-288.
Mo M, Hirokawa M, Satokawa H, Yasugi T,
Yamaki T, Ito T, Onozawa S, Kobata T, Shirasugi
N, Shokoku S, Sugano N, Sugiyama S, Hoshina
K, on behalf of guideline committee JapaneseSociety of Phlebology, Ogawa T, on behalf ofguideline committee of endovenous treatment forvaricose veins. Supplement of clinical practiceguidelines for endovenous thermal ablation forvaricose veins: Overuse for the inappropriate
indication. Ann Vasc Dis 2021:14:323-327.
Horio K, Marinho MM, Harada K, Muto J,
Nakatomi H, Saito N, Morita A, Watanabe E,
Mitsusishi M. “The effects of Grid Size for
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1029 https://doi.org/10.14894/faruawpsj.57.11_1025
14. Yanagie H, Fujino T, Yanagawa M, Terao T,
Imagawa T, Fujihara M, Morishita Y, Mizumachi
R, Murata Y, Dewi N, Ono Y, Ikushima I,
Seguchi K, Nagata M, Nonaka Y, Furuya Y, Hisa
T, Nagasaki T, Arimori K, Nakashima T, Sugihara
T, Kakimi K, Ono M, Nakajima J, Eriguchi M,
Higashi S, Takahashi H.: Tumor Growth Suppression With Novel Intra-arterial Chemotherapy
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Emulsion In Vivo.. In Vivo. 2021 Jan-Feb;35(1):239-248.
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PMID:
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15. Yanagie H, Yanagawa M, Morishita Y, Shinohara
A, Dewi N, Nonaka Y, Furuya Y, Mizumachi R,
Murata Y, Nakamura H, Suzuki M, Sakurai Y,
Tanaka H, Masunaga S, Ono K, Sugihara T,
Nashimoto M, Yamauchi H, Ono M, Nakajima J,
Takahashi H. : Suppression of Tumor Growth in a
Rabbit Hepatic Cancer Model by Boron Neutron
Capture Therapy With Liposomal Boron Delivery
Systems. In Vivo. 2021 Nov-Dec;35(6):3125-3135.
doi: 10.21873/invivo.12607. PMID: 34697143

572

Genomic Research Support Center(GresCent)
Director & Professor
Yutaka Osuga, M.D., Ph.D.

1. Organization
Genomic Research Support Center was establishedin 2017 to support appropriate and harmonious
achievements of advanced genomic researches at the
University of Tokyo Hospital. Genomic Research
Support Center deals with cancer, life-style disease,
hereditary disorders, and so on. This center is directedby Professor Yutaka Osuga. Experts of these fields,
including Associate Professor Nobuhiro Shojima,
participate in the activities as follows; (1) large scale
analysis of genomes utilizing next generation
sequencers and establishment of pipelines of genome
informatic analysis, (2) elucidation of hereditary
factors and pathogenesis of various diseases, (3)integrated research and education of genomic andclinical information, (4) analysis of polymorphismand mutation of genes involved in susceptibility andresponse to treatment in various diseases such as lifestyle disease, and (5) establishment of database andintegrated data mining of associated clinicalinformation.

2. Activities
In collaboration with RIKEN, we have identified
genetic variations conferring susceptibility to type 2
diabetes, myocardial infarction and renal dysfunctionin the Japanese population from the genome-wide
association study (GWAS) results. We identified type2 diabetes – associated loci, including missense
variants in genes related to insulin secretion (GLP1R).
To examine type 2 diabetes risk in East Asian
individuals, our team carried out a meta-analysis of
GWAS data from over 400,000 individuals. We

identified 61 loci that are newly implicated in
predisposition to type 2 diabetes. (Nature, 2020, 582,
240-245).
In collaboration with the Osaka University, RIKEN
and BioBank Japan, we assembled an ancestrally
diverse collection of GWAS of type 2 diabetes
through the UK Biobank, AGEN T2D and the
Diabetes Meta-Analysis of Trans-Ethnic association
studies (DIAMANTE) Consortium. Multi-ancestry
GWAS meta-analysis identified multiple lociattaining stringent genome-wide significance, whichwere delineated to multiple distinct association
signals (Nat Genet. 2022, 54(5):560-572). As
expected, ancestry-specific genetic risk score (GRS)
performed best in test GWAS from their respective
ancestry group. Multi-ancestry meta-analysis
maximizes power to detect association signals that areshared across ancestry groups. By modelingheterogeneity in allelic effects across ancestries, ourmeta-regression approach can also allow for
association signals that are driven by ancestryspecific causal variants, although power will belimited by the sample size available in that ancestry
group.
In collaboration with the Osaka University, RIKEN
and BioBank Japan, we profiled serum metabolites of
persons with type 2 diabetes with both diabetic
retinopathy and diabetic kidney diseases using acomprehensive non-targeted metabolomics approachwith mass spectrometry. We compared the abundanceof the serum metabolites between the persons with
type 2 diabetes with multiple complications andwithout any complications, identifying fivemetabolites, including N-acetylneuraminic acid573

significantly increased in those with the complications(Commun Med. 2023, 9;3(1):5). Our metabolome
analysis identified the serum metabolite features ofthe persons with type 2 diabetes with thecomplications, which could potentially be used as
biomarkers.
We conducted whole genome sequence andanalyzed the sequence data of over 2,000 subjects
with type 2 diabetes in collaboration with the Osaka
University, RIKEN and BioBank Japan. We aredeveloping the methods to predict diabetic
complications and deterioration of diabetes bybioinformatics algorithms including the Penalized
regression method, often used in machine learningand public OmiX database.
In collaboration with Department of Clinical
Genomics, we supported the meetings and expertpanel regarding cancer and rare diseases. We hadclinical and genomic WEB conference with hospitals
related to cancer treatment.
We shared genomic data with researchers abouttype 2 diabetes association study, Set3 (121,950
controls, 18,688 cases) and Set4 (7,065 controls,
2,483 cases) through national bioscience databasecenter, NBDC (https://humandbs.biosciencedbc.jp/
hum0014-v18#diabet3).
We made paper to inform for the participants of theresearch on ‘Realization of personalized medicine for
Metabolic syndrome related disease.’ in collaboration
with research ethics support center.
We used panel analysis applying next-generation
sequencer and revealed the genetic diagnosis on
extreme phenotypes of diseases related to life-styles
including, maturity onset diabetes of the young andlipodystrophy and predicted the prognosis andselected effective therapies.

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Yajnik CS, Yamamoto K, Yamauchi T, Yengo L,
Yoon K, Yu C, Yuan JM, Yusuf S, Zhang L,
Zheng W; FinnGen; eMERGE Consortium;
Raffel LJ, Igase M, Ipp E, Redline S, Cho YS,
Lind L, Province MA, Hanis CL, Peyser PA,
Ingelsson E, Zonderman AB, Psaty BM, Wang
YX, Rotimi CN, Becker DM, Matsuda F, Liu Y,
Zeggini E, Yokota M, Rich SS, Kooperberg C,
Pankow JS, Engert JC, Chen YI, Froguel P,
Wilson JG, Sheu WHH, Kardia SLR, Wu JY,
Hayes MG, Ma RCW, Wong TY, Groop L, MookKanamori DO, Chandak GR, Collins FS,
Bharadwaj D, Paré G, Sale MM, Ahsan H,
Motala AA, Shu XO, Park KS, Jukema JW, Cruz
M, McKean-Cowdin R, Grallert H, Cheng CY,
Bottinger EP, Dehghan A, Tai ES, Dupuis J, KatoN, Laakso M, Köttgen A, Koh WP, Palmer CNA,
Liu S, Abecasis G, Kooner JS, Loos RJF, North
KE, Haiman CA, Florez JC, Saleheen D, Hansen
T, Pedersen O, Mägi R, Langenberg C, Wareham
NJ, Maeda S, Kadowaki T, Lee J, Millwood IY,
Walters RG, Stefansson K, Myers SR, Ferrer J,
Gaulton KJ, Meigs JB, Mohlke KL, Gloyn AL,
Bowden DW, Below JE, Chambers JC, Sim X,
Boehnke M, Rotter JI, McCarthy MI, Morris AP.
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Asada K, Nakato R, Shozu K, Dozen A, Sone K,
Yoshida H, Kato T, Oda K, Osuga Y, Fujii T, vonKeudell G, Saloura V, Hamamoto R. The
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5:

02992-4.
PMID:
35017636;
PMCID:
PMC8752757.
Tomofuji Y, Suzuki K, Kishikawa T, Shojima N,
Hosoe J, Inagaki K, Matsubayashi S, Ishihara H,
Watada H, Ishigaki Y; BioBank Japan Project;
Inohara H, Murakami Y, Matsuda K, Okada Y,
Yamauchi T, Kadowaki T. Identification of serum
metabolome signatures associated with retinal
and renal complications of type 2 diabetes.
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HJ, Yin X, Lorenz KM, Mandla R, HuertaChagoya A, Rayner NW, Bocher O, Ana Luiza deSVA, Sonehara K, Namba S, Lee SSK, Preuss
MH, Petty LE, Schroeder P, Vanderwerff B, Kals
M, Bragg F, Lin K, Guo X, Zhang W, Yao J, Kim
YJ, Graff M, Takeuchi F, Nano J, Lamri A,
Nakatochi M, Moon S, Scott RA, Cook JP, Lee
JJ, Pan I, Taliun D, Parra EJ, Chai JF, Bielak LF,
Tabara Y, Hai Y, Thorleifsson G, Grarup N, Sofer
T, Wuttke M, Sarnowski C, Gieger C, Nousome
D, Trompet S, Kwak SH, Long J, Sun M, Tong L,
Chen WM, Nongmaithem SS, Noordam R, Lim
VJY, Tam CHT, Joo YY, Chen CH, Raffield LM,
Prins BP, Nicolas A, Yanek LR, Chen G, Brody
JA, Kabagambe E, An P, Xiang AH, Choi HS,
Cade BE, Tan J, Alaine Broadaway K,
Williamson A, Kamali Z, Cui J, Adair LS,
Adeyemo A, Aguilar-Salinas CA, Ahluwalia TS,
Anand SS, Bertoni A, Bork-Jensen J, Brandslund
I, Buchanan TA, Burant CF, Butterworth AS,
Canouil M, Chan JCN, Chang LC, Chee ML,
Chen J, Chen SH, Chen YT, Chen Z, Chuang LM,
Cushman M, Danesh J, Das SK, Janaka de Silva
H, Dedoussis G, Dimitrov L, Doumatey AP, Du
S, Duan Q, Eckardt KU, Emery LS, Evans DS,
Evans MK, Fischer K, Floyd JS, Ford I, Franco
OH, Frayling TM, Freedman BI, Genter P,
Gerstein HC, Giedraitis V, González-Villalpando
C, González-Villalpando ME, Gordon-Larsen P,

575

Gross M, Guare LA, Hackinger S, Han S,
Hattersley AT, Herder C, Horikoshi M, Howard
AG, Hsueh W, Huang M, Huang W, Hung YJ,
Hwang MY, Hwu CM, Ichihara S, Ikram MA,
Ingelsson M, Islam MT, Isono M, Jang HM,
Jasmine F, Jiang G, Jonas JB, Jørgensen T,
Kandeel FR, Kasturiratne A, Katsuya T, Kaur V,
Kawaguchi T, Keaton JM, Kho AN, Khor CC,
Kibriya MG, Kim DH, Kronenberg F, Kuusisto J,
Läll K, Lange LA, Lee KM, Lee MS, Lee NR,
Leong A, Li L, Li Y, Li-Gao R, Lithgart S,
Lindgren CM, Linneberg A, Liu CT, Liu J, Locke
AE, Louie T, Luan J, Luk AO, Luo X, Lv J, Lynch
JA, Lyssenko V, Maeda S, Mamakou V, Mansuri
SR, Matsuda K, Meitinger T, Metspalu A, Mo H,
Morris AD, Nadler JL, Nalls MA, Nayak U,
Ntalla I, Okada Y, Orozco L, Patel SR, Patil S,
Pei P, Pereira MA, Peters A, Pirie FJ, Polikowsky
HG, Porneala B, Prasad G, Rasmussen-Torvik LJ,
Reiner AP, Roden M, Rohde R, Roll K,
Sabanayagam C, Sandow K, Sankareswaran A,
Sattar N, Schönherr S, Shahriar M, Shen B, Shi J,
Shin DM, Shojima N, Smith JA, So WY,
Stančáková A, Steinthorsdottir V, Stilp AM,
Strauch K, Taylor KD, Thorand B,
Thorsteinsdottir U, Tomlinson B, Tran TC, TsaiFJ, Tuomilehto J, Tusie-Luna T, Udler MS,
Valladares-Salgado A, van Dam RM, van
Klinken JB, Varma R, Wacher-Rodarte N,
Wheeler E, Wickremasinghe AR, van Dijk KW,
Witte DR, Yajnik CS, Yamamoto K, Yamamoto K,
Yoon K, Yu C, Yuan JM, Yusuf S, Zawistowski
M, Zhang L, Zheng W; VA Million Veteran
Program, AMED GRIFIN Diabetes Initiative
Japan; Project BJ, BioBank PM, Center RG,
Consortium E; International Consortium for
Blood Pressure (ICBP); Meta-Analyses of
Glucose and Insulin-Related Traits Consortium(MAGIC); Raffel LJ, Igase M, Ipp E, Redline S,
Cho YS, Lind L, Province MA, Fornage M, Hanis
CL, Ingelsson E, Zonderman AB, Psaty BM,
Wang YX, Rotimi CN, Becker DM, Matsuda F,
Liu Y, Yokota M, Kardia SLR, Peyser PA,
Pankow JS, Engert JC, Bonnefond A, Froguel P,
Wilson JG, Sheu WHH, Wu JY, Geoffrey Hayes
M, Ma RCW, Wong TY, Mook-Kanamori DO,
Tuomi T, Chandak GR, Collins FS, Bharadwaj D,

Paré G, Sale MM, Ahsan H, Motala AA, Shu XO,
Park KS, Jukema JW, Cruz M, Chen YI, Rich SS,
McKean-Cowdin R, Grallert H, Cheng CY,
Ghanbari M, Tai ES, Dupuis J, Kato N, Laakso
M, Köttgen A, Koh WP, Bowden DW, Palmer
CNA, Kooner JS, Kooperberg C, Liu S, North KE,
Saleheen D, Hansen T, Pedersen O, Wareham NJ,
Lee J, Kim BJ, Millwood IY, Walters RG,
Stefansson K, Goodarzi MO, Mohlke KL,
Langenberg C, Haiman CA, Loos RJF, Florez JC,
Rader DJ, Ritchie MD, Zöllner S, Mägi R, Denny
JC, Yamauchi T, Kadowaki T, Chambers JC, Ng
MCY, Sim X, Below JE, Tsao PS, Chang KM,
McCarthy MI, Meigs JB, Mahajan A, Spracklen
CN, Mercader JM, Boehnke M, Rotter JI,
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576

BioResource Center
Director
Tetsuo Ushiku, M.D., Ph.D. (Professor, Department of Pathology and Diagnostic Pathology)

Deputy Director
Katsutoshi, Oda, M.D., Ph.D. (Professor, Division of Integrative Genomics)

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

Homepagehttps://www.h.u-tokyo.ac.jp/patient/depts/bio-resource/

Introduction and Organization
A wide variety of clinical and scientific research is
being conducted at The University of Tokyo Hospitaland Faculty of Medicine. When using samples obtained
from patients through surgery and laboratory tests,
researchers of each department have obtained informed
consent for the research and stored the samples in theirown laboratory. To utilize valuable resources more
effectively, the center specialized in collecting andstoring samples is needed. The University of Tokyo
Hospital is one of the core hospitals to promote cancer
genomic medicine in Japan and is required to equip
biobank to store tissue samples of multiple organs.
In these settings, a working group has started to workon the establishment of BioResource Center since 2020.
Members from the Departments of Clinical Genomics,
Pathology, Clinical Laboratory and Surgery, as well as
experts in basic medical research, discussed how to
inform and obtain consent of the patients, details oftissue sampling and storing protocols, and the processof utilizing samples in medical research. After theapproval by Hospital Executives, BioResource Center
was established as one of the Clinical ResearchServices of the University of Tokyo Hospital on Apr 1,
2021. This BiorResource Center Project was also
approved by Research Ethics Committee of the Facultyof Medicine on Aug 16, 2021.
Samples, clinical information, and research data withwritten informed consent of the patients are stored in

the center and are utilized in the research approved by
Research Ethics Committee. Staffs of the center andrepresentatives of clinical departments also hold acommittee to review the research protocols to check
whether the use of the stored samples is appropriate.

Clinical activities
Three doctors (director, deputy director and a staff) andtwo project academic specialists are in charge of theactivity. We work together with Department of Surgery,
Pathology, Clinical Laboratory and Surgical Center inobtaining patients’ consent and collecting samples.
Members of the Office of Research Support also
support us in the management of the center.
In FY2021, we worked on the sampling protocols,developed a system and a database to collect the
information of patients’ consent and stored samples,and set up a laboratory. Sampling of peripheral bloodand tissues started in March 2022. At the end of
FY2022, samples from 300 patients were collected andstored. In November 2022, scheme for medical
research using samples stored in BioResource Center
was approved by Research Ethics Committee of theFaculty of Medicine, making the researchers in thehospital available for the stored samples.
BioResource Center freezes and stores DNA andplasma extracted from peripheral blood and paired
normal/tumor tissues. Sample information such as
patient’s age, sex and cancer type are also collected.

577

The center will cover patients of Internal Medicine who
suffer from lifestyle diseases and intractable diseases
and pediatric patients in the future.

Teaching and Research activities
In FY2023, we offered samples for the whole-genome
analysis conducted as a national research project. We
hope to expand our activities in research as well as
educating specialists on banking method in the coming
year.

References
None

578

Department of Clinical Research
GovernanceDirector & Project Professor
Junji Moriya, M.D., Ph.D.

Research Associate
Kazuyoshi Ichihashi, Ph.D.
※The following information is the same as that of the previous year for certain reasons.

Websitehttp://www.h.u-tokyo.ac.jp/english/centers-services/organization/l4/
researchgovernance.html

History and Overview of theOrganization
The Department of Clinical Research Governance
was established independently from the ClinicalResearch Support Center on January 1st, 2015, for the
management of clinical research. The aim of thedepartment is an appropriate and rapid response tovarious issues surrounding clinical research in recent
years, to prevent problems related to research ethics
and research misconduct, and to promote highly
reliable clinical research. The intention of the
Department of Clinical Research Governance is toestablish a system that would enable the University ofTokyo Hospital to take the initiative in managing andpromoting clinical research so as to ensure thereliability of clinical research and compliance with the
ethics of clinical research promoted by university
hospitals providing advanced medical care.
The Department of Clinical Research Governance is
now composed of three offices: 1) Office of Strategic
Planning and Promotion, 2) Office of ResearchIntegrity and Promotion, and 3) Office of ClinicalCompliance. These offices mutually cooperate topromote and strengthen governance functions within
the hospital.
The following activities are carried out by the

Office of Strategic Planning and Promotion ; (1)formulating comprehensive strategies for research anddevelopment at the University of Tokyo Hospital, (2)adopting the role of administrative headquarters whenpublicly applying for large-scale research projects, (3)serving as a liaison for consultations regarding theacquisition of research funds and intellectual
properties, (4) examination financial self-reliancestrategies of the clinical research base, (5) discoveringneeds and seeds in clinical practice, (6) investigating
research activities at the University of Tokyo Hospitaland creating a database, (7) collecting clinicalresearch information from external organizations, (8)activities related to conflicts of interest at the
University of Tokyo Hospital, (9) clerical work related
to the Advanced Medicine Development Support
Management Committee, and (10) clerical work
related to the Special Clinical Research Steering
Committee.
The activities of the Office of Research Integrity
and Promotion are as follows; (1) responding to
problems related to research ethics and research
misconduct, (2) educational activities for clinicalresearchers; and (3) the dissemination of workshop
summaries.
The activities of the Office of Clinical Complianceare as follows; (1) auditing of clinical researches andclinical trials, (2) integrated management of579

outsourced auditing, (3) integrated management ofaudit results of the University of Tokyo Hospital, and(4) educational workshops and guidance related toauditing.
The Department of Clinical Research Governanceconsists of one director (a full-time post), one
Research Associate/URA in the Office of Strategic
Planning and Promotion, three staffs (2 auditors andone temporary staffs (an auditor staff) in the Office ofClinical Compliance, and two staffs in the Office of
Research Integrity and Promotion as of March 2022.

Activities
The Office of Strategic Planning and Promotion has
undertaken the following activities in the fiscal year2021.
1) Coordination of organization for clinical
trials/researches; assisting the holding of Specified
Clinical Research Steering Committee and theSpecified Clinical Research Auditing Committee, andassisting the preparation of reports on clinical research
activities as the Clinical Research Core Hospitals
under the Medical Care Act (Act No. 205 of July 30,1948) for surveys conducted by the Ministry of Health,
Labor and Welfare (MHLW).
2) Others; investigations of research paper publication
activities, co-operating the “Forum for Developmentof Seeds for Advanced Medicine”, etc.
The Office of Clinical Compliance has undertaken
the following activities in the fiscal year 2021.
1) Audit activities; as regard to trials/researches
conducted by the University of Tokyo Hospital, theoffice conducted a total of eight trials (six audits forinvestigator-initiated clinical trials, and two audits forSpecified Clinical Researches).
2) Consolidating information; the office collected all
the information on audit results including directly
outsourced by principal investigators, and has been
centrally managing the GCP inspections findings
conducted at the University of Tokyo Hospital.
3) Preparing documents; the office prepareddocuments of SOP in general auditing, templates forauditing of each trial, start-up meetings, and protocols,
along with maintenance of existing checklists.

4) MHLW program for educational workshops andguidance related to auditing; the office has a central
role in performing workshops in the fiscal year 2021,
and held a beginners workshop in September 2nd and3rd, and a mid-career workshop in November 18th and
19th.
The Office of Research Integrity and Promotion has
undertaken the following activities in the fiscal year2021.
1) Collecting and disseminating information forclinical quality assurance; the office has sent a total ofsix e-mails for all personnel in the University ofTokyo Hospital, along with disclosing a total of 16
information in the website of the Department ofClinical Research Governance.
2) Educational activities for clinical researchers; theoffice has held an e-learning seminar regarding to the
management of conflict of interest and quality
assurance in clinical researches (there were 1935
participants in a Step1 seminar, and 1888 participantsin a Step2 seminar).
3) Promotion of activities for research integrity; theoffice has engaged in creating a team for supporting
activities regarding to QMS in investigator-initiatedclinical trials conducted in the University of Tokyo
Hospital. The team consists of members of the Officeof Research Integrity and Promotion, and the ClinicalResearch Promotion Center. The team extracted
problems and points to consider as to working flows
of collecting and reporting information for deviations
or misconducts of clinical trials performed in the
University of Tokyo Hospital.

580

Department of Healthcare
Information Management
Professor
Kazuhiko Ohe, M.D.,Ph.D.

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

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

Lecturer
Shinichiro Yokota, PHN,RN,Ph.D., Hidenao Atarashi BMET, Ph.D.

Homepage

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

Introduction and Organization
In order for the University of Tokyo Hospital to respondstrategically and quickly to various changes in the
medical system and changes in the university hospitalorganization, and to operate by making maximum use of
medical information, In 2003, the hospital management
support departments, which had been separated into theCentral Medical Information Department, New Hospital
Development Planning Office (hospital measures),Management Improvement Planning Office (hospital
measures),
MedicalAffairs
Division,
andAdministration Division, were integrated andestablished in 2003. It was newly established in April
2013. The predecessor of the Central Medical
Information Department was the Information Processing
Department, which was established at the University ofTokyo Hospital in 1975 as an in-hospital measure. In
1983, the Ministry of Education (at that time) officiallyestablished the Central Medical Information Department
as one of the central medical facilities of the Universityof Tokyo Hospital.
At the same time, it became possible to accept doctoral
course students as the first graduate school of basic
medicine. The first professor and director of the Central
Medical Information Department was Shigemasa
Kaihara (deceased), who established medical
informatics in Japan, and is currently the second
generation. In 1997, Professor 1 and Assistant Professor

1, who had been affiliated with the Central Medical
Information Department, began to focus on graduate
school, and in 2003, as mentioned above, it became thePlanning Information Management Department. For the
relationship with the Graduate School of Medical
Informatics, please refer to the Medical Informatics
section of the Department of Social Medicine.
In addition to procuring, developing, implementing,and operating general hospital information systems andcomprehensive medical information network systems
centered on electronic medical record systems, thePlanning Information Management Department also
handles systems that support clinical research andmedical safety management. We are currently
developing a system for this purpose. In addition to
strategically managing and analyzing information
throughout the hospital and providing operational
support based on this information, the hospital is also
responsible for formulating mid- to long-term plans,
supporting their implementation, and coordinating plans.

Activities
Regarding medical information systems, we updated
the system in fiscal year 2017 (2017/12/28-2018/01/04)
and updated our unique ordering system and electronicsystem, which we have been using since 1994 and havecontinued to improve and update. We stopped using the581

medical record system and updated it to the Fujitsu
EgMAING-GX series package system. As it was acomplete system update, there were some difficulties
with data migration, and operations were disrupted at the
beginning of the update, but it took several months to getthings under control and up and running.
In addition, we have been participating in the project asa cooperating organization of MID-NET, a medical
information database infrastructure development projectthat is a joint project between the Pharmaceutical andFood Bureau of the Ministry of Health, Labor andWelfare and PMDA. We have started taking orders.
In addition, the national university hospital disastermedical data backup system, which has been in
operation since 2014, continued to be operated by ourdepartment as the main care department in 2017, and wascompletely updated in 2019.
A medical human resources development project
managed by the Ministry of Education, Culture, Sports,
Science and Technology began in the middle of 2017,
and faculty members from this department (Specially
Appointed Lecturer Ida and Assistant Professor Yamada)are participating in the steering committee to support thepromotion of the project. Details are available athttps://hep.m.u-tokyo.ac.jp/cms/.
The Ministry of Education, Culture, Sports, Science andTechnology's Human Resources Development Projectfor Utilizing Medical Real Data began in 2019, andMiyake and Kubota were hired as specially appointed
assistant professors in this department, and are in chargeof curriculum creation and management together with
Seki, the assistant professor in charge. Lectures andpractical training are mainly held on Saturdays as part of
the adult education course, and details can be found athttps://www.med-rwd.jp/.

Research activities
Please refer to the Department of Social Medicine andMedical Informatics.

582

University Hospital Medical
Information Network (UMIN)
CenterProfessor
Takahiro Kiuchi, M.D., Ph.D.

Associate Professor
Tsuyoshi Okuhara, Ph.D., M.P.H.

Instructor
Hiroko Okada, R.N., Ph.D., M.P.H.
Eiko Goto, R.D., Ph.D., M.P.H.
Rie Yokota, Ph.D., M.P.H.

Homepage

http://www.umin.ac.jp/

Introduction and Organization
The University hospital Medical Information Network(UMIN) (the original name was the University Medical
Information Network), was established in 1989.
While general-use computer systems were implemented at all national university hospitals around the 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 to connect
these computer systems in a network in order to share
information for better communication. Finally, theMinistry of Education, Culture, Sports, Science andTechnology approved a budget to initiate the UMIN
Center. The UMIN Center was founded within the
Hospital Computer Center, University of Tokyo
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 theobjectives 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 healthcare professionals
3. Support collaborative projects among university
hospitals
4. Support collaborative medical research
5. Standardize data format and support data collection
6. 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.

583

The UMIN Center subsequently started to provide threemajor information services: (1) the ELBIS (Electronic
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.

 Education: http://www.umin.ac.jp/education
CC-EPOC: Clinical Clerkship E-Portfolio of ClinicalTraining
PG-EPOC: E-Portfolio of Clinical Training 2
Debut2:
Dental Training Evaluation andTabulation System
L:E-learning system
ARIA:
Online Recruiting System for General
Use Medical Examination and Treatment
http://www.umin.ac.jp/uhosp/
 Intoxication database 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

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
ICDS:
Individual Case Data Sharing System

 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.

Research Activities
Please refer to Department of Health Communication
for information about research activities.

584

References
Please refer to Department of Health Communication.

585

Department of Disaster Medical
Management
Professor
Kent Doi, M.D.,Ph.D.

Assistant Professor
Hiroko Yuzawa M.D.,Ph.D. Kengo Hiwatashi M.D.

Homepagehttps://www.h.u-tokyo.ac.jp/patient/depts/dmm/

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 2021, Professor Kent Doi
has been assigned the post as the General Manager ofthe Department of Disaster Medical Management andwas 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
The Center provides education regarding disasters to
new employees and supports disaster-related training
activities in each department of the hospital. As foroff-campus educational activities, the center provides
support for planning disaster drills at other hospitals
and gives educational lectures.

586

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.

References
1.

2.

3.

4.

Kurano M, Jubishi D, Okamoto K, Hashimoto H,
Sakai E, Morita Y, Saigusa D, Kano K, Aoki J,
Harada S, Okugawa S, Doi K, Moriya K, Yatomi
Y. Dynamic modulations of urinary sphingolipid
and glycerophospholipid levels in COVID-19 andcorrelations with COVID-19-associated kidney
injuries. J Biomed Sci. 2022 Nov 10;29(1):94.
Yamakawa K, Yamamoto R, Terayama T,
Hashimoto H, Ishihara T, Ishimaru G, Imura H,
Okano H, Narita C, Mayumi T, Yasuda H,
Yamada K, Yamada H, Kawasaki T, Shime N,
Doi K, Egi M, Ogura H, Aihara M, Kushimoto S,
Nishida O; Special Committee of the Japanese
Clinical Practice Guidelines for the Managementof Sepsis and Septic Shock 2020 (J‐SSCG 2020),
the COVID‐19 Task Force. Japanese rapid/living
recommendations on drug management for
COVID-19: updated guidelines (July 2022).
Acute Med Surg. 2022 Oct 19;9(1):e789.
Kurano M, Okamoto K, Jubishi D, Hashimoto H,
Sakai E, Saigusa D, Kano K, Aoki J, Harada S,
Okugawa S, Doi K, Moriya K, Yatomi Y.
Dynamic modulations of sphingolipids andglycerophospholipids in COVID-19. Clin Transl
Med. 2022 Oct;12(10):e1069.
Ohashi-Fukuda N, Fukuda T, Doi K. Association
between time to advanced airway management
and survival during pediatric out-of-hospital
cardiac arrest. Resusc Plus. 2022 Jun 24;11:
100260.

Center for Disease Biology andIntegrative Medicine

588

Laboratory of Molecular
Biomedicine for Pathogenesis
Associate Professor
Satoko Arai, Ph.D.

Official Website

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

Research
Our laboratory focuses on clarification of thepathogenesis of various diseases and the related
physiological machineries in cellular and molecular
aspects. Based on our technical advantage in genemanipulation via gene knockout and transgenesis, wegive high priorities to in vivo analyses. This willdefinitively contribute to the direct therapeutic
application of our findings. Since our rationale is tochallenge to uncharacterized disease mechanisms andphysiologies, we will not restrict our interest, strategy
or technique employed, in certain specific field.
Rather, we will expand our research area by
establishing different collaborations with a broad
spectrum of researchers. We believe this fits to thepolicy of the CDBIM, which aims the development of
a comprehensive science including the fundamental
and clinical medicines, and the biotechnology. Overall,
we will attempt to discover novel biological insights
rather than to study details of previously characterized
physiologies, by targeting molecules newly identified
by ourselves. Now, we are focusing on the following
major projects.
AIM (Apoptosis Inhibitor of Macrophage) as a masterswitch to various modern diseases.
The rapid change in lifestyles and eating habits intoday’s society are thought to be the cause of various
disorders; metabolic syndrome and lifestyle-relateddiseases increase the risk of developing obesity,
diabetes, and cardiovascular disease; a fatty liver leads
to NASH and liver disease, may result in liver cancer;
autoimmune disease followed by obesity, chronic

renal failure, and Alzheimer’s disease are considered
as well. We hypothesize that such various modern
disorders, seemingly unrelated at first sight, share thecommon underlying pathological condition andmechanism, and the group of molecules exists as themaster switch, regulating the varied conditions.
We found a soluble apoptosis inhibitor factor
largely produced by tissue macrophage, named AIM(apoptosis inhibitor of macrophage). Our recent
studies showed that AIM plays an important role inregulating the pathological condition of the modern
diseases.
AIM is produced by macrophage and largely
presents in bloodstream as a soluble molecule. Once
AIM is incorporated into adipose tissue, it progressionof obesity. However, when this process undergoes
effectively and excessively under the obese condition,
oppositely to control the progression of obesity,
chronic inflammation of adipose tissue and insulin
resistance are triggered and Type II diabetes andatherosclerosis are worsen.
Moreover, because AIM binds to IgM in bloodstream, it leads to production of various autoantibodies, especially under the obese condition.
This suggests that the obesity is the cause of
autoimmune disease. Other studies showed that liverdisease, cancer, and kidney disease worsen under low
concentration of AIM. It is suggested that theconcentration of AIM in bloodstream differentiates theoutcome and the risk of getting various diseases.
The project was accepted for Advanced Researchand Development Programs for Medical Innovation,
Leading Advanced Projects for medical innovation

589(LEAP) 2019 (FY2019-2023), on Japan Agency for
Medical Research and Development (AMED).
Finding the mechanism on the regulation of AIM
activity will shed light on developing a diagnostics
and potential treatments to modern diseases. We will
focus on the details of involvement of AIM to thevarious diseases by generating a mouse model. Also,
cohort study is carried out using and analyzing thehuman specimen, aiming to develop a novel drug
treatment.
Additionally, we worked on the project regarding
the development of novel therapy against theinfectious diseases based on the phagocyticmechanism, founded by Research Program on
Emerging and Re-emerging Infectious Diseases(AMED FY2020-2021).

Lab Activities
We believe that the following three things are essential
for research in medical biology: ideas, strategies, andexperimental techniques. Therefore, the goal of oureducation is to let the students acquire as wide rangeof techniques as possible during their Master/PhD
courses and to cultivate ideas and strategies forresearch during their postdoctoral period. In addition,
since the establishment of our laboratory in 2006, wehave been constructing an international research
environment by regularly organizing a series ofseminars by leading overseas researchers and creating
as many opportunities as possible for young
researchers to have discussions in English, based on
the extensive friendships cultivated by Professor
Miyazaki's long-term overseas research experience. In
addition, we regularly hold joint meetings with
universities in Japan and abroad to exchange eachother's research progression and to explore thedevelopment of research through multifaceted
discussions, as well as to provide opportunities forstudents to present and discuss their research and tointeract with researchers. This year's seminars andmeetings were postponed in view of the situation
under the COVID-19.

Publications
1.

Matsuura T, Maehara N, Hirota A, Eguchi A,
Yasuda K, Taniguchi K, Nishijima A, Matsuhashi

N, Shiga Y, Ishii R, Iguchi Y, Tanabe K, Arai S,& Miyazaki T. Two independent modes of kidneystone suppression achieved by AIM/CD5L andKIM-1. Commun Biol. 5:783 (2022).

590

Laboratory ofStructural Physiology
Lecturer
Sho Yagishita, 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 in the
University of Tokyo in November, 2005. The Kasailaboratory has moved to the first building of Faculty of
Medicine in January, 2006. It belongs to the Section of
Functional Biology in the Graduate School of Medicine.
Its name has been changed from Division of Biophysics
to Laboratory of Structural Physiology in the April,2008. Dr. Kasai has also appointed as a principal
researcher in the International Research Center of
Neurointelligence (IRCN), the Institute of Advanced
Studies of the University of Tokyo since it hasestablished in 2017.10, and the laboratory is
cooperating the activity of IRCN. Dr. Kasai retired in
March 2022.
The 6 members of our laboratories in the April of2022 are Sho Yagishita (Lecturer), Mio Tajiri (Project
Researcher), Sachio Umemoto (Project Researcher),
Hidefumi Ohmi (M2), and as technical staffs,
Masayoshi Asaumi, and Akiko Abe.

Teaching activities
We gave two lectures of physiology forundergraduate students, was responsible for one
student experiment, one lecture of physiology andneuroscience for master course students. One
undergraduate student joined the activity of ourlaboratory for free quarter (FQ).

Research activities
We analyze monoamine functions in the brain at
multiple levels of the molecular, cellular, and system
by combining several experimental techniques
including
two-photon
excitation
microscopy,
molecular biology, electrophysiology, behavioral
experiments and animal MRI.
Dopamine sends dense projection to the nucleus
accumbens, which mainly consists of the neurons
express dopamine type 1 receptors (D1 neurons) andD2 receptors (D2 neurons). When an unexpected
reward is given in reward-based conditioning learning,
dopamine exhibits transient increase from the steadystate, which driving classical conditioning learning inwhich a conditioned stimulus (CS) such as sound isassociated with a reward (unconditioned stimulus, US)such as water. After the conditioning, animals predict
rewards from CS and elicit conditioned reflexes.
Furthermore, dopamine exhibits transient decrease
when the expected rewards do not come. We havepreviously shown that the D2 receptor detects thistransient decrease in dopamine. We also had identified
a time window in brain slices in which transient
increases in dopamine are detected by D1 neurons.
Along with this, we found learned behaviors andrelevant neural circuits that correspond to this timeframe (Ref. 1).

591

References
1. Yamaguchi K, Maeda Y, Sawada T, Iino Y, Tajiri M,
Nakazato R, et al. A behavioural correlate of thesynaptic eligibility trace in the nucleus accumbens.
Sci Rep. 2022 Feb 4;12(1):1921.

592

Laboratory of Biomedical
Equipment and Biomaterials
Professor
Taichi Ito, Ph.D.

Associate Professor
Kanako Harada, Ph.D.

Assistant Professor
Natsuko Inagaki, Ph.D.

Homepage

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

Introduction and Organization

Research activities

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.

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.

Teaching activities
Prof. Ito and Associate Prof. Harada are sharing duties
for undergraduate and graduate students of both
Graduate School of Medicine and Graduate School ofEngineering. They give lectures on biomedical
engineering at Graduate School of Medicine. Prof. Itogives a lecture concerning biosystem engineering,
separation technology I, biotechnology II, Basic
Biology, and Overview of Chemical Bioengineering at
the Chemical System Engineering course and Bioengineering course at Graduate School of Engineering
School. Associate Prof. Harada teaches at the courses
titledBioengineering
ExerciseforSocialImplementation 1・2, Engineering Competency III –Summer Camp–, Engineering Competency I –PBL–，
Basic Biology，Overview of Mechano Bioengineering,and Clinical Biomechanics.

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.

593- Peritoneal adhesion prevention- Hemostats- Drug delivery for peritoneal dissemination,
Mesothelioma, Liver cirrhosis- Hydrogel scaffolds for regeneration of islets andbones- Artificial Oxygen Carriers
In addition, Associate Professor Harada and her
students are developing surgical skill assessment
methods, surgical robots and robots assisting scientificexperiments.
1) Surgical Skill Assessment
Data sets collected during simulated surgery havebeen analyzed to quantify surgical skills. For example,
an image processing method to detect a surgical suture
has been developed to be used to quantify the
manipulation skills of expert surgeons.
2) Surgical robots
Surgical robotic systems for pediatric surgery,neurosurgery and eye surgery have been developed.
To study automation of robotic assistance, anautonomous robotic looping method has beendeveloped to assist anastomosis task in a small bodyspace.
3) Robots assisting scientific experiments
A robotic platform to assist scientific experiments,
such as the dissection of mouse, has been designed incollaboration with mathematicians, AI researchers,
robot researchers, and scientists. Tele-robotic
manipulation between Kyoto and Tokyo at thesubmillimeter scale was demonstrated.

References(1) Noriko Nakamura, Seiichi Ohta, Mariko Yamada,
Yukimitsu Suzuki, Natsuko F. Inagaki, Takeo
Yamaguchi, Taichi Ito "Development of apotassium ion-responsive star copolymer with
controlled aggregation/dispersion transition" ACS
Omega, 2022, 8(1), 1343–1352.
(2) Masashi Okawa, Aki Tanabe, Seiichi Ohta, Satoru
Nagatoishi, Kouhei Tsumoto, Taichi Ito"Extracellularmatrix-inspiredhydrogelofhyaluronan and gelatin crosslinked via a Link
module with a transglutaminase reactive sequence"
Communications Materials, 2022, 3(1), 81.
(3) Arvind K. Singh Chandel, Seiichi Ohta, Machiko
Taniguchi, Hiromi Yoshida, Daichi Tanaka,
Kiyohiko Omichi, Atsushi Shimizu, Mitsuko Isaji,
Kiyoshi Hasegawa, Taichi Ito "Balance ofantiperitoneal adhesion, hemostasis, and operabilityof compressed bilayer ultrapure alginate sponges"
Biomaterials Advances, 2022, 137, 212825.
(4) Seiichi Ohta, Kento Mitsuhashi, Arvind K. Singh
Chandel, Pan Qi, Noriko Nakamura, Akiko
Nakamichi, Hiromi Yoshida, Gento Yamaguchi,
Yuichi Hara, Ryo Sasaki, Masaya Fuke, Madoka
Takai, Taichi Ito "Silver-loaded carboxymethyl
cellulose nonwoven sheet with controlledcounterions for infected wound healing"
Carbohydrate Polymers, 2022, 286, 119289.
(5) Yuki Amano, Kazuma Sakura, Seiichi Ohta, Taichi
Ito"Cisplatin-chelated
iminodiacetic
acidconjugated hyaluronic acid nanogels for thetreatment of malignant pleural mesothelioma inmice" Molecular Pharmaceutics, 2022, 19(3), 853861.
(6) Taniguchi, Y., Sugiura, H., Yamanaka, T., Watanabe,S., Omata, S., Harada, K., ... & Arai, F. (2022). A
force measurement platform for a vitreoretinal
surgical simulator using an artificial eye module
integrated with a quartz crystal resonator.
Microsystems & Nanoengineering, 8(1), 74.
(7) Koyama, Y., Marinho, M. M., Mitsuishi, M., &Harada, K. (2022). Autonomous coordinatedcontrol of the light guide for positioning invitreoretinal surgery. IEEE Transactions on
Medical Robotics and Bionics, 4(1), 156-171.
(8) Marques Marinho, M., Oikawa, R., Hayashi, K.,
Takazawa, S., Harada, K., & Mitsuishi, M. (2023).
Design and validation of looping assistancemethods in robotic‐assisted neonatal surgicalsuturing in a chest model. The International
Journal of Medical Robotics and Computer
Assisted Surgery, 19(2), e2476.

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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://grn.tokyo/med/en/

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, suchas regenerative medicine and medical devices, is an
important and globally growing research field in595

which 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;

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Regen Ther 6, 100-107, 2017; Int J Mol Sci. 20(24).
pii: E6324, 2019; Bone. 137:115458, 2020; Nat
Commun. 12(1):6271, 2021; Cell Rep 40(10), 2022;
Nat Commun. 13(1):6187, 2022; Nat Commun.
13(1):2654, 2022). A fuller understanding of cell fatespecification processes during skeletal formation, we
believe, will enable the development of novel
therapeutic strategies, in which bone and cartilage
repair and regeneration are induced by the
manipulation of the specification processes.
2. The development of tissue-development modelingsystems using pluripotent stem cells
It would be ideal to study the mechanisms of tissue
formation and maintenance in in vivo working cells.
However, the number of cells that can be obtained invivo is often not sufficient for molecular-levelmechanistic studies; this is a technical limitation in
studying skeletal development and regeneration.
Pluripotent stem cells (PSCs; i.e., embryonic stem
cells — ES cells and induced pluripotent stem
cells — iPS cells), which have the ability to self-renew
and differentiate into all of the lineages present in thebody, are a promising tool for study; reproducing
organogenesis and metabolism in vitro potentiallyovercomes the above limitation. Considering thesafety, cost, and biological conciseness, it would bebetter to induce tissues from PSCs under definedconditions by using small molecules while avoiding
differentiation into lineages of no interest.
We have therefore been developing protocols for
directing mouse and human PSCs toward osteoblasts
under defined conditions using only small molecules,
while recapitulating in vivo osteoblast development(Stem Cell Reports 2:751, 2014). With the protocol,
we addressed a molecular mechanism in osteoblast
development (Stem Cell Reports. 15(1):125-139,
2020). We are also attempting to apply the protocols
to the generation of PSC-derived bone-like tissues, inwhich distinct cell populations regulating boneformation and maintenance (osteoblasts, osteocytes,
and osteoclasts) function three-dimensionally on
culture dishes (Science Advances 3:e1602875, 2017).
Such culture systems in combination with human
PSCs could enable us to reproduce human bonedevelopment and metabolism in a physiologically
relevant manner. These systems will also allow us tovisualize bone metabolism in vitro with imaging
techniques, contributing to drug discoveries for thetreatment of various bone diseases such as
osteoporosis, and to our understanding of the diseases'
pathophysiology and of the molecular mechanisms
underlying skeletal formation and maintenance.
3. The identification of bioactive factors that inducebone/cartilage formation and their application tobone/cartilage repair
Skeletal formation is regulated by various signaling
pathways and transcription factors. The manipulationof key pathways and/or factors would enable us to not
only induce skeletal formation and regeneration, butalso suppress the progression of skeletal degeneration.
Thus, we are carrying out molecular-biological andmouse genetic studies to elucidate the roles ofosteogenic and chondrogenic signaling pathways aswell as the modes of their actions. Based on thesebasic findings, we are also working on theidentification and application of bioactive moleculesthat induce osteogenesis and chondrogenesis.
We have been focusing on: (1) hedgehog (Hh)signaling-mediated cell fate specification duringosteoblast development (Development 131:1309,
2004； Journal of Biological Chemistry 282:17860,
2012; Journal of Biological Chemistry 288:9924,
2013), and (2) transcriptional regulation mediating
osteoblast differentiation and maturation (Developmental Cell 14:689, 2008; PLOS ONE, 2014). Thesestudies further extend to the development of the small
molecule-based treatment of bone fractures, using the
Hh signaling-activator molecule SAG (Biochemical
and Biophysical Research Communications 479:772,
2016) and bone regenerative therapy with SAG-loaded
calcium phosphate artificial bones (Biomaterials
34:5530, 2013). By combining biological findings
with engineering techniques, we are working on boneregeneration by plasmid delivery using polymericnanomicelles as nucleic acid carriers (Molecular
Therapy 15:1655, 2007) and the suppressive treatmentof cartilage degeneration by mRNA delivery(Scientific Reports 6:18743, 2016).
We have also identified novel small moleculesthat induce bone and cartilage formation (Biochemical
and Biophysical Research Communications 357:854,
2007; Annals of Rheumatic Diseases 72:748, 2013),

597

through the screening of compound libraries withcell-based sensors enabling the high-throughput
detection of osteoblast and chondrocyte differentiation(Biochemical and Biophysical Research Communications 376:375, 2008; Journal of Bone and Mineral
Metabolism 28:627, 2010).
4. The development of tissue-inductive implant
devices integrating tissue-regeneration signals andhighly functional and biocompatible biomaterials
In the current aging society, the treatment of tissue
defects in locomotive organs is a crucial task toachieve the extension of healthy life expectancy.
There is an urgent need for low-invasive reconstruction therapies that recover lost or damaged tissues
with the same functional and aesthetic qualities as
those in healthy states. The transplantation of donor
tissues obtained from patients’ healthy sites has been
widely used for tissue reconstruction (autologoustransplantation). However, this strategy often causes
post-operative pain and the cosmetic disturbance ofdonor sites. Although reconstruction with biomaterials
avoids donor site problems, its tissue induction
capacity is generally inferior to that of autologoustransplantation.
As signaling networks mediating the formation
and regeneration of tissue and organs are being
elucidated by recent advances in stem cell biology,
some biomaterial-based systems are being developed
for delivering signaling factors to target tissues. We
are studying these approaches as mentioned above. In
addition, the emergence of three-dimensional (3D)
printers has rapidly improved the techniques available
for controlling the shapes of scaffold materials. By
controlling the 3D shape of biomaterials, we havebeen attempting to improve the performance of
biomaterials for tissue repair. We developed custommade calcium phosphate artificial bone (CT-bone) thatis manufactured using 3D printers and have appliedthem to clinical settings in cooperation with the
Department of Oral and Maxillofacial Surgery, The
University of Tokyo Hospital (Journal of Artificial
Organs 9:234, 2006; Journal of Artificial Organs
12:200, 2009; Regenerative Therapy 5:1, 2016). We
have also worked on the development and applicationof tetrapod-shaped calcium phosphate artificial bone
(Tetrabone), which is fabricated at 1-mm size by

injection molding, and a custom-made titanium meshcage fabricated by laser sintering (Acta Biomaterialia
8:2340, 2012; Biomaterials 35:3229, 2014).
However, either signaling factors or biomaterials
alone are not sufficient for the clinically sufficient
regeneration of tissues, and interface units integratingthem are necessary for fully utilizing their performance. A candidate for the integrating interface unit isa high-performance hydrogel unit, which maintains
the spatial arrangement of signaling factors and candeliver them to target cells at a selected timing bytemporally controlled degradation. However, conventional hydrogels do not provide the characteristics
required for an integrating interface unit.
In cooperation with Professor Takamasa Sakai atthe Department of Bioengineering, UTokyo, we aredeveloping a high-performance hydrogel unit that
fulfills the necessary characteristics, based on
knowledge and techniques that we have accumulated
regarding the design and fabrication of novelhydrogels (Macromolecules 41:5379, 2008; Science
343:873, 2014; Advanced Materials 27:7407, 2015;
Nature Biomedical Engineering 1:44, 2017; Phys Rev
Lett. 125(26):267801, 2020; RSC Advances 11, 23637,
2021). The high-performance hydrogel unit would
integrate signaling factors with shape-controlled
scaffold materials, leading to the development of
implant devices that work as scaffolds for tissue repair
and also as carriers of bioactive factors. Through aseries of these studies, we are aiming to create a"four-dimensional scaffold system" that achieves
efficient tissue regeneration by controlling cellproliferation and differentiation in temporal andspatial manners. The system will not only beapplicable to the regeneration of other tissues; it will
also contribute to the development of basic
technologies for the temporal-spatial control of in situ
tissue formation, which is versatile in the prevention,
diagnosis, and treatment of various diseases.

Publications
1.

Kitaura Y, Nakamura U, Awada C, Yamaguchi M,
Kim M, Ikeda Y, Matsuo Y, Moriishi T, Sawase T,
Chung UI, Hojo H*, Ohba S*. Orally
administrable peptides derived from egg yolk
promote skeletal repair and ameliorate
degenerative skeletal disorders in mouse models.

598

Regen Ther 21:584-595, 2022
Nagata K, Hojo H, Chang SH, Okada H, Yano F,
Chijimatsu R, Omata Y, Mori D, Makii Y, Kawata
M, Kaneko T, Iwanaga Y, Nakamoto H,
Maenohara Y, Tachibana N, Ishikura H, Higuchi J,
Taniguchi Y, Ohba S, Chung UI, Tanaka S, Saito
T*. Runx2 and Runx3 differentially regulate
articular chondrocytes during surgically induced
osteoarthritis development. Nat Commun. 13(1):6187, 2022.
3. Iwahashi S, Lyu J, Tokumura K, Osumi R,
Hiraiwa M, Kubo T, Horie T, Demura S,
Kawakami N, Saito T, Park G, Fukasawa K,
Iezaki T, Suzuki A, Tomizawa A, Ochi H, Hojo H,
Ohba S, Hinoi E*. Conditional inactivation of theL-type amino acid transporter LAT1 inchondrocytes models idiopathic scoliosis in mice
J Cell Physiol. 2022 Sep 26. doi: 10.1002/jcp.
30883.
4. Hojo H*, Saito T, He X, Guo Q, Onodera S,
Azuma T, Koebis M, Nakao K, Aiba A, Seki M,
Suzuki Y, Okada H, Tanaka S, Chung UI,McMahon AP, Ohba S*. Runx2 regulates
chromatin accessibility to direct the osteoblast
program at neonatal stages. Cell Reports. 40(10),2022
5. Hojo H, Ohba S*. Sp7 Action in the Skeleton: Its
Mode of Action, Functions, and Relevance toSkeletal Diseases. Int J Mol Sci 23(10):5647,
2022
6. Nakayama M, Okada H, Seki M, Suzuki Y,
Chung UI, Ohba S, Hojo H*. Single-cell RNA
sequencing unravels heterogeneity of skeletal
progenitors and cell-cell interactions underlying
the bone repair process. Regen Ther. 21:9-18,
2022
7. Doi T*, Hojo H, Ohba S, Obayashi K, Endo M,
Ishizaki T, Katoh A, Kouji H. Involvement ofactivator protein-1 family members in β-catenin
and p300 association on the genome of PANC-1
cells. Heliyon. 8(2):e08890, 2022
8. Katashima T*, Kobayashi R, Ishikawa S, Naito
M, Miyata K, Chung UI, Sakai T. Decoupling
betweenTranslational
DiffusionandViscoelasticity in Transient Networks with
Controlled Network Connectivity. Gels. 8(12):830, 2022.
9. Saito Y*, Nakamura S, Tanaka A, Watanabe R,
Narimatsu H, Chung UI. Evaluation of thevalidity and reliability of the 10-meter walk test
using a smartphone application among Japaneseolder adults. Front Sports Act Living. 4:904924,
2022.
10. Ishikawa S, Yoshikawa Y, Kamata H*, Chung UI,
Sakai T*. Simple Preparation of Injectable
Hydrogels with Phase-Separated Structures That
Can Encapsulate Live Cells. ACS Appl Mater
2.

Interfaces. 14(31):35444-35453, 2022.
11. Saito Y*, Nakamura S, Tanaka A, Watanabe R,
Narimatsu H, Chung UI. Checking the validity
and reliability of the Japanese version of theMini-Cog using a smartphone application. BMC
Res Notes. 15(1):222, 2022.
12. Katashima T*, Kudo R, Naito M, Nagatoishi S,
Miyata K, Chung UI, Tsumoto K, Sakai T*.
Experimental Comparison of Bond Lifetime andViscoelastic Relaxation in Transient Networks
with Well-Controlled Structures. ACS Macro
Lett. 11(6):753-759, 2022.
13. Pham H, Svensson T*, Chung UI, Svensson AK.
Sleep Satisfaction May Modify the Association
between Metabolic Syndrome and BMI,
Respectively, and Occupational Stress inJapanese Office Workers. Int J Environ Res
Public Health. 19(9):5095, 2022.
14. Omatsu Y, Aiba S, Maeta T, Higaki K, Aoki K,
Watanabe H, Kondoh G, Nishimura R, Takeda S,
Chung UI, Nagasawa T*. Runx1 and Runx2
inhibit fibrotic conversion of cellular niches forhematopoietic stem cells. Nat Commun. 13(1):2654, 2022.
15. Fujiyabu T, Sakumichi N, Katashima T, Liu C,
Mayumi K, Chung UI, Sakai T*. Tri-branchedgels: Rubbery materials with the lowest
branching factor approach the ideal elastic limit.
Sci Adv. 8(14):eabk0010, 2022.
16. Matsubara T, Soma K, Yamada I, Fujita H,
Yoshitani J, Oka H, Okada H, Tanaka S*. Offset
nail fixation for intertrochanteric fractures
improves reduction and lag screw position. PLoS
One. 17(11):e0276903, 2022.
17. Tachibana N, Chijimatsu R, Okada H, Oichi T,
Taniguchi Y, Maenohara Y, Miyahara J, Ishikura
H, Iwanaga Y, Arino Y, Nagata K, Nakamoto H,
Kato S, Doi T, Matsubayashi Y, Oshima Y,
Terashima A, Omata Y, Yano F, Maeda S,
Ikegawa S, Seki M, Suzuki Y, Tanaka S, Saito T*.
RSPO2 defines a distinct undifferentiatedprogenitor in the tendon/ligament and suppresses
ectopic ossification. Sci Adv. 8(33):eabn2138,
2022
18. Omata Y, Okada H, Uebe S, Izawa N, Ekici AB,
Sarter K, Saito T, Schett G, Tanaka S*, Zaiss MM.
Interspecies Single-Cell RNA-Seq Analysis
Reveals the Novel Trajectory of Osteoclast
Differentiation and Therapeutic Targets. JBMR
Plus. 6(7):e10631, 2022.

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Laboratory of Microenvironmental
and Metabolic Health Sciences
Professor
Makoto Murakami, Ph.D.

Associate Professor
Seiichiroh Ohsako, Ph.D., D.V.M.

Assistant Professor
Yoshitaka Taketomi, Ph.D.

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 assistant professor, one research
assistant, one project assistant, one project researcher,
two visiting researchers, five graduate students(doctoral course), and four external researchers
conducted the researches together in 2023.
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

600

the molecular pathophysiology of diseases (e.g.
metabolic and immune diseases) that are problematicin modern society. Based on this, we will promote theresearch of Quality of Lipids (QOL) for Quality of Life
(QOL) and aim at building a theoretical foundation for
diagnosis, prevention and treatment of diseases
involving alteration of lipid metabolism.
1) Metabolic diseases
We previously reported that PLA2G5 (sPLA2-V),
secreted from hypertrophic white adipocytes duringobesity, hydrolyzes phosphatidylcholine (PC) in LDL
to release oleic and linoleic acids, which attenuate M1
polarization of macrophages and thereby protect fromdiet-induced obesity, adipose tissue inflammation, andinsulin resistance (Sato et al, Cell Metab, 2014), andthat PLA2G2D (sPLA2-IID), secreted from M2-likemacrophages in white adipose tissue, releases 3polyunsaturated fatty acids (PUFAs) to promote coldinduced adipocyte browning and thermogenesis (Satoet al, Cell Rep, 2020). In addition, we have recently
found that PLA2G2E (sPLA2-IIE) is highly induced inbrown and beige adipocytes in response to cold and thatits deletion leads to impairment of adipocyte browningand 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 liberates
endogenous choline remains unexplored. We found thatPNPLA7, 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 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 (Hirabayashi et al,
Cell Rep, 2023). In addition, skeletal muscle-specificPnpla7-null mice exhibit a sarcopenia-like phenotype
over 6 months.
2) Skin diseases
We previously reported that PLA2G2F (sPLA2IIF), which is specifically expressed in epidermal
keratinocytes, mobilizes lysoplasmalogen, a uniquelysophospholipid that has the ability to promoteepidermal hyperplasic diseases such as psoriasis andskin cancer (Yamamoto et al, J Exp Med, 2015), thatPNPLA1, a member of the intracellular iPLA2 family
whose mutations are linked to autosomal recessive
congenital ichthyosis, acts as a unique transacylase to
produce ω-O-acylceramide, an essential lipid
component for the skin barrier (Hirabayashi et al, Nat
Commun, 2017), and that PLA2G4E (cPLA2, whichacts as a N-acyltransferase that transfers a fatty acidfrom the sn-1 position of PC to the amino group ofphosphatidylethanolamine (PE) to give rise to N-acylPE (NAPE), a precursor of the anti-inflammatory lipid
N-acylethanolamine (NAE), counteracts psoriaticinflammation (Liang et al, FASEB J 2022). In addition,
genetic deletion of PLA2G4D (cPLA2, which has
PLA1 activity, exacerbates psoriasis, and that of
PLA2G4F (cPLA2, which has PLA2 activity with nosn-2 fatty acid selectivity, delays skin wound healing.
PLA2G3 (sPLA2-III) is expressed in epidermal
keratinocytes and its global or skin-specific deletion
leads to perturbation of skin barrier function due tofragile cornified envelope and loosened epidermal
tight junction. Accordingly, following topical antigen
challenge, global or skin-specific Pla2g3-deficient
mice display more severe atopic dermatitis-like
symptoms with increased expression of type 2
cytokines, serum IgE levels, eosinophil infiltration,scratching behavior, and disturbed skin microbiota.
Global or skin-specific deletion of EP4 (PGE2
receptor) or FP (PGF2 receptor) largely if not solely
recapitulate these phenotypes, and treatment with FP
or EP4 agonists rescues skin abnormalities in Pla2g3deficient mice. Moreover, global or skin-specificPla2g3-deficient mice exhibit more severe asthma
following percutaneous antigen challenge. These
results suggest that the epidermal PLA2G3-EP4/FP
axis plays an important role in skin barrier formation

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and thereby skin homeostasis, perturbation of whichleads to exacerbation of atopic march. Additionally,
we are analyzing the functions of the orphan enzymes
ABHD12B, which is markedly downregulated inpatients with scleroderma, and PNPLA5, which is
specifically expressed in sebaceous glands, in the skin.
3) Allergic and other immunological diseases
We previously reported that PLA2G3 secreted
from mast cells (MCs) promotes MC maturation by
driving the paracrine PGD2 circuit in cooperation withstromal fibroblasts (Taketomi et al, Nat Immunol 2013;
Taketomi et al, Cells 2021). In our continuing efforts tofully clarify the mechanism of MC maturation, we havefound that PLA2G3 is also coupled with another lipid
mediator, lysophosphatidic acid (LPA), which in turnacts on fibroblastic LPA1 receptor to upregulate
integrins, IL-33, ATX (LPA-producing enzyme) and
PGD2 synthase, thereby fine-tuning appropriate MC
maturation (submitted). PAF-AH2, a unique PLA2 thathydrolyzes oxidized phospholipids, ensures optimal
MC activation and thereby allergic responses throughproducing unique EPA/DHA metabolites (ω3 epoxides)(Shimanaka et al, Nat Med 2017). Furthermore,
PLA2G12A (sPLA2-XIIA) secreted from stromal
fibroblasts contributes to augment MC activation likely
through producing lysophospholipids.
PLA2 subtypes that regulate T cell immunity were
unknown. By transcriptional and functional screeningof PLA2 enzymes expressed in T cells, we have foundthat PLA2G12A is induced in Th17 cells and involvedin Th17 differentiation. Global and CD4+ T cellspecific Pla2g12a-deficient mice have fewer Th17 andT cells in the skin and draining lymph nodes, thereby
attenuating Th17-driven disease models such as
psoriasis, arthritis, and EAE. Mechanistically,
PLA2G12A produces LPE, which acts as a ligand forthe nuclear receptor RORt (Endo et al, Sci Immunol,2023), as well as LPA, which augments T ell activation
via LPA1 and LPA2 receptors.
4) Gut microbiota
Despite the restricted intestinal expression of
PLA2G2A (sPLA2-IIA) in BALB/c mice, its genetic
deletion leads to amelioration of skin carcinogenesis.
Metagenome, transcriptome and metabolome analyses
have revealed that Pla2g2a deficiency alters the gut
microbiota, accompanied by notable changes in theintestinal expression of genes related to immunity andmetabolism as well as the levels of various blood
metabolites and fecal bacterial lipids, suggesting that
PLA2G2A contributes to shaping of the gut microbiota(Miki et al, JCI Insight, 2022; Taketomi et al,
Metabolites 2022). In addition, mice deficient in
PLA2G10 (sPLA2-X), which is mainly expressed in thecolorectal epithelium, also have altered gut microbiota,
which eventually influences diet-induced obesity (inrevision). These results establish a role of the sPLA2
family as an endogenous factor capable of affecting
microbe–host interaction and thereby systemic
homeostasis and diseases.
5) Cancer
Extracellular vesicles (EVs) act as intercellularcommunicators by transferring protein and miRNAcargoes, yet the role of EV lipids remains unclear. We
found that the pro-tumorigenic action of lymphomaderived EVs is augmented via sPLA2-driven lipid
metabolism. Hydrolysis of EV phospholipids by
PLA2G10, which is induced in a specific population ofmacrophages in the lymphoma tissue, increases the
production of fatty acids, lysophospholipids and their
metabolites. sPLA2-treated EVs are smaller, selfaggregate, show better uptake, and increase cytokine
expression and lipid mediator signaling in recipienttumor-associated macrophages. Lymphoma growth in
EBV-infected mice is suppressed by a sPLA2 inhibitor,
while treating the mice with sPLA2-modified EVs canreverse this phenotype. Overall, the sPLA2-driven EV
modification promotes tumor development (Kudo et al,
Cell Metab 2022). It is tempting to speculate that themodification of EVs by sPLA2s may also occur in otherdiseases such as allergic and metabolic diseases, apossibility that is currently under investigation.
6) Neuronal and retinal diseases
Mutations in the PNPLA6 gene cause neuronal andretinal degeneration such as hereditary spastic
paraplegia (SPG39), Boucher-Neuhauser syndrome,
Oliver-McFariane syndrome, and Laurence-Moon
syndrome. PNPLA6 acts a phospholipase B (PLA1/A2+ lysophospholipase), hydrolyzing PC to give rise totwo fatty acids and GPC, in cells. Intriguingly, neuronspecific deletion of PNPLA6 and its closest homolog
PNPLA7 leads to severe neurodegenerative disorders
with muscle atrophy, reminiscent of SPG and ALS.
Moreover, tamoxifen-inducible, eye-specific deletionof PNPLA6 results in retinal degeneration, which could

602

be rescued by eye drops of choline, a PC degradation
product (in revision). Clarifying the regulatory roles oflipid metabolism driven by PNPLA6/PNPLA7 willshed light on the molecular mechanism underlying the
PNPLA6-related neuronal and retinal disorders.
Additionally, in collaboration with an external group,
we found that PLA2G2E is induced in neurons after
cerebral infarction and involved in protection against
neuronal damage by mobilizing the unique lipid
metabolite 15-HETrE (Nakamura et al, Neuron, 2023).
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 undergraduate medical students (M0).
Four undergraduate students (two M3 students andthree M1 students) are now participating in the
Murakami’s team throughout the year.

Publications
1.

2.

Rahman SMK, Hussain Z, Morito K, Takahashi N,
Sikder MM, Tanaka T, Ohta KI, Ueno M,
Takahashi H, Yamamoto T, Murakami M, Uyama
T, Ueda N. Formation of N-acylphosphatidylethanolamines by cytosolic phospholipase A2ε inan ex vivo murine model of brain ischemia.
Biochim Biophys Acta Mol Cell Biol Lipids. 1867,
159222, 2022.
Nagasaki Y, Kawai E, Maruoka S, Osumi M,
Tsukayama I, Kawakami Y, Takahashi Y, Okazaki
Y, Miki Y, Taketomi Y, Yamamoto K, Murakami
M, Suzuki-Yamamoto T. Lipid profiling reveals
the presence of unique lipid mediators in humanmilk from healthy and mastitic subjects. Biochem
Biophys Res Commun. 630, 84-91, 2022.

603

3.

4.

5.

6.

7.

8.

Tsukayama I, Kawakami Y, Tamenobu A, Toda K,
Maruoka S, Nagasaki Y, Mori Y, Sawazumi R,
Okamoto K, Kanzaki K, Ito H, Takahashi Y, MikiY, Yamamoto K, Murakami M, Suzuki-Yamamoto
T. Malabaricone C derived from nutmeg inhibits
arachidonate 5-lipoxygenase activity andameliorates psoriasis-like skin inflammation in
mice. Free Radic Biol Med. 193(Pt 1), 1-8, 2022.
Miyazaki T, Taketomi Y, Higashi T, Ohtaki H,
Takaki T, Ohnishi K, Hosonuma M, Kono N,
Akasu R, Haraguchi S, Kim-Kaneyama JR, Otsu
K, Arai H, Murakami M, Miyazaki A.
Hypercholesterolemic dysregulation of calpain in
lymphatic endothelial cells interferes withregulatory T-cell stability and trafficking.
Arterioscler Thromb Vasc Biol. 43, e66-e82, 2023.
Hirabayashi T, Kawaguchi M, Harada S, Mouri M,
Takamiya R, Miki Y, Sato H, Taketomi Y,
Yokoyama K, Kobayashi T, Tokuoka SM, Kita Y,
Yoda E, Hara S, Mikami K, Nishito Y, Kikuchi N,
Nakata R, Kaneko M, Kiyonari H, Kasahara K,
Aiba T, Ikeda K, Soga T, Kurano M, Yatomi Y,
Murakami M. Hepatic phosphatidylcholine
catabolism driven by PNPLA7 and PNPLA8
supplies endogenous choline to replenish themethionine cycle with methyl groups. Cell Rep. 42,111940, 2023.
Rahman SMK, Sasaki S, Uyama T, Hussain Z,
Sikder MM, Saiga H, Ohmura-Hoshino M, Ohta
KI, Miki Y, Hoshino K, Ueno M, Murakami M,
Ueda N. PLAAT1 deficiency alleviates high-fat
diet-induced hepatic lipid accumulation in mice.
FASEB J. 37, e23032, 2023.
Endo Y, Kanno T, Nakajima T, Ikeda K, Taketomi
Y, Yokoyama S, Sasamoto S, Asou HK, Miyako K,
Hasegawa Y, Kawashima Y, Ohara O, Murakami
M, Nakayama T. 1-Oleoyl-lysophosphatidylethanolamine stimulates RORγt activity in TH17 cells. Sci
Immunol. 8, eadd4346, 2023.
Nakamura A, Sakai S, Taketomi Y, Tsuyama J,
Miki Y, Hara Y, Arai N, Sugiura Y, Kawaji
H, Murakami M, Shichita T. PLA2G2E-mediatedlipid metabolism triggers brain-autonomous
neural repair after ischemic stroke. Neuron, 111,
S0896-6273(23)00483-X, 2023.

9.

10.

11.

12.

13.

14.

Murakami M. The phospholipase A2 superfamily
as a central hub of bioactive lipids and beyond.
Pharmacol. Ther. 244, 108382, 2023.（Review）
Harada, S., Taketomi, Y., Aiba, T., Kawaguchi, M.,
Hirabayashi, T., Uranbileg, B., Kurano, M.,
Yatomi, Y., Murakami M. The Lysophospholipase
PNPLA7 controls hepatic choline and methionine
metabolism. Biomolecules, 13, 471, 2023.
(Review)
Murakami M, Sato H, Taketomi Y. Modulation of
immunity by the secreted phospholipase A2
family. Immunol. Review 317, 42–70, 2023.
(Review)
Yamamoto K, Hakoi H, Nomura S, Murakami M.
The roles of sPLA2s in skin homeostasis anddisease. Biomolecules, 13, 668, 2023.（Review）
Murakami M, Taketomi Y. Current understandingof the pathophysiological roles of cytosolic andsecreted phospholipase A2s. Phospholipases inPhysiology and Pathology. Elsevier, 1, 55-84,
2023. (Review)
Kimura Y, Ekuban FA, Cai Zong, Sugie S, Zhang
X, Ito K, Yamamoto M, Ichihara S, Ohsako S,
Ichihara M. Role of Nrf2 in 1,2-dichloropropaneinduced cell proliferation and DNA damage in themouse liver. Toxicol Sci. 195, 28-41. 2023.

604

Laboratory of Animal Resources
Professor
Atsu Aiba, Ph.D.

Associate Professor
Hidetoshi Kassai, Ph.D.

Assistant Professor
Harumi Nakao, Ph.D., Ryo Saito, Ph.D., Shoko Noda-Narita M.D., Ph.D.

Project Assistant Professor
Yusuke Sakai, Ph.D.

Homepage

http://lar.cdbim.m.u-tokyo.ac.jp/index.html

Introduction and Organization
Our laboratory was established as the Division ofAnimal Research affiliated with the Faculty of
Medicine in April 1971. The building for animal
experimentation was completed and the accommodation and experimentation of laboratory animals
started in 1973. In 2003, the laboratory was
reorganized as the Section of Animal Research of theCenter for Disease Biology and Integrative Medicine(CDBIM). In 2008, the Laboratory of Animal
Resources was established to strengthen research activities in addition to the Section of Animal Resources.
The members of our laboratory and section are 6
teaching staffs, 6 technical support staffs, anadministrative staff, 2 assistant laboratory animal
technicians, 3 assistant clerks and a temporary staff(veterinarian). In addition, about 10 contracted
employees are involved in animal breeding andmaintenance of the animal facility.
The laboratory animals in our facility include dogs,
swine, rabbits, rats, mice, and marmosets. The numberof registered users of our facility was 675 at the end of
academic year 2022.
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 brain function
and brain metastasis. We also try to generate murine
and marmoset models for human genetic diseases.

605

1. Establishment of model marmosets for fragile X
syndrome
Common marmoset (Callithrix jacchus) is a
non-human primate and recently used for humanmodel, especially focusing on brain function. We haveestablished a novel protocol in which embryos arecollected from already mated females by oviductflushing and immediately transferred into the oviductof the very same donors following injections withgenome-editing components. Using this autologoustransfer protocol, we introduced guide RNAs for
FMR1 (fragile X mental retardation 1) gene encoding
fragile X mental retardation protein (FMRP) and Cas9
proteins into marmoset embryos. We obtained mutant
marmosets which carried mutations in coding regionof FMR1 gene. FMR1 mutant marmosets, which failto express the FMRP protein, exhibit epileptic-likeseizures and are lethal by 11 days of age.
Heterozygotes for FMR1 were successfully obtainedby crossing a mosaic male individual carrying
wild-type and mutant FMR1 alleles with wild-type
females. We are currently recording the movements
and vocalizations of the heterozygote underspontaneous behavior to determine whether thisanimal is a model for Fragile X Syndrome.
2. Elucidating the neural basis of consolation
behavior
Consolation behavior is affiliative social contact, forexample, a hug to alleviate pain or stress experienced
by another individual. In rodents, grooming behavior
toward a distressed mate is observed as a comfort-likebehavior. The division also attempted to detect
comforting behavior in inbred mice and constructed
an experimental system to see comforting behavior
prominently and efficiently.
Although Autism spectrum disorder (ASD) patientsare thought to have a tendency to have difficulty
sharing feelings and emotions with others (lower
levels of empathy), few studies have focused on thecausal relationship between ASD and reduction of
empathy in molecular research using animals. In order
to elucidate the mechanisms by which ASD cause lackof empathy at the neural circuit and molecular levels,
we have investigated whether the lack of
empathy-related behavior is observed in geneticallyengineered mouse models. Specifically, we havefocused on oxytocin and vasopressin, which are
expected to be therapeutic molecules for autism, andwe plan to examine how changes in consolation
behavior are observed in oxytocin receptor andvasopressin receptor knockout mice.
3. Functional analysis of the blood-brain barrier inbrain metastasis
The blood-brain barrier (BBB) plays an essential rolein brain metastasis of cancer. Although the analysis ofmolecules required for brain metastasis on the cancer
cell side has been well performed, the molecularmechanism of vascular endothelial cells, pericytes(mural cells) and astrocytes, which constitute the BBB,
has not been elucidated. Therefore, we aim to reveal
the molecular signaling involved in vascularpermeability and cancer brain metastasis byreconstituting the BBB in vitro model using vascularendothelial cells, pericytes, and astrocytes and by
genetically manipulating vascular endothelial cells inindividual mice.
In vitro BBB model indicated the necessity of
pericytes and astrocytes for BBB to regulate the brain
metastasis. The brain metastatic cell lines, establishedby repeating transplantation and isolation of brain
metastases in mice, showed highly metastatic featurein our in vitro BBB model. The mice with endothelial
cell-specific knockout of focal adhesion kinase (FAK)also indicated the different metastatic mechanism
between brain and trunk metastasis. The brain
metastases in the endothelial cell-specific knockout
mice of FAK are accelerated, although the metastasesin the trunk have been reported to be suppressed.
Now we plan to elucidate the specific mechanism
needed for brain metastasis by analyzing theinteraction between cancer cells and BBB.

References
1.

2.

Mori K, Koebis M, Nakao K, Kobayashi S,
Kiyama Y, Watanabe M, Manabe T, Iino Y, andAiba A.
Loss of calsyntenin paralogs disrupts interneuron
stability and mouse behavior.
Mol Brain, 15(1), 23, 2022.
Harbers M, Nakao H, Watanabe T, Matsuyama K,
Tohyama S, Nakao K, Kishimoto Y, Kano M, and

606

3.

4.

5.

6.

Aiba A.
mGluR5 Is Substitutable for mGluR1 in
Cerebellar Purkinje Cells for Motor Coordination,
Developmental Synapse Elimination, and Motor
Learning.
Cells, 11(13), 2004, 2022.
Hiraike Y, Tsutsumi S, Wada T, Oguchi M, Saito
K, Nakamura M, Ota S, Koebis M, Nakao H,
Aiba A, Nagano G, Ohno H, Oki K, Yoneda M,
Kadowaki T, Aburatani H, Waki H, and Yamauchi
T.
NFIA determines the cis-effect of genetic
variation on Ucp1 expression in murine
thermogenic adipocytes.
iScience, 25(8), 104729, 2022.
Abe YO, Yoshitane H, Kim DW, Kawakami S,
Koebis M, Nakao K, Aiba A, Kim JK, andFukada Y.
Rhythmic transcription of Bmal1 stabilizes thecircadian timekeeping system in mammals.
Nat Commun, 13(1), 4652, 2022.
Hojo H, Saito T, He X, Guo Q, Onodera S,
Azuma T, Koebis M, Nakao K, Aiba A, Seki M,
Suzuki Y, Okada H, Tanaka S, Chung UI,McMahon AP, and Ohba S.
Runx2 regulates chromatin accessibility to direct
the osteoblast program at neonatal stages.
Cell Rep, 40(10), 111315, 2022.
Ayuzawa N, Nishimoto M, Kawarazaki W, Oba S,
Marumo T, Aiba A, and Fujita T.
Rac1 deficiency impairs postnatal developmentof the renal papilla.
Sci Rep, 12(1), 20310, 2022.

607

Laboratory of Molecular Radiology
Professor
Kiyoshi Miyagawa, M.D., Ph.D.

Associate Professor
Noriko Hosoya, M.D., Ph.D.

LecturerAtsushi Enomoto, Ph.D.

Research Associate
Takaaki Yasuhara, Ph.D.

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608

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

609

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.

5.

Enomoto A, Fukasawa T, Terunuma H,
Nakagawa K, Yoshizaki A, Sato S, Miyagawa K.
Decrease in MAP3Ks expression enhances thecell death caused by hyperthermia. Int J
Hyperthermia 39:200-208, 2022.
Yasuhara T, Kato R, Yamauchi M, Uchihara Y,
Zou L, Miyagawa K, Shibata A. RAP80
suppresses the vulnerability of R-loops during
DNA double-strand break repair. Cell Rep 38:
110335, 2022.
Ando T, Kage H, Shinozaki-Ushiku A, Tatsuno K,
Tsutsumi S, Nagayama K, Nakajima J, Kohsaka
S, Miyagawa K, Aburatani H, Mano H, Nagase T.
Composite clonal analysis reveals transition of
NSCLC subtypes through accumulation of genemutations: A case report. JTO Clin Res Rep
3:100277, 2022.
Taguchi A, Rokutan H, Oda K, Tanikawa M,
Tanimoto S, Sone K, Mori M, Tsuruga T,
Kohsaka S, Tatsuno K, Shinozaki-Ushiku A,
Miyagawa K, Mano H, Aburatani H, Ushiku T,
Osuga Y. Genetic diagnosis of pseudomyxoma
peritonei originating from mucinous borderline
tumor inside an ovarian teratoma. BMC Med
Genomics 15:51, 2022.
Fukasawa T, Yoshizaki-Ogawa A, Enomoto A,
Miyagawa
K,
SatoS,
Yoshizaki
A.
Pharmacotherapy of Itch-antihistamines and6.

histamine receptors as G protein-coupled
receptors. Int J Mol Sci 23:6579, 2022.
Fukasawa T, Yoshizaki-Ogawa A, Enomoto A,
Miyagawa K, Sato S, Yoshizaki A. Involvementof molecular mechanisms between T/B cells andIL-23: From palmoplantar pustulosis to
autoimmune diseases. Int J Mol Sci 23:8261,
2022.

610

Laboratory of Biomedical
Informatics
Associate Professor
Takeshi Imai, Ph.D.
※The following information is the same as that of the previous year for certain reasons.

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.

611

Research activities
Our primary research domains are: (1) methods toknowledge representation and processing knowledge inhealthcare, (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 to612

diagnosis by experts.
In addition to the researches, we have worked onother studies such as automatic selection of theunderlying 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.

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

8.

9.

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 theaccuracy 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)614

Department of Medical Education
Studies
Professor
Masato Eto, M.D., Ph.D.

Lecturer
Masashi Izumiya, M.D., Ph.D.

History and organization
International Research Center for Medical
Education, established in 2000, had functioned as acenter for the whole university and kept relations with
Graduate School of Medicine in various ways. IRCME
became an affiliated center for education and researchunder the control of Graduate School of Medicine sinceApril 2013. IRCME previously consisted of two
departments of International Cooperative Study in
Medical Education, and Planning & Cooperation forInternational Cooperative Projects and Information on
Medical Education. Names of two new departments are
Department of Medical Education Studies andDepartment of International Cooperation for Medical
Education.
The mission of Department of Medical Education
Studies includes promotion of medical education not
only in Faculty of Medicine of the University of Tokyo
but also of the whole country. Specific contents are as
follows:(1) Research in medical education and dissemination
within and outside of the University
Medical and health professions education needs tocontinue revisions to meet health care needs of thecountry or the region. However, since every country or
region has different culture or social system,
experiences to apply updated evidence to the realsettings to revise the system.
(2) Support to undergraduate and postgraduate education in the University
Through the support to education in Faculty of

Medicine and the University Hospital, we show theeffective ness of such teaching practice and apply it toother medical schools in Japan for future reform.

Activities
This department promotes research related to
medical education field. As the studies of medical
education develop very rapidly all over the world, thedepartment expands research to construct theories andemphasizes activities of educational practice or
improvement.
In the University, this department provides
information and members as to the education of Facultyof Medicine in such as academic affair committee,
medical education reform working group, and clinicalclerkship. Moreover, the department offers educational
activities such as PBL (problem-based learning) andclinical skill practical training. The department
operates OSCE (objective structured clinicalexamination). The department also runs and manages“Tsutsuji no kai” under the consortium with Tokyo
Medical Dental University to develop simulated
patients indispensable for education of medical
interview.
This department promotes practical activities for the
pre-graduate education of medical students andresearch in fields related to medical education. In thefield of pre-graduate education, the department aims tonurture and produce human resources who can lead
medicine and medical care in Japan, as well as toprovide educational content of international standard.

615

In addition, against the backdrop of the rapid
development of digital technology in recent years, thedepartment will conduct research to provide effective
and efficient medical education utilizing these newtechnologies.
The faculty members of this division are active
members of the Academic Affairs Committee, working
groups on educational reform, clinical clerkships, andother committees related to education at the Faculty of
Medicine. The department also conducts PBL tutorials,
clinical introductory training, and interprofessional
education (IPE) in collaboration with otherdepartments and universities. Furthermore, thedepartment is focusing on simulation education for
medical students using the clinical simulation centerorganized in the hospital. The department is also incharge of the administration of the OSCE (objective
structured clinical examination) with the Educational
Affairs of Administrative Division. In addition, thedepartment operates and manages the Tsutsuji no kai, aconsortium with Tokyo Medical and Dental University,
to train simulated patients, which is essential for
medical interviewing education.
The department is also in charge of conducting
institutional research (IR) and class/curriculum surveys
for continuous evaluation and improvement of medical
education, as well as the administrative office of theMedical Education Improvement Committee.

616

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/home
Introduction and Organization
International Research Center for Medical Education(IRCME), established in 2000, had functioned as acenter for the whole university and kept relations with
Graduate School of Medicine in various ways.
IRCME became an affiliated center for education andresearch under the Graduate School of Medicine
umbrella since April 2013. IRCME currently consistsof the Department of Medical Education and theDepartment of International Cooperation for Medical
Education (ICME). Since April 2018, the Department
of International Cooperation in Medical Education,
which had been operated in an integrated manner with
the Department of Medical Education, has been
operated independently. It is one of the departments of
the IRCME, and encompasses international
cooperation in areas related to medical education, as
well as practice and research in areas that connect
policies and actual clinical practice, such as global
health, community medicine, and general practice.

Education
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.

Research(1) International Cooperation in the Field of HealthProfessions Education: Through participation ininternational cooperation projects in Asia and othercountries, we explore what education and policies in
the health and medical fields should be like. He is also
involved in surveys and research on the accepting
medical and nursing professionals from overseas andon cultural and language frictions. Through joint
research with related institutions in Taiwan andIndonesia, we aim to gain experience in evaluation
methods, policy recommendations, and coordination
among related parties, as well as to disseminate theresearch results and become a core research center inthis field.
(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 pass/fail decision is made. Various
changes are seen in the concept of assessment itself.
Current studies include the development of workbased assessment methods, verification of reliability
and validity of assessment tools, and the improvementof methods for standard setting of pass/fail judgment
criteria.
(3) Research related to ACP (advance care planning):

617

We continue researching how and where the elderly
want to end their own life and the relationship between
their family's thoughts.
(4) Practice and research in the field linking healthpolicy and clinical practice: Studies are done for how
to train the professionals contributing to communitybased integrated care system.

References
1.

2.

3.

Schuwirth L, Colliver J, Gruppen L, Kreiter C,
Mennin S, Onishi H, ... & Wagner M. Research on
Assessment Practices. In International Best
Practices for Evaluation in the Health Professions(pp. 59-75). CRC Press; 2022
Tsuchida T, Onishi H, Ono Y, Machino A, Inoue
F, & Kamegai M. Factors associated withpreferred place of death among older adults: aqualitative interview study in Tama City, Tokyo,
Japan. BMJ open. 2022; 12(5): e059421.
Ernawati DK, Sutiari NK, Astuti IW, Onishi H, &Sunderland B. Correlation between intercultural
sensitivity and collaborative competencies
amongst Indonesian healthcare professionals.
Journal of Interprofessional Education & Practice.
2022; 29: 100538.

618

Global Nursing Research Center
Director, Professor
Noriko Yamamoto-Mitani, R.N, Ph.D.

Vice Director, Professor
Megumi Haruna, Ph.D., R.M., R.N.
Mari Ikeda, Ph.D., R.N., CCP.

Project Professor
Karis Kin-Fong Cheng, Ph.D., R.N., FAAN.

Project Senior Lecturer
Kojiro Morita, M.P.H., R.N., P.H.N., Ph.D.
Hiromi Tobe, R.N., P.H.N.,Ph.D.

Project Assistant Professor
Sameh Eltaybani, Ph.D.

Project Researcher
Manami Takaoka, Ph.D., R.N., P.H.N..

Homepagehttps://gnrc.m.u-tokyo.ac.jp/en/

Introduction and Organization
With a falling birthrate and a super-aging society, Japanis in need of a paradigm shift toward a medical andnursing care that supports the aging, as well as thosedealing with chronic health conditions, to lead lives
with maximum independence and well-being. In orderto provide a healthy life expectancy for its people, itwill be necessary for Japan to face its forthcoming
challenges and bring about the realization of a ‘care’society that lightens the difficulty of the living andbrings a self-reliant way of life to the Japanese nation.
Nursing, which plays a central role in providing care,must develop into a new field as a science for therealization of this ‘care’ society. Currently, however,the dominant paradigm employed in various nursing
fields embraces a structure that supports the training ofclinical nurses, not the development 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 thatsystematizes this type of care. In particular, our focus
is to create a transdisciplinary 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

619

ranges from fundamental research to studies withcommercial application.
Thus, the Global Nursing Research Center has been
established as an affiliated research center, which is thefirst of its kind in nursing science. The GNRC willcontinue to execute the following three goals:
1) Establish an innovative nursing research field basedon transdisciplinary integration;2) Carry out cutting-edge research and present it to theworld with young researchers pursuing the sciences;
3) Build up a foundation of these new fields throughrepeated research trials that will strengthen the newresearch and education systems.

Establishing an Innovative Nursing Research
Field
1. Division of Care Innovation
The Division of Care Innovation promotes various
research activities, such as robotics nursing, biologicalnursing, visualized nursing, clinical nursing technology
and reverse translational research, with the aim of‘developing and producing patient care products thatlighten unfavorable conditions of daily life due to thehealth 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, andmaking policy proposals.’
3. Division of Global Collaborative Research
The Division of Global Collaborative Researchpromote collaborative research and create a network of
research groups among global partners to resolve
global health issues and create a platform to share andincrease the visibility of our outcomes locally andinternationally.
4. Achievements
In 2022, 3 international joint research projects and 11
industry-government-academia research project were
undertaken. In addition, 95 original English articles
were published.

Executing Innovative Research
1. International Invited Faculty
In 2022, we had one Project Professor: Prof. Karis KinFong Cheng: National University of Singapore, andinvited 13 other researchers.
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.
We provided 14 themes for our post-doctoral program,including (1) Leadership for Change in Healthcare, (2)Excellence in Academic Writing, (3) Meta-analysis～
Advanced research methodology～, and (4) Qualitative
Research and Mixed Methods for Healthcare.
In 2022, one PD researcher participated in this program,and completed the program.
3. Other Universities’ Young Researchers
In 2022, our PD seminars and lectures were opened toyoung researchers from other universities, and by theend of the year, a total of 1363 participants attended.
4. Other activities
The "Nursing Lecture Series," featuring lectures byfour deans of the top 50 QS-ranked universities, washeld. The 26th East Asia Forum of Nursing Scholars(EAFONS) was held in collaboration with the Japan
Association of Nursing Program Universities (JANPU)
as an academic meeting. The Spring International
Program was also held to provide an opportunity forgraduate students from Japan and abroad to learn andshare innovative approaches and methodologies innursing science.

Building Future Research
1. Global Nursing Research Center FundThe Global Nursing Research Center Fund wascontinued for the purpose of fostering young
researchers.
Accomplishments
1. Asaoka, H., Koido, Y., Kawashima, Y., Ikeda, M.,
Miyamoto, Y., & Nishi, D. (2022). Longitudinal

620

2.

3.

4.

5.

6.

7.

change in depressive symptoms among healthcare
professionals with and without COVID-19
vaccine hesitancy from October 2020 to June 2021
in Japan. Industrial health, 60(4), 387–394.
https://doi.org/10.2486/indhealth.2021-0164
Honda, C., Sumikawa, Y., Yoshioka-Maeda, K.,
Iwasaki-Motegi, R., & Yamamoto-Mitani, N.
(2022). Confusions and responses of managerial
public health nurses during the COVID-19
pandemic in Japan. Public health nursing (Boston,
Mass.), 39(1), 161–169. https://doi.org/10.1111/
phn.13011
Hsu, W. J., Minematsu, T., Nakagami, G.,
Koudounas, S., Tomida, S., Nakai, A., Kunimitsu,
M., Nitta, S., & Sanada, H. (2022). Identificationof microRNAs responsive to shear loading in rat
skin. International wound journal, 19(2), 351–361.
https://doi.org/10.1111/iwj.13635
Iwasaki-Motegi, R., Yoshioka-Maeda, K., Honda,
C., & Yamamoto-Mitani, N. (2022). Prefectural
public health nurses' support in human resource
development of municipal public health nurses inJapan. [Nihon koshu eisei zasshi] Japanese journalof public health, 69(6), 417–423. https://doi.org/
10.11236/jph.21-078
Kida, R., & Takemura, Y. (2022). Working
Conditions and Fatigue in Japanese Shift Work
Nurses: A Cross-sectional Survey. Asian nursing
research, 16(2), 80–86. https://doi.org/10.1016/j.
anr.2022.03.001
Koudounas, S., Minematsu, T., Mugita, Y.,
Tomida, S., Nakai, A., Nakagami, G., & Sanada,
H. (2021). Inhibiting effect of synthetic urine on
the growth and mobility of Pseudomonas
aeruginosa, Escherichia coli, Proteus mirabilis andKlebsiella pneumoniae shifts to a promoting effectduring culture. Journal of Nursing Science andEngineering, 8, 220-229. https://doi.org/10.
24462/jnse.8.0_220
Matsumoto, H., Igarashi, A., Hagiwara, Y., &Yamamoto-Mitani, N. (2022). Relational Designfor Dementia and Job Significance (ReDeSign):
Study protocol for a randomized controlled trial ofan online dementia training for retail workers.
Contemporary Clinical Trials Communications,26, 100896. https://doi.org/10.1016/j.conctc.2022.
100896

8.

9.

10.

11.

12.

13.

Murakami, M., Yonezawa, K., Shimizu, S.,
Haruna, M., Sasagawa, E., & Usui, Y. (2022).
Newborn-oriented and environmental factors for
newborns' skin barrier functions. Japan journal ofnursing science: JJNS, 19(2), e12457. https://doi.org/10.1111/jjns.12457
Murayama, R., Abe-Doi, M., Kogure, T.,
Takahashi, T., Kanno, C., Ishigaki, M., & Sanada,
H. (2021). The influence of peripheral intravenous
catheterization on the sleep quality of ophthalmic
inpatients: An observational study. Journal of
Nursing Science and Engineering, 8, 134-142.
https://doi.org/10.24462/jnse.8.0_134
Qin, Q., Oe, M., Ohashi, Y., Shimojima, Y.,
Imafuku, M., Dai, M., Nakagami, G., Yamauchi,T., Yeo, S., & Sanada, H. (2022). Factors
Associated with the Local Increase of Skin
Temperature‘ 'Hotspo’,' of Callus in Diabetic
Foot: A Cross-Sectional Study. Journal of diabetes
science and technology, 16(5), 1174–1182.
https://doi.org/10.1177/19322968211011181
Sugawara, C., Yamana, H., Sasagawa, E.,
Yonezawa, K., Hikita, N., Morita, K., Matsui, H.,
Yasunaga, H., & Haruna, M. (2022). Factors
Associated with Surgical Treatment in Postpartum
Women with Mastitis or Breast Abscess: A
Retrospective Cohort Study. Breastfeeding
medicine : the official journal of the Academy ofBreastfeeding Medicine, 17(3), 233–238. https://doi.org/10.1089/bfm.2021.0244
Yonezawa, K., Haruna, M., Yamamoto-Hanada,K., & Ohya, Y. (2022). Exacerbation and severityof allergic symptoms during pregnancy and theirimpact on mental health. International journal ofwomen's dermatology, 8(1), e002. https://doi.org/
10.1097/JW9.0000000000000002
Yoshinaga, N., Nakagami, G., Fukahori, H.,
Shimpuku, Y., Sanada, H., & Sugama, J. (2022).
Initial impact of the COVID-19 pandemic on time
Japanese nursing faculty devote to research:
Cross-sectional survey. Japan journal of nursing
science : JJNS, 19(1), e12454. https://doi.org/
10.1111/jjns.12454

621

Center for Diversity in Medical
Education and Research
Director/Professor
Kiyoto Kasai, M.D., Ph.D.

Vice Director/Associate Professor
Yoshihiro Satomura, M.D., Ph.D.

Homepagehttps://cdmer.jp

Introduction and Organization
The University of Tokyo Center for Diversity in
Medical Education and Research was established in
April 2021. The main purpose of the center is topromote education and research on diversity andinclusion in medicine. As part of this, the center aims
to provide training programs for medical students withdisabilities.
The center is working on the education, support,
research and organizational change/ co-production
divisions in close collaboration with the Graduate
School of Medicine and Faculty of Medicine andDisability Services Office in the University of Tokyo.
The center aims to improve the quality of patientcentered medical services by the inclusion of medical
professionals with disabilities in the team medical care.

Education
Through education on diversity and inclusion in
medicine, we will develop medical personnel including
physicians and medical researchers who understand thesignificance of patient-public involvement (PPI) in
medical research and development, and who have a coproduction mindset in medical research and practice.
For this purpose, we will be giving lecture to medical
students in some of the existing educational programs.
For a more integrated and systematic education on
diversity and inclusion in medicine, we are preparing
to establish the “ Human Resource Development
Program for Diversity and Inclusion in Medicine”. In

this program, participating students will take theinitiative in deepening their learning based on thephilosophy of co-production and will not only be
exposed to academic theory, but also participate in thepractical field.

Research
There are many research issues that need to beclarified in order to promote diversity and inclusion in
medicine. The actual situation regarding the presence
rate of personnel with disabilities, and reasonableaccommodation in medical education and practicesettings needs to be clarified. Research on stigma heldby health care providers, considered one of the mostsignificant barriers to participation of medical
personnel with disabilities, and the development ofanti-stigma educational intervention methods are alsoneeded. We will also need to explore the conditions fororganizations in which personnel with disabilities canplay an active role safely.

Publications
1.

Yamagishi M, Satomura Y, Sakurada H, Kanehara
A, Sakakibara E, Okada N, Koike S, Yagishita S,
Ichihashi K, Kondo S, Jinde S, Fukuda M, Kasai
K: Retrospective Chart Review-based Assessment
Scale for Adverse Childhood Events andExperiences.
Psychiatry
andClinical
Neurosciences Reports 1: e58, 2022. 17 November
2022. http://dx.doi.org/10.1002/pcn5.58

622

2.

3.

4.

5.

6.

7.

Kanehara A, Morishima R, Takahashi Y, Koike H,
Usui K, Sato S, Uno A, Sawai Y, Kumakura Y,
Yagishita S, Usami S, Morita M, Morita K, Kanata
S, Okada N, Yamasaki S, Nishida A, Ando S,
Koike S, Shibuya T, Joseph S, Kasai K: Youngcarers in Japan: Reliability and validity testing of
the BBC/University of Nottingham young carers
survey questionnaire and prevalence estimation in
5,000 adolescents. Psychiatry and Clinical
Neurosciences Reports. 1: e46, 2022. Sep 2022.
DOI: 10.1002/PCN5.46
Kiyono T, Ando S, Morishima R, Fujikawa S,
Kanata S, Morimoto Y, Endo K, Yamasaki S,
Usami S, Hiraiwa-Hasegawa M, Nishida A, Kasai
K: Sex-based differences in the longitudinalassociation between autistic traits and positive
psychotic experiences in adolescents: A
population-based cohort study. Schizophrenia
Research. 2022 Aug;246:1-6. doi: 10.1016/j.
schres.2022.05.027.PMID: 35696856
Morishima R, Koike H, Kanehara A, Usui K,
Okada N, Ando S, Kasai K: Implementation of
online classes during national school closure due
to COVID-19 and mental health symptoms ofadolescents: A cross-sectional survey of 5000
students. Psychiatry and Clinical Neurosciences
Reports. June 2022. https://doi.org/10.1002/pcn5.
17Kanehara A, Koike H, Fujieda Y, Yajima S,
Kabumoto A, Kumakura Y, Morita K, Miyamoto
Y, Nochi M, Kasai K: Culture-dependent anduniversal constructs and promoting factors for theprocess of personal recovery in users of mental
health services: Qualitative findings from Japan.
BMC Psychiatry. 2022 Feb 10;22(1):105. doi:
10.1186/s12888-022-03750-4.
Kasai K, Kumagaya S, Takahashi Y, Sawai Y, Uno
A, Kumakura Y, Yamagishi M, Kanehara A,
Morita K, Tada M, Satomura Y, Okada N, Koike
S, Yagishita S: "World-Informed" neurosciencefor diversity and inclusion: An organizationalchange in cognitive sciences. Clin EEG Neurosci.
2022 Jun 12. PMID: 35695218 DOI: 10.1177/
15500594221105755.
Kasai K, Yagishita S, Tanaka SC, Koike S, Murai
T, Nishida A, Yamasaki S, Ando S, Kawakami N,
Kanehara A, Morita K, Kumakura Y, Takahashi Y,

Sawai Y, Uno A, Sakakibara E, Okada N,
Okamoto Y, Nochi M, Kumagaya SI, Fukuda
M: Personalized values in life as point ofinteraction with the world: Developmental/
neurobehavioral basis and implications forpsychiatry. Psychiatry Clin Neurosci Rep 1: e12,
June 2022. DOI:10.1002/pcn5.12.

623

Office ofInternational Academic Affairs
HeadShinichi Sato

Assistant Professors
Keiko Nanishi
David Kipler
Florence Ene

Homepage: http://koryu.m.u-tokyo.ac.jp
Status and functions
The Office of International Academic Affairs(OIAA) is under the direct authority of the Dean of
the Faculty of Medicine. Its three most importantroles, as defined by the Committee on International
Academic Affairs, are facilitating 1) international
academic exchange, 2) international academic andresearch agreements, and 3) education and research
activities.

Activities
This report details the activities of the OIAA during
the 2022-23 academic year (1 April 2022 through 31
March 2023).
1. International Academic Exchange
1.1 Student guidance on education and research
The OIAA assists international students inapplying for various scholarships, and the OIAA oncampus screening committee evaluates applicants forscholarships that require university recommendations.
To promote friendship among international students,
the OIAA organizes a get-together every summer atCapo Pellicano, a restaurant in the Faculty of
Medicine Experimental Research Building, and aschool trip every spring. The get-together party in thesummer of 2022 was canceled because of the COVID-

19 pandemic, but the school trip in the spring of 2023
was conducted as usual.
The OIAA oversees undergraduate clinical training(elective clerkships) for international students at the
University of Tokyo Hospital. Border restrictions inJapan forced the cancellation of many elective
clerkships that were scheduled. After October 2022,
the situation returned to normal, resulting in the
hosting of 13 international students in 2022-23.
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 2023, the University of Tokyo Facultyof Medicine has agreements for exchange programs—
which provide one to two months of clinicaltraining—with the University of Pennsylvania, Johns
Hopkins University, University of Michigan,
University of Hawaii, Seoul National University,
National Taiwan University, National University ofSingapore, Karolinska Institute and Ludwig

624

Maximilian University of Munich. The OIAA
nominates qualified students for each university andassists in their preparation for study abroad.
Although students were nominated for electives
scheduled for April through July 2022, the pandemic
caused the host institutions to cancel many electives,
resulting only 12 students could complete theirelective.
1.3 Support for overseas training of graduates
The OIAA assists graduates in preparing documents
for applications to graduate schools and otherinstitutions abroad and in obtaining medical licensurein other countries. During 2022-23, the OIAA
received no requests for preparing Medical Student
Performance Evaluations.
2. International Academic and Research
Agreements
During the 2022-23 academic year, theinterdepartmental agreement with the University of
Munich was renewed. We continued interaction withstrategic partnership universities such as the
University of Chicago and National Taiwan
University, including jointly hosting workshops
online, which was possible during the COVID-19
pandemic.
3. Education and Research Activities
Dr. Florence Ene supervised and taught the Medical
English I/II courses.
David Kipler trained graduate and undergraduate
students in writing research articles and making oralpresentations in English.
Dr. Keiko Nanishi served as a lecturer in the Schoolof International Health, where she supervised
graduate students and conducted research oninternational health.

Publications
1:

Nanishi K, Okawa S, Hongo H, Shibanuma A,
Abe SK, Tabuchi T. Influence of the COVID-19
pandemic on breastfeeding support for healthymothers and the association between compliancewith WHO recommendations for breastfeeding
support and exclusive breastfeeding in Japan.

PeerJ. 2022 May 19;10:e13347.
2: Okawa S, Hosokawa Y, Nanishi K, Zaitsu M,
Tabuchi T. Threatened abortion, threatenedpremature labor, and preterm birth during thefirst state of emergency for COVID-19 in 2020 inJapan. J Obstet Gynaecol Res. 2022 May;48(5):1116-1125.

625

MD Scientist Training Program
Professor and Director
Kenzo Hirose, M.D., Ph.D.

Assistant Professor
Yuki Sugaya, M.D., Ph.D.
Takeshi Sawada, M.D., Ph.D.

Project Assistant Professor
Yoshitaka Kurikawa, M.D., Ph.D.

Homepage

http://www.ut-mdres.umin.jp/ (in Japanese)

Introduction and Organization
The MD Scientist Training Program (MDSTP) was
founded in 2008 to achieve the goal of systematicallyproviding an intensive basic medical research training
framework to the next generation of MD scientists
during their MD training at the School of Medicine,
The University of Tokyo. Capitalizing on the advances
made by launching a reliable and sustainable program
through the leadership of its first directors, Prof.
Shigeo Okabe (2008-2010), Prof. Masahide Kikkawa(2011-2014), and Prof. Haruhiko Bito (2015-2020),
the Program currently consists of its director Prof.
Kenzo Hirose and 3 staff members, Yuki Sugaya(assistant professor), Takeshi Sawada (assistantprofessor) and Yoshitaka Kurikawa (project assistantprofessor), and over 100 students who are seeking
extracurricular basic medical research training throughthe Program’s framework. With the help of two
assistants for clerical work, it provides a variety of
support programs to assist the research activities of
medical students. From 2011 on, the MDSTP at the
University of Tokyo has cooperated with its sister
programs at Kyoto University, Osaka University andNagoya University.
The number of the enrolled students during the launchyear (2008) of the MDSTP was 6. Since then, theProgram has expanded and now enrolls about 100

students (during Year 3 to 6 of the Medical School). A
sizable number of students write research honors
theses during their final year, which they defend to
become certificated as MDSTP graduates. The numberof research publications in scientific journal or awards
at international scientific meetings, which resulted
from these theses, is growing.

Achieving basic medical researchtraining in parallel with medical
education
The Program offers a platform of activities aimed atproviding an early exposure to basic medical researchand to basic skills required for achieving leadership inacademic medicine.
During the first 2 years after the entrance to the
University of Tokyo, we initially organize a lecture
series entitled ‘Introduction to Medical Biology’. In
this lecture series, top researchers of various fields at
the University of Tokyo provide exciting but
intelligible talks to students with little medical
knowledge. This helps students to get introduced
various research subjects in various fields of medical
research and strongly motivate them to find bythemselves a laboratory suitable to their aspirations.
Furthermore, we offer an opportunity to read the
textbook ‘Molecular Biology of the Cell’ in English,

626

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.

COVID-19 pandemic in the destination countries, 7
students were unable to travel abroad. Instead, theystudied cutting-edge medical care in domestic
hospitals.

From Year 3 on, as the students choose the labs andprincipal investigators with whom to do science with,
the Program organizes journal clubs for basic medical
research and courses of medical researchcommunications are held every 2 weeks. In the journalclub, students are trained to critically read recent
scientific papers published in top journals, often in thepresence of the first authors, if they are available. In
medical research communications courses, thestudents discuss scientific topics and research issues
with a native English speaker with a strong researchbackground.

2) Organizing an MD scientist training program
retreat
A MDSTP retreat was held on February 11 and 12,2023 at the Yamanaka-Naito Seminar House in
Yamanashi prefecture to present ongoing research
progress in a closed meeting among peers. More than
50 participants, mostly medical school students, butalso some medical interns, graduate students andProgram-affiliated professors attended it. Lively
discussions among peers were exciting throughout themeeting and the feedback from all participants wasoutstanding and unequivocal in emphasizing thecritical importance for a research progress retreat topromote 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.

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. In 2022, a total of 17 students
received the Program’s support for carrying out basic
medical research abroad and to present their researchachievements at international scientific meetings. We
also support exposure to clinical training in foreign
hospitals with the Osamu Otsubo Tetsumon
Fellowship. In 2022, 8 students gained invaluable
experience as student clinical clerks in various
university hospitals abroad. However, due to the3) Cooperating with other medical universities acrossJapan
With the availability of governmental support from2011 to 2020, the MDSTP at the University of Tokyo
has been in close touch with sister organizations at
Kyoto University, Osaka University and Nagoya
University. With a view to enhancing collaborative
efforts in improving the basic medical researchtraining at the 4 medical schools, joint retreats were
held to promote communication and networking
among the medical students with research minds. The
previous retreat was held in Nagoya in 2019, at theoccasion of the Japan Medical Congress. More than90 people including medical school students andteachers from all over Japan participated in this retreat
and enthusiastically discussed about their research andfuture career as researchers. From 2021, a newpartnership of the four universities, the MD Scientist
Training Initiative, has been launched with the aim ofworking more closely together than ever before,
including lab tours and research exchanges. In 2022,
we held three lab tours visiting laboratories at 4
universities, with over 50 students participating and627

considering study exchanges at domestic universities.
The MSDTP also currently cooperates with 11 otheruniversities in eastern Japan to organize annual
research students’ retreats. In 2022, the annual
summer retreat was held under the auspices of Chiba
University. More than 90 people participated in theretreat and presented their ongoing research progress
and plans.

Activities (2022)
The number of registered students: 160 (3rd and 4th
grade: 72, 5th and 6th: 88)
Lectures for students in Years 1 and 2
Introduction to Medical Biology: 13 lectures
Group reading of Molecular Biology of the Cell: 13
lectures
Seminar for students (in Year 3 or above)
Journal Club for basic medical research: 6 lectures
Medical Research Communications: 54 lectures
Presentation of research progress: 2 (the retreat of MD
scientist training program in the University of Tokyoand the annual research students’ retreats with
universities in eastern Japan)
The number of students receiving travel supports forresearch: 17 (including support for international anddomestic online conference)
The number of students receiving Osamu Otsubo
Tetsumon Fellowship: 15
The number of Year 6 students who passed theirhonors thesis defense: 8 (the Dean’s Prize and theSatoshi Arima memorial fellowship were awarded to 2
and 2 student, respectively)628

Museum of Health and Medicine
Director
Kazuhiko Ohe

Associate
Atsushi Kitade※The following information is the same as that of the previous year for certain reasons.

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”

629

and the special exhibition “Mental Diseases”.
In April 2019, we reopened our museum in theSouth Clinical Research Building of The University ofTokyo Hospital.
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.

630

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://ohrs-u-tokyo.jp
Top page of online application system: https://u-tokyo.bvits.com/esct/
Introduction and Organization
The Office for Human Research Studies (OHRS) wasestablished in October 2009 for the advancement ofresearch ethics standards. OHRS aims to protect therights, health, and dignity of research participants.
Based on this principle, OHRS is providing research
ethics support services to researchers at Graduate
School of Medicine and Faculty of Medicine, theUniversity of Tokyo and the University of Tokyo
Hospital to enable them to better perform their studies
in an ethical manner. Our primary task is the management of the Ethics Committee secretariat. Additionally,
OHRS plans and manages research ethics seminars,
provides ethics education to researchers throughconsultation and develops human resources for future
research ethics specialists.

Activities
・Management of Ethics Committee
・Prior review of research activity documents (except
for clinical trial, GCP), at Graduate School of
Medicine and Faculty of Medicine, the University ofTokyo and the University of Tokyo Hospital.
Correspond in response to various research ethics
inquiries.

・Coordination of various matters with Ethics
Committee members, and other similar bodies anduniversities.
・New clinical documentary examinations inconnection with,-Medical treatments to implemented for the firsttime at the University of Tokyo Hospital,-Examination of the clinical use of the unapproved
medicines and medical devices,・ Preparation and maintenance of the organ transplantation manuals for the liver, kidney and hearttransplants.
◇ Specific items reviewed and examined by each
Ethics Committee in fiscal year 2022
・Research Ethics Committee (except for clinical
trial, GCP):
248 new applications, 1095 minor alterations ofapproved studies
・Clinical Research Review Board:147
・New clinical documentary examinations: 102

631

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 2022 with 3699 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.

632

The Office for Clinical Practice andMedical Education
Professor
Masato Eto, M.D., Ph.D.

Research Associate
Yuki Matsushita, M.D., Ph.D.

Homepagehttps://igaku-kyoiku.m.u-tokyo.ac.jp/training/

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.

633

Research activities“Research of the coherence between the students’ daily
life and psychological conditions, and the outcome at
the graduation” is being conducted. The results werereleased in the domestic and international conferencesof medical education in 2018 and 2019, and published
for an international paper in 2021. Presently thisresearch is being conducted in multiple institutional
investigation. Moreover, “Research of the effect of
online medical interview trainings” is being conducted.

634

Advisory Office for Conflict ofInterest
Professor
Keishi Fujio (Chair, Advisory Board for Conflict of Interest)

Professor
Kazuhiko Fukatsu (Vice Chair, Advisory Board for Conflict of Interest)
Dr. Saeko Aketani (Director, Advisory Office for Conflict of Interest)

History and Organization Overview
The Advisory Office for Conflict of Interest of the
Graduate School of Medicine and University Hospital
was newly established in April 2016 as anadministrative department of the Advisory Board for
Conflict of Interest of the School of Medicine.
At the University of Tokyo, an Advisory Board for
Conflict of Interest has been established in eachdepartment under the university-wide Conflict ofInterest Management Committee, and appropriate
conflict of interest management is required for
employees. The School of Medicine has establishedrules to prevent conflicts of interest in the Faculty of
Medicine and has established an Advisory Board for
Conflict of Interest to manage conflicts of interest in
clinical research conducted at the School of Medicine
and the University Hospital.
In research conducted at the School of Medicine, itis necessary to promote industry-academia
collaboration activities in order to return the results tosociety and contribute to the health of the people. On
the other hand, in clinical research involving humansubjects, it is essential to protect the rights of theresearch subjects, and the results of the research may
affect the health of the public, and the fairness of theresearch is particularly required. In this way, conflictsof interest are inevitable in research activities at the
School of Medicine, and appropriate management anddisclosure of conflicts of interest are required.
In Japan, the Ministry of Health, Labour andWelfare (Clinical Trials Act) and the Japan Medical

Association have published guidelines for managing
conflicts of interest in clinical research, and thecriteria for judgment are gradually being clarified, and
the Advisory Office for Conflict of Interest of the
School of Medicine manages conflicts of interest
based on these guidelines.

Business• The Advisory Board for Conflict of Interest at the
School of Medicine manages conflicts of interest
pertaining to clinical research.
Targets
・Clinical research undergoing review by the
School of Medicine's Ethics Committee, encompassing studies in epidemiology, observation,intervention, and human genome and genetic
analysis・Clinical trials undergoing review by the
University Hospital IRB
・Clinical research to which the Act on Securing
the Safety of Regenerative Medicine, etc. applies
submitted by the University Hospital・Clinical research conducted by the University
Hospital as a single center or chief facility(however, the review will be conducted by the
University of Tokyo Accredited ClinicalResearch Review Board)• Administrative confirmation related to selfdeclaration of conflicts of interest for issues towhich the Clinical Trials Act applies• Preparation of examination materials for the635

management of conflicts of interest of the Japan
Agency for Medical Research and Development(AMED) and the Health, Labour and Welfare
Scientific Research Fund
• Task of submitting conflict of interest selfdeclaration forms for faculty and staff members• Management of Conflicts of Interest of School of
Medicine and University Hospital Committee
Members
In FY2022, the Conflict of Interest Advisory Board
consisted of six members, including external one, andconducted 11 committee meetings.

Education & Training
At the research ethics seminars hosted by the
Graduate School of Medicine and the School of
Medicine, the Advisory Office for Conflict of Interest
manages the segment on conflict of interest in clinicalresearch and conducts the training sessions.

OthersIn July 2018, the research ethics review application
system was revamped, and the operation for electronic
submission of conflict of interest self-declaration
forms, which were previously submitted in paper
format by each researcher, was initiated on the system.
By the end of March 2019, the transition measuresnecessary to comply with the Clinical Research Act
were completed for research projects to which theClinical Research Act applies (part of the research
projects with invasion or intervention). Furthermore,during 2018, a procedural manual for conflict ofinterest reviews was created for research projects towhich the Clinical Research Act applies. Additionally,for projects to which the ethical guidelines for medical
research involving human subjects apply, theprocedural manual was revised within the same year
to address the digitization of conflict of interest selfdeclaration forms and similar advancements. In
response to the revision of the ethical guidelines
during the 2021 fiscal year, we are formulatingprocedures for managing conflicts of interest when
ethical reviews are conducted collectively by external
entities.
From April 2022 to March 2023, the Conflict ofInterest Advisory Office, acting as the secretariat for
the Conflict of Interest Advisory Committee, handled
about 2200 new and amended applications for clinicalresearch projects (observation, intervention, IRB,
regenerative medicine safety laws, clinical researchlaws) in total.